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BackgroundColonic motility in constipation can be assessed non-invasively using MRI.ObjectiveTo compare MRI with high-resolution colonic manometry (HRCM) for predicting treatment response.DesignPart 1: 44 healthy volunteers (HVs), 43 patients with irritable bowel syndrome with constipation (IBS-C) and 37 with functional constipation (FC) completed stool diaries and questionnaires and underwent oral macrogol (500–1000 mL) challenge. Whole gut transit time (WGTT), segmental colonic volumes (CV), MRI-derived Motility Index and chyme movement by ‘tagging’ were assessed using MRI and time to defecation after macrogol recorded. Left colonic HRCM was recorded before and after a 700 kcal meal. Patients then proceeded to Part 2: a randomised cross-over study of 10-days bisacodyl 10 mg daily versus hyoscine 20 mg three times per day, assessing daily pain and constipation.ResultsPart 1: Total CVs median (range) were significantly greater in IBS-C (776 (595–1033)) and FC (802 (633–951)) vs HV (645 (467–780)), p<0.001. Patients also had longer WGTT and delayed evacuation after macrogol. IBS-C patients showed significantly reduced tagging index and less propagated pressure wave (PPW) activity during HRCM versus HV. Compared with FC, IBS-C patients were more anxious and reported more pain. Abnormally large colons predicted significantly delayed evacuation after macrogol challenge (p<0.02), impaired manometric meal response and reduced pain with bisacodyl (p<0.05).Part 2: Bisacodyl compared with hyoscine increased bowel movements but caused more pain in both groups (p<0.03).ConclusionAn abnormally large colon is an important feature in constipation which predicts impaired manometric response to feeding and treatment responses. HRCM shows that IBS-C patients have reduced PPW activity.Trial registration numberThe study was preregistered on ClinicalTrials.gov, Reference: NCT03226145.

QRISK algorithms use data from millions of people to help clinicians identify individuals at high risk of cardiovascular disease (CVD). Here, we derive and externally validate a new algorithm, which we have named QR4, that incorporates novel risk factors to estimate 10-year CVD risk separately for men and women. Health data from 9.98 million and 6.79 million adults from the United Kingdom were used for derivation and validation of the algorithm, respectively. Cause-specific Cox models were used to develop models to predict CVD risk, and the performance of QR4 was compared with version 3 of QRISK, Systematic Coronary Risk Evaluation 2 (SCORE2) and atherosclerotic cardiovascular disease (ASCVD) risk scores. We identified seven novel risk factors in models for both men and women (brain cancer, lung cancer, Down syndrome, blood cancer, chronic obstructive pulmonary disease, oral cancer and learning disability) and two additional novel risk factors in women (pre-eclampsia and postnatal depression). On external validation, QR4 had a higher C statistic than QRISK3 in both women (0.835 (95% confidence interval (CI), 0.833–0.837) and 0.831 (95% CI, 0.829–0.832) for QR4 and QRISK3, respectively) and men (0.814 (95% CI, 0.812–0.816) and 0.812 (95% CI, 0.810–0.814) for QR4 and QRISK3, respectively). QR4 was also more accurate than the ASCVD and SCORE2 risk scores in both men and women. The QR4 risk score identifies new risk groups and provides superior CVD risk prediction in the United Kingdom compared with other international scoring systems for CVD risk.

IMPORTANCE: Genitourinary syndrome of menopause can be treated with vaginal estrogen therapy. However, there are concerns about the safety of vaginal estrogen therapy in patients with breast cancer. OBJECTIVE: To determine whether the risk of breast cancer–specific mortality was higher in females with breast cancer who used vaginal estrogen therapy vs females with breast cancer who did not use hormone replacement therapy (HRT). DESIGN, SETTING, AND PARTICIPANTS: This cohort study analyzed 2 large cohorts, one each in Scotland and Wales, of females aged 40 to 79 years with newly diagnosed breast cancer. These population-based cohorts were identified from national cancer registry records from 2010 to 2017 in Scotland and from 2000 to 2016 in Wales and were followed up for breast cancer–specific mortality until 2020. