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Objectives: The authors aimed to develop a moral intervention and to determine whether it was more effective in preventing doping than an educational (i.e., knowledge-based) intervention; their primary outcome was doping likelihood, and the secondary outcomes were moral identity, moral disengagement, moral atmosphere, and anticipated guilt.Methods: Eligible athletes (N = 303) in the United Kingdom and Greece took part in the study. The authors randomly assigned 33 clubs to either the moral or the educational intervention. They measured outcomes pre- and postintervention and at 3- and 6-month follow-up.Results: Athletes in both interventions in both countries reported lower doping likelihood and moral disengagement and higher guilt from pre- to postintervention. These effects were maintained at the 3- and 6-month follow-ups. There were no effects on moral identity or moral atmosphere.Conclusions: In addition to disseminating information about doping, doping prevention programs should include content that focuses on moral variables. [ABSTRACT FROM AUTHOR]

Background: Emergency general surgical patients are inherently at high risk of malnutrition. Early decision‐making with implementation is fundamental to patient recovery. For many patients, parenteral nutrition (PN) is the only feeding option available. The present study assessed the timing and outcomes of this decision‐making process. Methods: A sample of at least 10 consecutive adult patients admitted as a general surgical emergency to eight UK hospitals over 1 year who had received PN was identified. Patient demographics, basic descriptors and nutritional data were captured. Process measures regarding dates decisions were made or activities completed were extracted from records, as were outcome measures including PN complications. Six time frames examining the process of PN delivery were analysed. Associations between categorical and binary variables were investigated with a chi‐squared test with significance determined as p < 0.05. Results: In total, 125 patients were included. Intestinal obstruction was the most common diagnosis with 59% of all patients deemed high risk on nutritional assessment at admission. Median time to decision for PN was 5 days following admission (n = 122, interquartile range = 7). Patients received PN for a mean of 11 days. Eighty‐five percent of patients developed a complication, with a phosphate abnormality being the most commonly reported (54%). Only altered blood glucose levels appeared to correlate with a delay in starting PN (p < 0.01). Conclusions: The present study shows there are delays in the decision to use PN in the acutely ill surgical patient. Once initiated, the pathway is relatively short. There are high rates of electrolyte abnormalities in this population. [ABSTRACT FROM AUTHOR]

Background: Good quality parenting in early childhood is reliably associated with positive mental and physical health over the lifespan. The hypothesis that early parenting quality has significant long‐term financial benefits has not been previously tested. Methods: Design: Longitudinal study with follow‐up from 2012 to 2016. Setting: UK multicentre study cohort (London, South‐East England). Participants: 174 young people drawn from 2 samples, one at moderate risk of poor outcomes and one at high risk, assessed aged 4–6 years then followed up in early adolescence (mean age 12.1 years). Measures: The primary outcome was total costs: health, social care, extra school support, out‐of‐home placements and family‐born expenditure, determined through semistructured economic interviews. Early parenting quality was independently assessed through direct observation of parent–child interaction. Results: Costs were lower for youths exposed to more sensitive parenting (most sensitive quartile mean £1,619, least sensitive quartile mean £21,763; p <.001). Costs were spread across personal family expenditure and education, health, social and justice services. The cost difference remained significant after controlling for several potential confounders. These included demographic variables (family poverty, parental education); exposure to child abuse; and child/young person variables including level of antisocial behaviour in both childhood and adolescence, IQ and attachment security. Conclusions: This study is the first showing that more sensitive early parental care predicts lower costs to society many years later, independent of poverty, child and youth antisocial behaviour levels and IQ. Savings are likely to increase as individuals grow older since early parenting quality predicts health, behavioural and occupational outcomes in adulthood. The findings provide novel evidence for the public health impact of early caregiving quality and likely financial benefits of improving it. [ABSTRACT FROM AUTHOR]

Summary: We estimated and characterized the imminent fracture risk (1–2 years) of high-risk fracture patients through a multinational (UK, Spain, Denmark) cohort study. Older individuals with newly diagnosed osteoporosis and individuals who had a fracture while on treatment with a bisphosphonate were at a high risk of imminent fracture. Purpose: To characterize and estimate 1- to 2-year fracture risk in high-risk fracture patients. Methods: Multi-cohort study in (database/study period) UK (CPRD/1995–2017), Spain (SIDIAP/2006–2016) and Denmark (DHR/1995–2016) including individuals ≥ 50 years old in NDO (newly diagnosed osteoporosis), OFx (incident osteoporotic fracture), BP (incident oral bisphosphonates use) or FWOT (fracture while on treatment with bisphosphonates). Outcomes (ICD-10/READ): hip, clinical spine, non-hip, non-spine and hip/humerus/distal forearm fracture. Follow-up: from cohort entry until death, migration/transfer or end of the study. Statistics: baseline characteristics and incidence rate (IR per 1000 persons). Results (1-year IR): NDO included 69,899 (UK), 37,901 (Spain) and 158,191 (Denmark) individuals. Spanish-IR was lowest for hip (4.7), clinical spine (2.5) and major osteoporotic fracture (MOF) (17.3) and highest in Denmark (74.2, 26.0 and 120.1, respectively). OFx included 83,514 (UK), 51,044 (Spain) and 509,551 (Denmark) individuals. IR in Denmark was highest for hip (24.1) and MOF (47.2), in Spain was highest for the clinical spine (9.4) and lowest for hip (9.5) and in the UK was lowest for the clinical spine (2.8) and MOF (20.7). BP included 148,507 (UK), 52,037 (Spain) and 204,010 (Denmark) individuals. Spanish-IR was lowest for hip (5.0) and MOF (21.1) and highest in Denmark (20.3 and 48.6, respectively). FWOT included 28,930 (UK), 1,865 (Spain) and 31,882 (Denmark) individuals. Clinical spine-IR was highest for Spain (12.0). Hip-IR was lowest for Spain (7.6) and highest for Denmark (33.6). Comparing young subjects, those who have FWOT started with an increased fracture rate. Conclusion: OFx and FWOT individuals experience higher re-fracture incidence rates than those with osteoporosis with or without treatment. [ABSTRACT FROM AUTHOR]

Objectives: Polypharmacy in people living with HIV (PLWH) increases the risks of medicine‐related problems (events or circumstances involving drug therapy that actually or potentially interfere with desired health outcomes). We aimed to examine the feasibility and acceptability of a Medicines Management Optimisation Review (MOR) toolkit in HIV outpatients. Methods: This was a multi‐centre randomized controlled study across four HIV centres. In all, 200 PLWH on combination antiretroviral therapy, either > 50 years old or < 50 years with other comorbidities, were enrolled to have a MOR or received standard pharmaceutical care. The primary outcome was the difference in the number of medicine‐related problems (MRPs) between intervention and standard care groups at baseline and 6 months. Acceptability, cost of the intervention and health‐related quality of life were also examined. Results: In all, 164 patients were analysed: 70 in the intervention group and 94 in the standard care group. A significant number of MRPs were detected in those patients receiving MOR compared with the standard care group at baseline (93 vs. 2; p = 0.001, z = −8.6, r = 0.6) and 6 months (33 vs. 3; p = 0.001, z = −5.7, r = 0.4). A significant reduction in the number of new MRPs at 6 months in the intervention group versus baseline was also observed (p = 0.001, Z = −3.7, r = 0.2); 44% of MRPs were fully resolved at baseline and 51% at 6 months. No changes in health‐related quality of life following MOR or between MOR and standard care groups were observed. The MORs were highly acceptable among patients and healthcare professionals. Conclusions: The MOR toolkit was feasible and acceptable, suggesting that HIV outpatient services might consider implementing MOR for targeted populations under their care. [ABSTRACT FROM AUTHOR]

Background hospital level healthcare in the home guided by comprehensive geriatric assessment (CGA) might provide a less costly alternative to hospitalisation for older people. Objective to determine the cost-effectiveness of CGA admission avoidance hospital at home (HAH) compared with hospital admission. Design/intervention a cost-effectiveness study alongside a randomised trial of CGA in an admission avoidance HAH setting, compared with admission to hospital. Participants/setting older people considered for a hospital admission in nine locations across the UK were randomised using a 2:1 randomisation schedule to admission avoidance HAH with CGA (N  = 700), or admission to hospital with CGA when available (N  = 355). Measurements quality adjusted life years, resource use and costs at baseline and 6 months; incremental cost-effectiveness ratios were calculated. The main analysis used complete cases. Results adjusting for baseline covariates, HAH was less costly than admission to hospital from a health and social care perspective (mean −£2,265, 95% CI: −4,279 to −252), and remained less costly with the addition of informal care costs (mean difference −£2,840, 95% CI: −5,495 to −185). There was no difference in quality adjusted survival. Using multiple imputation for missing data, the mean difference in health and social care costs widened to −£2,458 (95% CI: −4,977 to 61) and societal costs remained significantly lower (−£3,083, 95% CI: −5,880 to −287). There was little change to quality adjusted survival. Conclusions CGA HAH is a cost-effective alternative to admission to hospital for selected older people. [ABSTRACT FROM AUTHOR]

In response to the COVID-19 pandemic, guidelines on reduced fractionation for patients treated with curative-intent radiotherapy were published, aimed at reducing the number of hospital attendances and potential exposure of vulnerable patients to minimise the risk of COVID-19 infection. We describe the changes that took place in the management of patients with stage I–III lung cancer from April to October 2020. Lung Radiotherapy during the COVID-19 Pandemic (COVID-RT Lung) is a prospective multicentre UK cohort study. The inclusion criteria were: patients with stage I–III lung cancer referred for and/or treated with radical radiotherapy between 2nd April and 2nd October 2020. Patients who had had a change in their management and those who continued with standard management were included. Data on demographics, COVID-19 diagnosis, diagnostic work-up, radiotherapy and systemic treatment were collected and reported as counts and percentages. Patient characteristics associated with a change in treatment were analysed using multivariable binary logistic regression. In total, 1553 patients were included (median age 72 years, 49% female); 93 (12%) had a change to their diagnostic investigation and 528 (34%) had a change to their treatment from their centre's standard of care as a result of the COVID-19 pandemic. Age ≥70 years, male gender and stage III disease were associated with a change in treatment on multivariable analysis. Patients who had their treatment changed had a median of 15 fractions of radiotherapy compared with a median of 20 fractions in those who did not have their treatment changed. Low rates of COVID-19 infection were seen during or after radiotherapy, with only 21 patients (1.4%) developing the disease. The COVID-19 pandemic resulted in changes to patient treatment in line with national recommendations. The main change was an increase in hypofractionation. Further work is ongoing to analyse the impact of these changes on patient outcomes. • The first wave of the COVID-19 pandemic led to changes in the management of patients with stage I–III lung cancer. • Diagnostic investigations were altered in 12% of patients referred for radical radiotherapy. • A third of patients had a change to standard of care treatment. • Men, patients aged ≥70 years or those with stage III lung cancer were more likely to have their treatment changed. • 2.1% of patients had a diagnosis of COVID-19 before, during or after radiotherapy. [ABSTRACT FROM AUTHOR]

Background: Dental attendances to paediatric emergency departments (PEDs) represent suboptimal use of resources of an unknown scale. Aim: To evaluate dental attendances at two PEDs in the UK and compare traumatic dental injury (TDI) and non‐traumatic dental conditions (NTDCs). Design: Retrospective data were collected for a 12‐month period including demographics, attendance pattern, assessment, and management. Maxillofacial conditions were excluded, and attendances were grouped as TDI and NTDC. Results: Of 667 attendances, 35.1% (n = 234) were TDI and 64.9% (n = 433) NTDC. Nineteen children reattended. Proportionately, more TDI attenders were male, White British, of lower mean age, and resided in less deprived areas than NTDCs. Over half (52.3%, n = 339) of attendees resided in the 10% most deprived UK areas. Saturday and Monday were modal attendance days; attendance peaked in summer. Over half (56.4%, n = 376) attended out of hours. A majority (74.8%, n = 499) self‐referred and half accessed no other service prior to PED attendance. No PED dental input was received for 38.7% (n = 258), and dental treatment was received for 12.4% (n = 83). Antibiotics were provided for 42.1% (n = 281), and 15.4% (n = 103) were admitted. Conclusion: Dental abscesses and toothache accounted for half of attendances, many of these children may be managed in primary care. Improved signposting to alternative dental services for non‐urgent conditions may better allocate resources to those with urgent need. [ABSTRACT FROM AUTHOR]

Objective: Recent studies suggest mental health in youths is deteriorating. The current policy in the United Kingdom emphasizes the role of schools for mental health promotion and prevention, but little data exist on what aspects of schools influence mental health in pupils. This study explored school-level influences on the mental health of young people in a large school-based sample from the United Kingdom.Method: Baseline data from a large cluster randomized controlled trial collected between 2016 and 2018 from mainstream secondary schools selected to be representative in relation to their quality rating, size, deprivation, mixed or single-sex pupil population, and country were analyzed. Participants were pupils in their first or second year of secondary school. The study assessed whether school-level factors were associated with pupil mental health.Results: The study included 26,885 pupils (response rate = 90%; age range, 11‒14 years; 55% female) attending 85 schools in the United Kingdom. Schools accounted for 2.4% (95% CI: 2.0%‒2.8%; p < .0001) of the variation in psychopathology, 1.6% (95% CI: 1.2%‒2.1%; p < .0001) of depression, and 1.4% (95% CI: 1.0%‒1.7%; p < .0001) of well-being. Schools in urban locations, with a higher percentage of free school meals and of White British, were associated with poorer pupil mental health. A more positive school climate was associated with better mental health.Conclusion: School-level variables, primarily related to contextual factors, characteristics of pupil population, and school climate, explain a small but significant amount of variability in mental health of young people. This information might be used to identify schools that are in need of more resources to support mental health of young people.Clinical Trial Registration Information: MYRIAD: My Resilience in Adolescence, a Study Examining the Effectiveness and Cost-Effectiveness of a Mindfulness Training Programme in Schools Compared With Normal School Provision; https://www.isrctn.com/; 86619085. [ABSTRACT FROM AUTHOR]

Background: Depression is highly heterogeneous in its clinical presentation. Those with attention deficit/hyperactivity disorder (ADHD) may be at risk of a more chronic and impairing depression compared to those with depression alone according to studies of young people. However, no studies to date have examined ADHD in recurrently depressed adults in mid-life.Method: In a sample of women in mid-life (n=148) taken from a UK based prospective cohort of adults with a history of recurrent depression, we investigated the prevalence of ADHD and the association of ADHD with clinical features of depression.Results: 12.8% of the recurrently depressed women had elevated ADHD symptoms and 3.4% met DSM-5 diagnostic criteria for ADHD. None of the women reported having a diagnosis of ADHD from a medical professional. ADHD symptoms were associated with earlier age of depression onset, higher depression associated impairment, a greater recurrence of depressive episodes and increased persistence of subthreshold depression symptoms over the study period, higher levels of irritability and increased risk of self-harm or suicide attempt. ADHD symptoms were associated with increased risk of hospitalisation and receiving non-first-line antidepressant medication.Limitations: ADHD was measured using a questionnaire measure. We focussed on mothers in a longitudinal study of recurrent depression, so the findings may not apply to males or other groups.Conclusions: Higher ADHD symptoms appear to index a worse clinical presentation for depression. Clinical implications include that in women with early onset, impairing and recurrent depression, the possibility of underlying ADHD masked by depression needs to be considered. [ABSTRACT FROM AUTHOR]

Background: The "physiological breech birth" one‐day training program is based on evidence about the physiology of breech births and how clinicians learn breech skills. Previous evaluations have demonstrated positive effects on confidence and knowledge, but the training's effect on clinical practice and outcomes is unknown. Methods: A mixed‐methods evaluation was conducted in eight National Health Service hospitals in England and Northern Ireland. Changes in confidence and knowledge were assessed using pretraining and post‐training surveys. Mode of birth and maternal birth positions were evaluated using audit data covering one year before the training and one year after, for all singleton vaginal breech births at term. Findings: A total of 263 participants completed the surveys. Confidence in managing breech births in both upright and supine positions significantly increased, as did participant knowledge. Audited data for 1402 women were collected. Overall vaginal birth rates remained similar in both periods. Among singleton vaginal breech births >37 weeks, the use of upright birthing positions increased significantly (P =.002). The study was not powered to detect differences in other outcomes, but pilot data were collected to inform the design of future studies. Conclusions: Increase in use of upright birthing positions suggests that physiological breech birth training is likely to lead to clinical practice changes, which may help support maternal choice in line with current guidance. However, provision of a one‐day training program did not change overall vaginal breech birth rates. Adequately powered research is needed to determine effects of clinical practice changes on clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: Childhood obesity has become a serious global healthcare challenge. No UK data currently define its anaesthetic and perioperative implications. We aimed to determine obesity prevalence amongst UK children undergoing general anaesthesia and the incidence of predefined adverse perioperative events, and to compare perioperative obesity rates with National Child Measurement Programme (NCMP) data.Methods: During a site-selected consecutive 7-day study period, all children (2-16 yr) undergoing general anaesthesia were included. Anonymised hospital, surgical, and procedural details; demographic data; and adverse perioperative events were collected prospectively by Paediatric Anaesthesia Trainee Research Network (PATRN) collaborators.Results: For this study, 102 UK hospitals participated and 4232 cases were included in the final analysis; 76% of hospitals did not routinely calculate BMI. In addition, 3030 (71.6%; 95% confidence interval [CI]: 70.2-73.0%) children of healthy weight were compared with 537 (12.7%; 11.7-13.7%) children who were overweight and 478 (11.3%; 10.3-12.2%) children with obesity. Children with obesity (n=71; 14.9%) more commonly underwent (adeno)tonsillectomy than children of healthy weight (n=282; 9.3%; P<0.001; odds ratio [OR] 2.15; 95% CI: 1.58-2.92). Fewer children with obesity (n=365; 77% vs n=2552; 85%) were anaesthetised by consultant anaesthetists (OR 0.62; 95% CI: 0.48-0.79). Mask ventilation was difficult for 3.7% of children with obesity vs 0.6% of children of healthy weight (difference 3.0%; 95% CI: 1.3-4.7%; P<0.001). Comparison with NCMP data demonstrated an over-representation of obesity amongst the paediatric surgical population.Conclusions: This large multicentre cohort study suggests a concerning prevalence of children with obesity presenting for anaesthesia. These results should be used to inform optimal provision of care for this population and support perioperative healthcare initiatives to address the burden of childhood obesity.Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT03994419. [ABSTRACT FROM AUTHOR]

Background: We sought to define the prevalence and nature of patient-reported drug allergies, determine their impact on prescribing, and explore drug allergy knowledge and attitudes amongst anaesthetists.Methods: We performed a prospective cross-sectional study in 213 UK hospitals in 2018. Elective surgical patients were interviewed, with a detailed allergy history taken in those self-reporting drug allergy. Anaesthetists completed a questionnaire concerning perioperative drug allergy.Results: Of 21 219 patients included, 6214 (29.3 %) (95% confidence interval [CI]: 28.7-29.9) reported drug allergy. Antibiotics, NSAIDs, and opioids were the most frequently implicated agents. Of a total of 8755 reactions, 2462 (28.1%) (95% CI: 29.2-31.1) were categorised as high risk for representing genuine allergy after risk stratification. A history suggestive of chronic spontaneous urticaria significantly increased the risk of reporting drug allergy (odds ratio 2.68; 95% CI: 2.4-3; P<0.01). Of 4756 anaesthetists completing the questionnaire, 1473 (31%) (95% CI: 29.7-32.3) routinely discuss perioperative allergy risk with patients. Prescribing habits in the presence of drug allergy labels differ depending on the implicated agent. Most anaesthetists (4678/4697; 99.6%) (95% CI: 99.4-99.8) prescribe opioids when reactions are consistent with side-effects, although 2269/4697 (48%) (95% CI: 46.9-49.7) would avoid the specific opioid reported.Conclusions: Almost 30% of UK elective surgical patients report a history of drug allergies, but the majority of reported reactions are likely to be non-allergic reactions. Allergy labels can impact on perioperative prescribing through avoidance of important drugs and use of less effective alternatives. We highlight important knowledge gaps about drug allergy amongst anaesthetists, and the need for improved education around allergy. [ABSTRACT FROM AUTHOR]

Introduction: Radiotherapy is a mainstay of cancer therapy for a wide variety of anatomical areas. An unfortunate side effect of treatment can be radiation damage to the skin which can be a painful and debilitating problem. Previous experience from the experimental use of Flamigel® in two large-scale clinical studies on affected skin has proven sufficiently positive for the addition of a new product in the Flamigel® family (now commercially available in the UK as Flamigel RT®, Flen Health UK). The aim of this investigation is to evaluate the use of this new product to study how effective it is in the prevention and/or treatment of radiation-induced skin damage. Materials and methods: A survey was conducted among radiotherapy specialist teams in dedicated UK radiotherapy centres between 1 January 2017 and 31 October 2017. This report is of a preliminary evaluation conducted by UK-based specialists on 108 patients undergoing radiotherapy. The scoring system for skin reactions of the 'Radiation Therapy Oncology Group' was used. Results: Results show that the use of Flamigel® has the potential to soothe (p = 0·0001), reduce pain (p = 0·0001) and reduce pruritus (p = 0·004). The product met the expectations of the clinicians involved (p < 0·0001) of whom most were happy to continue use or to recommend its use to colleagues (p < 0·0001). Conclusions: Flamigel® is an effective treatment in the management of radiation-induced skin reactions. Erythema was unchanged through the study period (p = 0·42). No adverse reactions were reported after the use of Flamigel from twice to six times a day. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate the association between oral anticoagulant type (direct oral anticoagulants (DOACs) vs vitamin K antagonists (VKAs)) and incident dementia or mild cognitive impairment (MCI) among patients with newly diagnosed atrial fibrillation (AF).Methods: Using linked electronic health record (EHR) data from the Clinical Practice Research Datalink in the UK, we conducted a historical cohort study among first-time oral anticoagulant users with incident non-valvular AF diagnosed from 2012 to 2018. We compared the incidence of (1) clinically coded dementia and (2) MCI between patients prescribed VKAs and DOACs using Cox proportional hazards regression models, with age as the underlying timescale, accounting for calendar time and time on treatment, sociodemographic and lifestyle factors, clinical comorbidities and medications.Results: Of 39 200 first-time oral anticoagulant users (44.6% female, median age 76 years, IQR 68-83), 20 687 (53%) were prescribed a VKA and 18 513 (47%) a DOAC at baseline. Overall, 1258 patients (3.2%) had GP-recorded incident dementia, incidence rate 16.5 per 1000 person-years. DOAC treatment for AF was associated with a 16% reduction in dementia diagnosis compared with VKA treatment in the whole cohort (adjusted HR 0.84, 95% CI: 0.73 to 0.98) and with a 26% reduction in incident MCI (adjusted HR 0.74, 95% CI: 0.65 to 0.84). Findings were similar across various sensitivity analyses.Conclusions: Incident EHR-recorded dementia and MCI were less common among patients prescribed DOACs for new AF compared with those prescribed VKAs. [ABSTRACT FROM AUTHOR]

Background: Increasing demand on emergency healthcare systems has prompted introduction of new healthcare service models including the provision of GP services in or alongside emergency departments. In England this led to a policy proposal and £100million (US$130million) of funding for all emergency departments to have co-located GP services. However, there is a lack of evidence for whether such service models are effective and safe. We examined diagnostic errors reported in patient safety incident reports to develop theories to explain how and why they occurred to inform potential priority areas for improvement and inform qualitative data collection at case study sites to further refine the theories.Methods: We used a mixed-methods design using exploratory descriptive analysis to identify the most frequent and harmful sources of diagnostic error and thematic analysis, incorporating realist methodology to refine theories from an earlier rapid realist review, to describe how and why the events occurred and could be mitigated, to inform improvement recommendations. We used two UK data sources: Coroners' reports to prevent future deaths (30.7.13-14.08.18) and National Reporting and Learning System (NRLS) patient safety incident reports (03.01.05-30.11.15).Results: Nine Coroners' reports (from 1347 community and hospital reports, 2013-2018) and 217 NRLS reports (from 13 million, 2005-2015) were identified describing diagnostic error related to GP services in or alongside emergency departments. Initial theories to describe potential priority areas for improvement included: difficulty identifying appropriate patients for the GP service; under-investigation and misinterpretation of diagnostic tests; and inadequate communication and referral pathways between the emergency and GP services. High-risk presentations included: musculoskeletal injury, chest pain, headache, calf pain and sick children.Conclusion: Initial theories include the following topics as potential priority areas for improvement interventions and evaluation to minimise the risk of diagnostic errors when GPs work in or alongside emergency departments: a standardised initial assessment with streaming guidance based on local service provision; clinical decision support for high-risk conditions; and standardised computer systems, communication and referral pathways between emergency and GP services. These theories require refinement and testing with qualitative data collection from case study (hospital) sites. [ABSTRACT FROM AUTHOR]

This paper analyzes a UK-based psychoeducational intervention for users of online child sexual exploitation material (CSEM). It is founded on 17 months of anthropological research in group programs with 81 participants and 15 staff. The article argues that group exercises help participants reframe knowledge about their offending, and ultimately reinforce the theoretical concept of discipline (Foucault) toward internal and external surveillance, normalization, and decreased risk. The paper first discusses factors participants believed contributed to offending. It then analyzes the program and participants' experiences, focusing on exercises about the mind (fantasy), Internet usage (disclosure and relationships), needs met by offending (Good Lives and true needs), and planning for the future (relapse prevention). Critical is that participants are encouraged to reengage offline lives and enact discipline on and to the online world. Thus, the article ends with an anthropologically-minded discussion about digital norms, online morality, and implications for Internet offender psychoeducational practice. [ABSTRACT FROM AUTHOR]

Introduction: Chemsex in a European context is the use of any of the following drugs to facilitate sex: crystal methamphetamine, mephedrone and gamma‐hydroxybutyrate (GHB)/gamma‐butyrolactone (GBL) and, to a lesser extent, cocaine and ketamine. This study describes the prevalence of self‐reported recreational drug use and chemsex in HIV‐positive men who have sex with men (MSM) accessing HIV services in four countries. It also examines the problematic impacts and harms of chemsex and access to chemsex‐related services. Methods: This is a cross‐sectional multi‐centre questionnaire study of HIV‐positive MSM accessing nine HIV services in the UK, Spain, Greece and Italy. Results: In all, 1589 HIV‐positive MSM attending HIV services in four countries completed the questionnaire. The median age of participants was 38 years (interquartile range: 32–46 years) and 1525 (96.0%) were taking antiretroviral therapy (ART). In the previous 12 months, 709 (44.6%) had used recreational drugs, 382 (24.0%) reported chemsex and 104 (6.5%) reported injection of chemsex‐associated drugs ('slamsex'). Of the 382 engaging in chemsex, 155 (40.6%) reported unwanted side effects as a result of chemsex and 81 (21.2%) as a result of withdrawal from chemsex. The reported negative impacts from chemsex were on work (25.1%, 96), friends/family (24.3%, 93) and relationships (28.3%, 108). Fifty‐seven (14.9%) accessed chemsex‐related services in the past year, 38 of whom (67%) felt the service met their needs. Discussion: A quarter of participants self‐reported chemsex in the past 12 months. There were high rates of harms from chemsex across all countries, including negative impacts on work, friends/family and relationships. Although a minority of those engaging in chemsex accessed support, most found this useful. [ABSTRACT FROM AUTHOR]

Introduction: Electronic nicotine delivery systems (ENDS) may improve public health if they facilitate smokers switching away from cigarettes. Conceptually, switching is facilitated when ENDS provide adequate nicotine delivery. Switching rates among smokers who purchased the JUUL System ("JUUL") were compared in the United Kingdom (UK), where regulations limit nicotine concentration to 20 mg/mL versus North America (N.Am.; United States and Canada), where higher concentrations are available.Aims and Methods: Adult established smokers (age ≥21, smoked ≥100 cigarettes, smoking some days or every day at baseline) who newly purchased JUUL were recruited into a longitudinal study (UK: N = 1247; N.Am.: N = 8835). Complete switching (no smoking for ≥30 days) was assessed 1, 3, and 6 months after purchase; propensity score matching (PSM) and logistic regression compared switching after adjusting for baseline characteristics.Results: In both N.Am. and UK, ≥82% of participants reported using the highest JUUL nicotine concentration available (UK: 18 mg/mL; N.Am.: 59 mg/mL). Unadjusted switching rates did not differ at 1 month (17%-18%); unadjusted and adjusted rates were significantly higher in N.Am. (vs. UK) at 3 and 6 months. In the PSM sample, after additional covariate adjustment, rates were significantly higher in N.Am. (vs. UK) at 3 months (31.5% vs. 22.7%; odds ratio [95% confidence interval, CI] = 1.59 [1.25, 2.02]) and 6 months (38.0% vs. 26.0%; odds ratio [95% CI] = 1.79 [1.37, 2.35]).Conclusions: These results suggest availability of ENDS in nicotine concentrations greater than 20 mg/mL may be associated with increased switching among adult smokers. Differences in smoking and ENDS use characteristics did not explain associations of location and switching; however, between-country differences may be affected by unmeasured factors.Implications: Switching rates were lower among smokers who purchased the JUUL System ("JUUL") in the UK, where regulations limit nicotine concentration to 20 mg/mL versus N.Am. (United States and Canada), where higher concentrations are available-before and after controlling for differences in smoking and ENDS use characteristics. These results suggest availability of ENDS in nicotine concentrations greater than 20 mg/mL may be associated with increased switching among adult smokers. Between-country differences may be affected by unmeasured factors; future research should consider these factors and the extent to which regulatory policy environments may explain differences in switching among adult smokers. [ABSTRACT FROM AUTHOR]

Introduction: The advertising of e-cigarettes in the UK is regulated through the revised EU Tobacco Products Directive and the Tobacco and Related Products Regulations, with further rules set out in the Advertising Standards Authority (ASA) Committees of Advertising (CAP) Code. Focusing on the ASA CAP Code Rules, we examined e-cigarette advertising regulation compliance in traditional advertising channels and on social media.Methods: We conducted a content analysis of UK e-cigarette and related product advertising using a randomly selected sample (n = 130) of advertising in traditional channels and on Instagram which appeared between January and December 2019. All ads were independently double-coded to assess compliance with each CAP Code Rule.Results: In traditional channels, our sample of advertising had largely good compliance. Only very small numbers of these ads appeared to be clearly in breach of any of the ASA rules (5% were in breach of Rule 22.7; 2% of Rule 22.9; and 1% of Rule 22.10). In contrast, we judged that all of the Instagram sample (n = 30) was in breach of Rule 22.12. For some rules, it was not possible to make definitive judgments about compliance, given uncertainty regarding how a rule should be interpreted and applied.Conclusions: We found overall good compliance for advertising in traditional channels, but assessed all of our social media advertising samples was in breach of regulations. Current guidance on e-cigarette advertising could be improved to facilitate e-cigarette advertising assessment and regulation. It would be beneficial to bring consumer perspectives into the assessment of regulation compliance.Implications: The regulation of e-cigarette advertising is a global concern. The UK Government has a statutory obligation to review the Tobacco and Related Products Regulations by May 2021. This study assessed compliance with current UK e-cigarette advertising regulations on placement and content. We identified areas where greater clarity is needed and outlined implications for future regulation. [ABSTRACT FROM AUTHOR]

UK policy for adults with intellectual disabilities no longer supports state-provided building-based day care but promotes personalised care and support under individuals' control with choice of community-based opportunities. The research explored experiences of this new terrain and the informal learning involved. An initial scoping review was followed by interviews with key service providers in one urban and one rural area in England and one of each in Scotland. Next, ethnographic fieldwork with people with intellectual disabilities involved a flexible mix of observations, interviews, focus groups, and participant-generated visual data. Thematic analysis involved an iterative mix of deductive and inductive coding. Findings showed informal peer learning ranged from ad hoc to structurally supported. Though learning was often tacit, support was valued and agency developed. The availability of local supportive people and schemes and time spent in them to develop new skills and identities was vital to people self-building community lives. This research looked at the experiences of people with intellectual disabilities, as they and their friends and family respond to policy change bringing in more personalisation and individual choice. Often people with intellectual disabilities and those supporting them do not recognise their everyday learning. Learning outside schools/colleges gets little research attention. We looked at the learning involved in people managing their own daily lives in their communities. Staff and volunteers are helping people to learn from each other in organisations, and this can become more formal peer learning, peer mentoring and peer support programmes. Advocacy groups create a sense of belonging and shared purpose, encouraging peer learning through the sharing of knowledge, experiences and problem solving. When new projects start up or traditional day services change, the staff or volunteers may not involve people with intellectual disabilities in the planning. This means people with intellectual disabilities miss opportunities to learn. [ABSTRACT FROM AUTHOR]

We report a disease and mortality event involving swans, seals, and a fox at a wildlife rehabilitation center in the United Kingdom during late 2020. Five swans had onset of highly pathogenic avian influenza virus infection while in captivity. Subsequently, 5 seals and a fox died (or were euthanized) after onset of clinical disease. Avian-origin influenza A virus subtype H5N8 was retrospectively determined as the cause of disease. Infection in the seals manifested as seizures, and immunohistochemical and molecular testing on postmortem samples detected a neurologic distribution of viral products. The fox died overnight after sudden onset of inappetence, and postmortem tissues revealed neurologic and respiratory distribution of viral products. Live virus was isolated from the swans, seals, and the fox, and a single genetic change was detected as a potential adaptive mutation in the mammalian-derived viral sequences. No human influenza-like illness was reported in the weeks after the event. [ABSTRACT FROM AUTHOR]

Background: Faecal calprotectin (FC) testing to detect inflammatory bowel disease (IBD) was recommended for use in UK general practice in 2013. The actual use of FC testing following the national recommendations is unknown.Aim: To characterise the use of FC testing for IBD in UK general practice.Design and Setting: A retrospective cohort study of routine electronic patient records from The Health Improvement Network database from UK general practice.Method: The study included 6 965 853 adult patients (aged ≥18 years), between 2006 and 2016. FC test uptake, the patients tested, and patient management following testing were characterised.Results: A total of 17 027 patients had 19 840 FC tests recorded. The mean age of tested patients was 44.2 years. The first FC tests were documented in 2009. FC test use was still increasing in 2016. By 2016, 66.8% (n = 493/738) of practices had started FC testing. About one-fifth (20.7%, n = 1253/6051) of tests were carried out in patients aged ≥60 years. Only 7.8% (n = 473/6051) of the FC test records were preceded by symptoms eligible for FC testing. Only 3.1% (n = 1720/55 477) of patients with eligible symptoms have received FC testing since the national recommendations were published. There was only a small number of patients with symptoms, FC test, and a IBD diagnosis. In total, 71.3% (n = 1416/1987) of patients with a positive and 47.7% (n = 1337/2805) with a negative FC test were referred or further investigated.Conclusion: Uptake of FC testing in clinical practice has been slow and inconsistent. The indication of non-compliance with national recommendations may suggest that these recommendations lack applicability to the general practice context. [ABSTRACT FROM AUTHOR]

Background: Pancreatic cancer has the worst survival rate among all cancers. Almost 70% of patients in the UK were diagnosed at Stage IV.Aim: This study aimed to investigate the symptoms associated with the diagnoses of pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine neoplasms (PNEN), and comparatively characterise the symptomatology between the two tumour types to inform earlier diagnosis.Design and Setting: A nested case-control study in primary care was conducted using data from the QResearch® database. Patients aged ≥25 years and diagnosed with PDAC or PNEN during 2000 to 2019 were included as cases. Up to 10 controls from the same general practice were matched with each case by age, sex, and calendar year using incidence density sampling.Method: Conditional logistic regression was used to investigate the association between the 42 shortlisted symptoms and the diagnoses of PDAC and (or) PNEN in different timeframes relative to the index date, adjusting for patients' sociodemographic characteristics, lifestyle, and relevant comorbidities.Results: A total of 23 640 patients were identified as diagnosed with PDAC and 596 with PNEN. Of the symptoms identified, 23 were significantly associated with PDAC, and nine symptoms with PNEN. The two alarm symptoms for both tumours were jaundice and gastrointestinal bleeding. The two newly identified symptoms for PDAC were thirst and dark urine. The risk of unintentional weight loss may be longer than 2 years before the diagnosis of PNEN.Conclusion: PDAC and PNEN have overlapping symptom profiles. The QCancer® (pancreas) risk prediction model could be updated by including the newly identified symptoms and comorbidities, which could help GPs identify high-risk patients for timely investigation in primary care. [ABSTRACT FROM AUTHOR]

Background: Over 90% of the 50,000 deaf children in the UK have hearing parents, many of whom were not expecting a deaf child and may require specialist support. Deaf children can experience poorer long-term outcomes than hearing children across a range of domains. After early detection by the Universal Newborn Hearing Screening Programme, parents in the UK receive support from Qualified Teachers of the Deaf and audiologists but resources are tight and intervention support can vary by locality. There are challenges faced due to a lack of clarity around what specific parenting support interventions are most helpful.Methods: The aim of this research was to complete a systematic scoping review of the evidence to identify early support interventions for parents of deaf infants. From 5577 identified records, 54 met inclusion criteria. Two reviewers screened papers through three rounds before completing data extraction and quality assessment.Results: Identified parent support interventions included both group and individual sessions in various settings (including online). They were led by a range of professionals and targeted various outcomes. Internationally there were only five randomised controlled trials. Other designs included non-randomised comparison groups, pre / post and other designs e.g. longitudinal, qualitative and case studies. Quality assessment showed few high quality studies with most having some concerns over risk of bias.Conclusion: Interventions commonly focused on infant language and communication followed by parental knowledge and skills; parent wellbeing and empowerment; and parent/child relationship. There were no interventions that focused specifically on parent support to understand or nurture child socio-emotional development despite this being a well-established area of poor outcome for deaf children. There were few UK studies and research generally was not of high quality. Many studies were not recent and so not in the context of recent healthcare advances. Further research in this area is urgently needed to help develop evidence based early interventions. [ABSTRACT FROM AUTHOR]

Background: Agitation is common in people with dementia and negatively affects the quality of life of both people with dementia and carers. Non-drug patient-centred care is the first-line treatment, but there is a need for other treatment when this care is not effective. Current evidence is sparse on safer and effective alternatives to antipsychotics. We assessed the efficacy and safety of mirtazapine, an antidepressant prescribed for agitation in dementia.Methods: This parallel-group, double-blind, placebo-controlled trial-the Study of Mirtazapine for Agitated Behaviours in Dementia trial (SYMBAD)-was done in 26 UK centres. Participants had probable or possible Alzheimer's disease, agitation unresponsive to non-drug treatment, and a Cohen-Mansfield Agitation Inventory (CMAI) score of 45 or more. They were randomly assigned (1:1) to receive either mirtazapine (titrated to 45 mg) or placebo. The primary outcome was reduction in CMAI score at 12 weeks. This trial is registered with ClinicalTrials.gov, NCT03031184, and ISRCTN17411897.Findings: Between Jan 26, 2017, and March 6, 2020, 204 participants were recruited and randomised. Mean CMAI scores at 12 weeks were not significantly different between participants receiving mirtazapine and participants receiving placebo (adjusted mean difference -1·74, 95% CI -7·17 to 3·69; p=0·53). The number of controls with adverse events (65 [64%] of 102 controls) was similar to that in the mirtazapine group (67 [66%] of 102 participants receiving mirtazapine). However, there were more deaths in the mirtazapine group (n=7) by week 16 than in the control group (n=1), with post-hoc analysis suggesting this difference was of marginal statistical significance (p=0·065).Interpretation: This trial found no benefit of mirtazapine compared with placebo, and we observed a potentially higher mortality with use of mirtazapine. The data from this study do not support using mirtazapine as a treatment for agitation in dementia.Funding: UK National Institute for Health Research Health Technology Assessment Programme. [ABSTRACT FROM AUTHOR]

Background: Up to 20% of UK children experience socio-emotional difficulties which can have serious implications for themselves, their families and society. Stark socioeconomic and ethnic inequalities in children's well-being exist. Supporting parents to develop effective parenting skills is an important preventive strategy in reducing inequalities. Parenting interventions have been developed, which aim to reduce the severity and impact of these difficulties. However, most parenting interventions in the UK focus on early childhood (0-10 years) and often fail to engage families from ethnic minority groups and those living in poverty. Strengthening Families, Strengthening Communities (SFSC) is a parenting programme designed by the Race Equality Foundation, which aims to address this gap. Evidence from preliminary studies is encouraging, but no randomised controlled trials have been undertaken so far.Methods/design: The TOGETHER study is a multi-centre, waiting list controlled, randomised trial, which aims to test the effectiveness of SFSC in families with children aged 3-18 across seven urban areas in England with ethnically and socially diverse populations. The primary outcome is parental mental well-being (assessed by the Warwick-Edinburgh Mental Well-Being Scale). Secondary outcomes include child socio-emotional well-being, parenting practices, family relationships, self-efficacy, quality of life, and community engagement. Outcomes are assessed at baseline, post intervention, three- and six-months post intervention. Cost effectiveness will be estimated using a cost-utility analysis and cost-consequences analysis. The study is conducted in two stages. Stage 1 comprised a 6-month internal pilot to determine the feasibility of the trial. A set of progression criteria were developed to determine whether the stage 2 main trial should proceed. An embedded process evaluation will assess the fidelity and acceptability of the intervention.Discussion: In this paper we provide details of the study protocol for this trial. We also describe challenges to implementing the protocol and how these were addressed. Once completed, if beneficial effects on both parental and child outcomes are found, the impact, both immediate and longer term, are potentially significant. As the intervention focuses on supporting families living in poverty and those from minority ethnic communities, the intervention should also ultimately have a beneficial impact on reducing health inequalities.Trial Registration: Prospectively registered Randomised Controlled Trial ISRCTN15194500 . [ABSTRACT FROM AUTHOR]

Background: Mortality remains unacceptably high in patients with heart failure and reduced left ventricular ejection fraction (LVEF) despite advances in therapeutics. We hypothesised that a novel artificial intelligence approach could better assess multiple and higher-dimension interactions of comorbidities, and define clusters of β-blocker efficacy in patients with sinus rhythm and atrial fibrillation.Methods: Neural network-based variational autoencoders and hierarchical clustering were applied to pooled individual patient data from nine double-blind, randomised, placebo-controlled trials of β blockers. All-cause mortality during median 1·3 years of follow-up was assessed by intention to treat, stratified by electrocardiographic heart rhythm. The number of clusters and dimensions was determined objectively, with results validated using a leave-one-trial-out approach. This study was prospectively registered with ClinicalTrials.gov (NCT00832442) and the PROSPERO database of systematic reviews (CRD42014010012).Findings: 15 659 patients with heart failure and LVEF of less than 50% were included, with median age 65 years (IQR 56-72) and LVEF 27% (IQR 21-33). 3708 (24%) patients were women. In sinus rhythm (n=12 822), most clusters demonstrated a consistent overall mortality benefit from β blockers, with odds ratios (ORs) ranging from 0·54 to 0·74. One cluster in sinus rhythm of older patients with less severe symptoms showed no significant efficacy (OR 0·86, 95% CI 0·67-1·10; p=0·22). In atrial fibrillation (n=2837), four of five clusters were consistent with the overall neutral effect of β blockers versus placebo (OR 0·92, 0·77-1·10; p=0·37). One cluster of younger atrial fibrillation patients at lower mortality risk but similar LVEF to average had a statistically significant reduction in mortality with β blockers (OR 0·57, 0·35-0·93; p=0·023). The robustness and consistency of clustering was confirmed for all models (p<0·0001 vs random), and cluster membership was externally validated across the nine independent trials.Interpretation: An artificial intelligence-based clustering approach was able to distinguish prognostic response from β blockers in patients with heart failure and reduced LVEF. This included patients in sinus rhythm with suboptimal efficacy, as well as a cluster of patients with atrial fibrillation where β blockers did reduce mortality.Funding: Medical Research Council, UK, and EU/EFPIA Innovative Medicines Initiative BigData@Heart. [ABSTRACT FROM AUTHOR]

Introduction: The use of arthroscopy to alleviate the symptoms of osteoarthritis has been questioned by recent high quality evidence. This has led to the development of guidelines by specialist and national bodies advocating against its use. Aims: To examine the trends of the rates of arthroscopy in patients with knee osteoarthritis over the past five years and determining compliance with guidelines. Methods: Multi-centre, retrospective audit in five hospital trusts in the United Kingdom. The number of arthroscopies performed by month from 2013 to 2017 was identified through hospital coding. Fifty randomly selected records from the year 2017 were further analysed to assess compliance with NICE guidelines. Results: Between 2013 and 2017, the number of arthroscopies performed annually in five trusts dropped from 2028 to 1099. In the year 2017, 17.7% of patients with no mechanical symptoms and moderate-to-severe arthritis pre-operatively had arthroscopy. Conclusion: Knee arthroscopy continues to be used as a treatment for osteoarthritis, against national guidelines. Whilst overall numbers are declining, further interventions, including implementation of high-quality conservative care is required to further eliminate unnecessary procedures. [ABSTRACT FROM AUTHOR]

Introduction: Haemolysis is considered one of the major contributors of nonconformities and sample rejection in coagulation testing. Materials and methods: Two lyophilized plasmas were distributed to 800 centres registered for prothrombin time (PT), activated partial thromboplastin time (APTT) and either Clauss fibrinogen or thrombin time (TT) in the UK NEQAS BC programme. The same pool of normal plasma was used to prepare both samples, to one of which red blood cell haemolysate was added to mimic haemolysis at 3 g/L haemoglobin concentration. Participants were asked to complete a questionnaire about their laboratory approach to dealing with haemolysed samples, including strategies used to deal with different levels of haemolysis. Results: Results for tests performed did not show great differences between the two samples. It should be noted that artificially constructed haemolysed samples may not behave in the same way as patient samples (ie, may not be commutable). However, the possibility of carrying out a large multicentre study for detection of haemolysis was demonstrated. Inconsistency in practice was observed with 226/551 (41%) of centres indicated they reject haemolysed samples solely on visual checks, and 163 (30%) using initial visual checks with further sample rejection evaluation by analyser flags. Furthermore, 333 (72%) of centres indicated that the level of haemolysis affects sample rejection decisions, while 132 (28%) stated it did not. Conclusion: Variability of responses for dealing with haemolysed samples reflects a lack of clear consistency in the pre‐analytical area of sample processing. [ABSTRACT FROM AUTHOR]

Background: With genome-wide association data for many exposures and outcomes now available from large biobanks, one-sample Mendelian randomization (MR) is increasingly used to investigate causal relationships. Many robust MR methods are available to address pleiotropy, but these assume independence between the gene-exposure and gene-outcome association estimates. Unlike in two-sample MR, in one-sample MR the two estimates are obtained from the same individuals, and the assumption of independence does not hold in the presence of confounding.Methods: With simulations mimicking a typical study in UK Biobank, we assessed the performance, in terms of bias and precision of the MR estimate, of the fixed-effect and (multiplicative) random-effects meta-analysis method, weighted median estimator, weighted mode estimator and MR-Egger regression, used in both one-sample and two-sample data. We considered scenarios differing by the: presence/absence of a true causal effect; amount of confounding; and presence and type of pleiotropy (none, balanced or directional).Results: Even in the presence of substantial correlation due to confounding, all two-sample methods used in one-sample MR performed similarly to when used in two-sample MR, except for MR-Egger which resulted in bias reflecting direction and magnitude of the confounding. Such bias was much reduced in the presence of very high variability in instrument strength across variants (IGX2 of 97%).Conclusions: Two-sample MR methods can be safely used for one-sample MR performed within large biobanks, expect for MR-Egger. MR-Egger is not recommended for one-sample MR unless the correlation between the gene-exposure and gene-outcome estimates due to confounding can be kept low, or the variability in instrument strength is very high. [ABSTRACT FROM AUTHOR]

Background: The causal nature of the observed associations between serum lipids and apolipoproteins and kidney function are unclear.Methods: Using two-sample and multivariable Mendelian randomization (MR), we examined the causal effects of serum lipids and apolipoproteins on kidney function, indicated by the glomerular-filtration rate estimated using creatinine (eGFRcrea) or cystatin C (eGFRcys) and the urinary albumin-to-creatinine ratio (UACR). We obtained lipid- and apolipoprotein-associated genetic variants from the Global Lipids Genetics Consortium (n = 331 368) and UK Biobank (n = 441 016), respectively, and kidney-function markers from the Trøndelag Health Study (HUNT; n = 69 736) and UK Biobank (n = 464 207). The reverse causal direction was examined using variants associated with kidney-function markers selected from recent genome-wide association studies.Results: There were no strong associations between genetically predicted lipid and apolipoprotein levels with kidney-function markers. Some, but inconsistent, evidence suggested a weak association of higher genetically predicted atherogenic lipid levels [indicated by low-density lipoprotein cholesterol (LDL-C), triglycerides and apolipoprotein B] with increased eGFR and UACR. For high-density lipoprotein cholesterol (HDL-C), results differed between eGFRcrea and eGFRcys, but neither analysis suggested substantial effects. We found no clear evidence of a reverse causal effect of eGFR on lipid or apolipoprotein traits, but higher UACR was associated with higher LDL-C, triglyceride and apolipoprotein B levels.Conclusion: Our MR estimates suggest that serum lipid and apolipoprotein levels do not cause substantial changes in kidney function. A possible weak effect of higher atherogenic lipids on increased eGFR and UACR warrants further investigation. Processes leading to higher UACR may lead to more atherogenic lipid levels. [ABSTRACT FROM AUTHOR]

Background: Two-sample Mendelian randomization (MR) allows the use of freely accessible summary association results from genome-wide association studies (GWAS) to estimate causal effects of modifiable exposures on outcomes. Some GWAS adjust for heritable covariables in an attempt to estimate direct effects of genetic variants on the trait of interest. One, both or neither of the exposure GWAS and outcome GWAS may have been adjusted for covariables.Methods: We performed a simulation study comprising different scenarios that could motivate covariable adjustment in a GWAS and analysed real data to assess the influence of using covariable-adjusted summary association results in two-sample MR.Results: In the absence of residual confounding between exposure and covariable, between exposure and outcome, and between covariable and outcome, using covariable-adjusted summary associations for two-sample MR eliminated bias due to horizontal pleiotropy. However, covariable adjustment led to bias in the presence of residual confounding (especially between the covariable and the outcome), even in the absence of horizontal pleiotropy (when the genetic variants would be valid instruments without covariable adjustment). In an analysis using real data from the Genetic Investigation of ANthropometric Traits (GIANT) consortium and UK Biobank, the causal effect estimate of waist circumference on blood pressure changed direction upon adjustment of waist circumference for body mass index.Conclusions: Our findings indicate that using covariable-adjusted summary associations in MR should generally be avoided. When that is not possible, careful consideration of the causal relationships underlying the data (including potentially unmeasured confounders) is required to direct sensitivity analyses and interpret results with appropriate caution. [ABSTRACT FROM AUTHOR]

Objective To investigate the occurrence of venous thromboembolic events (VTE) in a large cohort of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) across the European Union, Turkey, Russia, UK and North America. Methods Patients with a definite diagnosis of AAV who were followed for at least 3 months and had sufficient documentation were included. Data on VTE, including either deep vein thrombosis or pulmonary embolism, were collected retrospectively from tertiary vasculitis centres. Univariate and multivariate regression models were used to estimate odds ratios (ORs) and 95% CIs. Results Over a median follow-up of 63 (interquartile range: 29, 101) months, VTE occurred in 278 (9.7%) of 2869 AAV patients with a similar frequency across different countries (from 6.3% to 13.7%), and AAV subtype [granulomatosis with polyangiitis: 9.8% (95% CI: 8.3, 11.6%); microscopic polyangiitis: 9.6% (95% CI: 7.9, 11.4%); and eosinophilic granulomatosis with polyangiitis: 9.8% (95% CI: 7.0, 13.3%)]. Most VTE (65.6%) were reported in the first-year post-diagnosis. Multiple factor logistic regression analysis adjusted for sex and age showed that skin (OR 1.71, 95% CI: 1.01, 2.92), pulmonary (OR 1.78, 95% CI: 1.04, 3.14) and kidney [eGFR 15–60 ml/min/1.73 m2, OR 2.86 (95% CI: 1.27, 6.47); eGFR <15 ml/min/1.73 m2, OR 6.71 (95% CI: 2.94, 15.33)] involvement were independent variables associated with a higher occurrence of VTE. Conclusion Two-thirds of VTE occurred during the initial phase of active disease. We confirmed previous findings from smaller studies that a decrease in kidney function, skin involvement and pulmonary disease are independently associated with VTE. [ABSTRACT FROM AUTHOR]

Introduction: We examined the mediating role of friends smoking in the association between depressive symptoms and daily/weekly cigarette smoking from adolescence into adulthood.Methods: Data were drawn from the Nicotine Dependence In Teens study (NDIT, Canada) and the Avon Longitudinal Study of Parents and Children (ALSPAC, UK) studies. Three age groups were investigated in NDIT: age 13-14 (n = 1189), 15-16 (n = 1107), and 17-18 (n = 1075), and one in ALSPAC (n = 4482, age 18-21). Multivariable mediation models decomposed the total effect (TE) of depressive symptoms on smoking into a natural direct effect (NDE) and natural indirect effect (NIE) through friends smoking.Results: The odds ratios (ORs) for the TE were relatively constant over time with estimates ranging from 1.12 to 1.35. Friends smoking mediated the association between depressive symptoms and smoking in the two youngest samples (OR [95% confidence interval [CI] 1.09 [1.01,1.17] in 13- to 14-year-olds; 1.10 [1.03,1.18] in 15- to 16-year-olds). In the two older samples, NDE of depressive symptoms was close to the TE, suggestive that mediation was absent or too small to detect.Conclusion: Friends smoking mediates the association between depressive symptoms and daily/weekly cigarette smoking in young adolescents.Implications: If young adolescents use cigarettes to self-medicate depressive symptoms, then interventions targeting smoking that ignore depressive symptoms may be ineffective. Our results also underscore the importance of the influence of friends in younger adolescents, suggestive that preventive intervention should target the social environment, including social relationships. [ABSTRACT FROM AUTHOR]

Aim: Optimal airway management during out-of-hospital cardiac arrest (OHCA) is uncertain. Complications from tracheal intubation (TI) may be avoided with supraglottic airway (SGA) devices. The AIRWAYS-2 cluster randomised controlled trial (ISRCTN08256118) compared the i-gel SGA with TI as the initial advanced airway management (AAM) strategy by paramedics treating adults with non-traumatic OHCA. This paper reports the trial cost-effectiveness analysis.Methods: A within-trial cost-effectiveness analysis of the i-gel compared with TI was conducted, with a six-month time horizon, from the perspective of the UK National Health Service (NHS) and personal social services. The primary outcome measure was quality-adjusted life years (QALYs), estimated using the EQ-5D-5L questionnaire. Multilevel linear regression modelling was used to account for clustering by paramedic when combining costs and outcomes.Results: 9296 eligible patients were attended by 1382 trial paramedics and enrolled in the AIRWAYS-2 trial (4410 TI, 4886 i-gel). Mean QALYs to six months were 0.03 in both groups (i-gel minus TI difference -0.0015, 95% CI -0.0059 to 0.0028). Total costs per participant up to six months post-OHCA were £3570 and £3413 in the i-gel and TI groups respectively (mean difference £157, 95% CI -£270 to £583). Based on mean difference point estimates, TI was more effective and less costly than i-gel; however differences were small and there was great uncertainty around these results.Conclusion: The small differences between groups in QALYs and costs shows no difference in the cost-effectiveness of the i-gel and TI when used as the initial AAM strategy in adults with non-traumatic OHCA. [ABSTRACT FROM AUTHOR]

Incontinence-associated dermatitis (IAD) relates to skin breakdown from exposure to urine or faeces, and its management involves implementation of structured skin care regimens incorporating appropriate use of skin barrier products to protect the skin from exposure to moisture and irritants. Medi Derma-PRO Skin Protectant Ointment and Medi Derma-PRO Foam & Spray Incontinence Cleanser are part of the Total Barrier Protection™ (Medicareplus International) range indicated for management of moderate-to-severe IAD and other moisture-associated skin damage (MASD). This article summarises the findings of multi-centred patient evaluations of Medi Derma-PRO Skin Protectant Ointment and Medi Derma-PRO Foam & Spray Incontinence Cleanser, and aims to demonstrate the clinical and cost benefits of using these products for the prevention and management of MASD. [ABSTRACT FROM AUTHOR]

Background: Out-of-hours (OOH) hospital admissions for patients receiving end-of-life care are a common cause of concern for patients, families, clinicians, and policymakers. It is unclear what issues, or combinations of issues, lead OOH clinicians to initiate hospital care for these patients.Aim: To investigate the circumstances, processes, and mechanisms of UK OOH services-initiated end-of-life care hospital admissions.Design and Setting: Systematic literature review and narrative synthesis.Method: Eight electronic databases were searched from inception to December 2019 supplemented by hand-searching of the British Journal of General Practice. Key search terms included: 'out-of-hours services', 'hospital admissions', and 'end-of-life care'. Two reviewers independently screened and selected articles, and undertook quality appraisal using Gough's Weight of Evidence framework. Data was analysed using narrative synthesis and reported following PRISMA Complex Intervention guidance.Results: Searches identified 20 727 unique citations, 25 of which met the inclusion criteria. Few studies had a primary focus on the review questions. Admissions were instigated primarily to address clinical needs, caregiver and/or patient distress, and discontinuity or unavailability of care provision, and they were arranged by a range of OOH providers. Reported frequencies of patients receiving end-of-life care being admitted to hospital varied greatly; most evidence related to cancer patients.Conclusion: Although OOH end-of-life care can often be readily resolved by hospital admissions, it comes with multiple challenges that seem to be widespread and systemic. Further research is therefore necessary to understand the complexities of OOH services-initiated end-of-life care hospital admissions and how the challenges underpinning such admissions might best be addressed. [ABSTRACT FROM AUTHOR]

Background: We aimed to estimate multimorbidity trajectories and quantify socioeconomic inequalities based on childhood and adulthood socioeconomic position (SEP) in the risks and rates of multimorbidity accumulation across adulthood.Methods and Findings: Participants from the UK 1946 National Survey of Health and Development (NSHD) birth cohort study who attended the age 36 years assessment in 1982 and any one of the follow-up assessments at ages 43, 53, 63, and 69 years (N = 3,723, 51% males). Information on 18 health conditions was based on a combination of self-report, biomarkers, health records, and prescribed medications. We estimated multimorbidity trajectories and delineated socioeconomic inequalities (based on childhood and adulthood social class and highest education) in multimorbidity at each age and in longitudinal trajectories. Multimorbidity increased with age (0.7 conditions at 36 years to 3.7 at 69 years). Multimorbidity accumulation was nonlinear, accelerating with age at the rate of 0.08 conditions/year (95% CI 0.07 to 0.09, p < 0.001) at 36 to 43 years to 0.19 conditions/year (95% CI 0.18 to 0.20, p < 0.001) at 63 to 69 years. At all ages, the most socioeconomically disadvantaged had 1.2 to 1.4 times greater number of conditions on average compared to the most advantaged. The most disadvantaged by each socioeconomic indicator experienced an additional 0.39 conditions (childhood social class), 0.83 (adult social class), and 1.08 conditions (adult education) at age 69 years, independent of all other socioeconomic indicators. Adverse adulthood SEP was associated with more rapid accumulation of multimorbidity, resulting in 0.49 excess conditions in partly/unskilled compared to professional/intermediate individuals between 63 and 69 years. Disadvantaged childhood social class, independently of adulthood SEP, was associated with accelerated multimorbidity trajectories from age 53 years onwards. Study limitations include that the NSHD cohort is composed of individuals of white European heritage only, and findings may not be generalizable to the non-white British population of the same generation and did not account for other important dimensions of SEP such as income and wealth.Conclusions: In this study, we found that socioeconomically disadvantaged individuals have earlier onset and more rapid accumulation of multimorbidity resulting in widening inequalities into old age, with independent contributions from both childhood and adulthood SEP. [ABSTRACT FROM AUTHOR]

Background: Overconsumption of energy from food is a major contributor to the high rates of overweight and obesity in many populations. There is growing evidence that interventions that target the food environment may be effective at reducing energy intake. The current study aimed to estimate the effect of decreasing the proportion of higher energy (kcal) foods, with and without reducing portion size, on energy purchased in worksite cafeterias.Methods and Findings: This stepped-wedge randomised controlled trial (RCT) evaluated 2 interventions: (i) availability: replacing higher energy products with lower energy products; and (ii) size: reducing the portion size of higher energy products. A total of 19 cafeterias were randomised to the order in which they introduced the 2 interventions. Availability was implemented first and maintained. Size was added to the availability intervention. Intervention categories included main meals, sides, cold drinks, snacks, and desserts. The study setting was worksite cafeterias located in distribution centres for a major United Kingdom supermarket and lasted for 25 weeks (May to November 2019). These cafeterias were used by 20,327 employees, mainly (96%) in manual occupations. The primary outcome was total energy (kcal) purchased from intervention categories per day. The secondary outcomes were energy (kcal) purchased from nonintervention categories per day, total energy purchased per day, and revenue. Regression models showed an overall reduction in energy purchased from intervention categories of -4.8% (95% CI -7.0% to -2.7%), p < 0.001 during the availability intervention period and a reduction of -11.5% (95% CI -13.7% to -9.3%), p < 0.001 during the availability plus size intervention period, relative to the baseline. There was a reduction in energy purchased of -6.6% (95% CI -7.9% to -5.4%), p < 0.001 during the availability plus size period, relative to availability alone. Study limitations include using energy purchased as the primary outcome (and not energy consumed) and the availability only of transaction-level sales data per site (and not individual-level data).Conclusions: Decreasing the proportion of higher energy foods in cafeterias reduced the energy purchased. Decreasing portion sizes reduced this further. These interventions, particularly in combination, may be effective as part of broader strategies to reduce overconsumption of energy from food in out-of-home settings.Trial Registration: ISRCTN registry ISRCTN87225572. [ABSTRACT FROM AUTHOR]

Background: Hypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomere-encoding genes, but little is known about the clinical significance of these variants in the general population.Objectives: The goal of this study was to compare lifetime outcomes and cardiovascular phenotypes according to the presence of rare variants in sarcomere-encoding genes among middle-aged adults.Methods: This study analyzed whole exome sequencing and cardiac magnetic resonance imaging in UK Biobank participants stratified according to sarcomere-encoding variant status.Results: The prevalence of rare variants (allele frequency <0.00004) in HCM-associated sarcomere-encoding genes in 200,584 participants was 2.9% (n = 5,712; 1 in 35), and the prevalence of variants pathogenic or likely pathogenic for HCM (SARC-HCM-P/LP) was 0.25% (n = 493; 1 in 407). SARC-HCM-P/LP variants were associated with an increased risk of death or major adverse cardiac events compared with controls (hazard ratio: 1.69; 95% confidence interval [CI]: 1.38-2.07; P < 0.001), mainly due to heart failure endpoints (hazard ratio: 4.23; 95% CI: 3.07-5.83; P < 0.001). In 21,322 participants with both cardiac magnetic resonance imaging and whole exome sequencing, SARC-HCM-P/LP variants were associated with an asymmetric increase in left ventricular maximum wall thickness (10.9 ± 2.7 mm vs 9.4 ± 1.6 mm; P < 0.001), but hypertrophy (≥13 mm) was only present in 18.4% (n = 9 of 49; 95% CI: 9%-32%). SARC-HCM-P/LP variants were still associated with heart failure after adjustment for wall thickness (hazard ratio: 6.74; 95% CI: 2.43-18.7; P < 0.001).Conclusions: In this population of middle-aged adults, SARC-HCM-P/LP variants have low aggregate penetrance for overt HCM but are associated with an increased risk of adverse cardiovascular outcomes and an attenuated cardiomyopathic phenotype. Although absolute event rates are low, identification of these variants may enhance risk stratification beyond familial disease. [ABSTRACT FROM AUTHOR]

Background: Engagement of people with lived experience and members of the public is an ethically and scientifically essential component of health research. Authentic engagement means they are involved as full partners in research projects. Yet engagement as partnership is uncommon in practice, especially during priority-setting for research projects. What is needed for agenda-setting to be shared by researchers and people with lived experience and/or members of the public (or organisations representing them)? At present, little ethical guidance exists on this matter, particularly that which has been informed by the perspectives of people with lived experience and members of the public. This article provides initial evidence about what they think are essential foundations and barriers to shared decision-making in health research priority-setting and health research more broadly.Methods: An exploratory, qualitative study was conducted in 2019. 22 semi-structured interviews were performed with key informants from the UK and Australia.Results: Three main types of foundations were thought to be essential to have in place before shared decision-making can occur in health research priority-setting: relational, environmental, and personal. Collectively, the three types of foundations addressed many (but not all) of the barriers to power sharing identified by interviewees.Conclusions: Based on study findings, suggestions are made for what researchers, engagement practitioners, research institutions, and funders should do in their policy and practice to support meaningful engagement. Finally, key international research ethics guidelines on community engagement are considered in light of study findings. [ABSTRACT FROM AUTHOR]

Recent research suggests genetic variation in the Klotho locus may modify the association between APOE ɛ4 and cognitive impairment. We tested for associations and interactions between these genotypes versus risk of dementia, cognitive abilities, and brain structure in older UK Biobank participants. Klotho status was indexed with rs9536314 heterozygosity (versus not), in unrelated people with versus without APOE ɛ4 genotype, corrected for various confounders. APOE ɛ4 associated with increased risk of dementia, worse cognitive abilities, and brain structure. Klotho was associated with better reasoning. There were no interactions; potentially suggesting an age- and pathology-dependent Klotho effect. [ABSTRACT FROM AUTHOR]

Introduction: Standardized packaging was phased in between May 2016 and May 2017 in the United Kingdom and July 2017 and July 2018 in Norway. In both countries, the health warnings on packs prior to standardized packaging being implemented were from the former Tobacco Products Directive library of warnings (text warnings covering 43% of the pack front and pictorial warnings covering 53% of the pack reverse). The warnings on packs, postimplementation, were from the current Tobacco Products Directive library of warnings (novel pictorial warnings covering 65% of the pack front and reverse) for the United Kingdom but unchanged in Norway.Aims and Methods: Longitudinal online surveys were conducted prior to standardized packaging (United Kingdom: April-May 2016; Norway: May-June 2017) and postimplementation (United Kingdom: September-November 2017 and May-July 2019; Norway: August-September 2018). We explored smokers' response to the on-pack warnings (salience, cognitive reactions, and behavioral reactions).Results: In the United Kingdom, noticing warnings on packs, reading or looking closely at them, thinking about them, thinking about the health risks, avoidant behaviors, forgoing cigarettes, and being more likely to quit due to the warnings significantly increased from waves 1 to 2, and then decreased from waves 2 to 3, but remained higher than at wave 1. In Norway, noticing warnings, reading or looking closely at them, thinking about them, thinking about the health risks, and being more likely to quit due to the warnings significantly decreased from waves 1 to 2; avoidant behaviors and forgoing cigarettes remained unchanged.Conclusions: The inclusion of large novel pictorial warnings on standardized packs increases warning salience and effectiveness.Implications: Two longitudinal online surveys in the United Kingdom and Norway explored the impact of standardized packaging on warning salience and effectiveness. That warning salience and effectiveness only increased in the UK postimplementation, where standardized packaging was implemented alongside new larger pictorial warnings on the pack front and reverse, and not in Norway, where standardized packaging was introduced but older smaller text warnings (pack front) and pictorial warnings (pack reverse) were retained, highlights the importance of removing full branding and introducing stronger warnings simultaneously. [ABSTRACT FROM AUTHOR]

White matter hyperintensities (WMH) are among the most common radiological abnormalities in the ageing population and an established risk factor for stroke and dementia. While common variant association studies have revealed multiple genetic loci with an influence on their volume, the contribution of rare variants to the WMH burden in the general population remains largely unexplored. We conducted a comprehensive analysis of this burden in the UK Biobank using publicly available whole-exome sequencing data (n up to 17 830) and found a splice-site variant in GBE1, encoding 1,4-alpha-glucan branching enzyme 1, to be associated with lower white matter burden on an exome-wide level [c.691+2T>C, β = -0.74, standard error (SE) = 0.13, P = 9.7 × 10-9]. Applying whole-exome gene-based burden tests, we found damaging missense and loss-of-function variants in HTRA1 (frequency of 1 in 275 in the UK Biobank population) to associate with an increased WMH volume (P = 5.5 × 10-6, false discovery rate = 0.04). HTRA1 encodes a secreted serine protease implicated in familial forms of small vessel disease. Domain-specific burden tests revealed that the association with WMH volume was restricted to rare variants in the protease domain (amino acids 204-364; β = 0.79, SE = 0.14, P = 9.4 × 10-8). The frequency of such variants in the UK Biobank population was 1 in 450. The WMH volume was brought forward by ∼11 years in carriers of a rare protease domain variant. A comparison with the effect size of established risk factors for WMH burden revealed that the presence of a rare variant in the HTRA1 protease domain corresponded to a larger effect than meeting the criteria for hypertension (β = 0.26, SE = 0.02, P = 2.9 × 10-59) or being in the upper 99.8% percentile of the distribution of a polygenic risk score based on common genetic variants (β = 0.44, SE = 0.14, P = 0.002). In biochemical experiments, most (6/9) of the identified protease domain variants resulted in markedly reduced protease activity. We further found EGFL8, which showed suggestive evidence for association with WMH volume (P = 1.5 × 10-4, false discovery rate = 0.22) in gene burden tests, to be a direct substrate of HTRA1 and to be preferentially expressed in cerebral arterioles and arteries. In a phenome-wide association study mapping ICD-10 diagnoses to 741 standardized Phecodes, rare variants in the HTRA1 protease domain were associated with multiple neurological and non-neurological conditions including migraine with aura (odds ratio = 12.24, 95%CI: 2.54-35.25; P = 8.3 × 10-5]. Collectively, these findings highlight an important role of rare genetic variation and the HTRA1 protease in determining WMH burden in the general population. [ABSTRACT FROM AUTHOR]

Background: Monitoring is the mainstay of chronic kidney disease management in primary care; however, there is little evidence about the best way to do this.Aim: To compare the effectiveness of estimated glomerular filtration rate (eGFR) derived from serum creatinine and serum cystatin C to predict renal function decline among those with a recent eGFR of 30-89 ml/min/1.73 m2.Design and Setting: Observational cohort study in UK primary care.Method: Serum creatinine and serum cystatin C were both measured at seven study visits over 2 years in 750 patients aged ≥18 years with an eGFR of 30-89 ml/min/1.73 m2 within the previous year. The primary outcome was change in eGFR derived from serum creatinine or serum cystatin C between 6 and 24 months.Results: Average change in eGFR was 0.51 ml/min/1.73 m2/year when estimated by serum creatinine and -2.35 ml/min/1.73 m2/year when estimated by serum cystatin C. The c-statistic for predicting renal decline using serum creatininederived eGFR was 0.495 (95% confidence interval [CI] = 0.471 to 0.519). The equivalent c-statistic using serum cystatin C-derived eGFR was 0.497 (95% CI = 0.468 to 0.525). Similar results were obtained when restricting analyses to those aged ≥75 or <75 years, or with eGFR ≥60 ml/min/1.73 m2. In those with eGFR <60 ml/min/1.73 m2, serum cystatin C-derived eGFR was more predictive than serum creatinine-derived eGFR for future decline in kidney function.Conclusion: In the primary analysis neither eGFR estimated from serum creatinine nor from serum cystatin C predicted future change in kidney function, partly due to small changes during 2 years. In some secondary analyses there was a suggestion that serum cystatin C was a more useful biomarker to estimate eGFR, especially in those with a baseline eGFR <60 ml/min/1.73 m2. [ABSTRACT FROM AUTHOR]

Background: To support shared decision making and improve the management of polypharmacy, it is recommended that GPs take into account quantitative information on the benefits and harms of treatments (QIRx). Quantitative evidence shows GPs' knowledge of this is low.Aim: To explore GPs' attitudes to and understanding of QIRx for long-term conditions.Design and Setting: Qualitative interview study in UK general practice.Method: Semi-structured interviews were carried out with 15 GPs. Audiorecordings were transcribed verbatim and a framework approach was used for analysis.Results: Participants described knowing or using QIRx for only a few treatments. There was awareness of this knowledge deficit coupled with low confidence in statistical terminology. Some GPs perceived an absence of this information as an important barrier to optimal care, while others were content to follow guidelines. In the absence of this knowledge, other strategies were described to individualise treatment decisions. The idea of increasing the use of QIRx appealed to most participants, with imagined benefits for patients and themselves. However, potential barriers were described: a need for accessible information that can be understood and integrated into real-world practice, system factors, and communication challenges.Conclusion: GPs were aware of their knowledge deficit with regard to an understanding of QIRx. Most participants were positive about the idea of increasing their use of QIRx in practice but described important challenges, which need to be considered when designing solutions. [ABSTRACT FROM AUTHOR]

Background: Unstable ankle fractures represent a substantial burden of disease, accounting for a mean hospital stay of nine days, a mean cost of £4,491 per patient and 20,000 operations per year. There is variation in UK practice around weight-bearing instructions after operatively managed ankle fracture. Early weight-bearing may reduce reliance on health services, time off work, and improve functional outcomes. However, concerns remain about the potential for complications such as implant failure. This is the protocol of a multicentre randomised non-inferiority clinical trial of weight-bearing following operatively treated ankle fracture.Methods: Adults aged 18 years and over who have been managed operatively for ankle fracture will be assessed for eligibility. Baseline function (Olerud and Molander Ankle Score [OMAS]), health-related quality of life (EQ-5D-5L), and complications will be collected after informed consent has been obtained. A randomisation sequence has been prepared by a trial statistician to allow for 1:1 allocation to receive either instruction to weight-bear as pain allows from the point of randomisation, two weeks after the time of surgery ('early weight-bearing' group) or to not weight-bear for a further four weeks ('delayed weight -bearing' group). All other treatment will be as per the guidance of the treating clinician. Participants will be asked about their weight-bearing status weekly until four weeks post-randomisation. At four weeks post-randomisation complications will be collected. At six weeks, four months, and 12 months post-randomisation, the OMAS, EQ-5D-5L, complications, physiotherapy input, and resource use will be collected. The primary outcome measure is ankle function (OMAS) at four months post-randomisation. A minimum of 436 participants will be recruited to obtain 80% power to detect a non-inferiority margin of -6 points on the OMAS 4 months post-randomisation. A within-trial health economic evaluation will be conducted to estimate the cost-effectiveness of the treatment options.Discussion: The results of this study will inform national guidance with regards to the most clinically and cost-effective strategy for weight-bearing after surgery for unstable ankle fractures.Trial Registration: ISRCTN12883981 , Registered 02 December 2019. [ABSTRACT FROM AUTHOR]

Abstract: Identifying genetic risk factors for lumbar spine disorders may lead to knowledge regarding underlying mechanisms and the development of new treatments. We conducted a genome-wide association study involving 100,811 participants with genotypes and longitudinal electronic health record data from the Electronic Medical Records and Genomics Network and Geisinger Health. Cases and controls were defined using validated algorithms and clinical diagnostic codes. Electronic health record-defined phenotypes included low back pain requiring healthcare utilization (LBP-HC), lumbosacral radicular syndrome (LSRS), and lumbar spinal stenosis (LSS). Genome-wide association study used logistic regression with additive genetic effects adjusting for age, sex, site-specific factors, and ancestry (principal components). A fixed-effect inverse-variance weighted meta-analysis was conducted. Genetic variants of genome-wide significance (P < 5 × 10-8) were carried forward for replication in an independent sample from UK Biobank. Phenotype prevalence was 48.8% for LBP-HC, 19.8% for LSRS, and 7.9% for LSS. No variants were significantly associated with LBP-HC. One locus was associated with LSRS (lead variant rs146153280:C>G, odds ratio [OR] = 1.17 for G, P = 2.1 × 10-9), but was not replicated. Another locus on chromosome 2 spanning GFPT1, NFU1, and AAK1 was associated with LSS (lead variant rs13427243:G>A, OR = 1.10 for A, P = 4.3 × 10-8) and replicated in UK Biobank (OR = 1.11, P = 5.4 × 10-5). This was the first genome-wide association study meta-analysis of lumbar spinal disorders using electronic health record data. We identified 2 novel associations with LSRS and LSS; the latter was replicated in an independent sample. [ABSTRACT FROM AUTHOR]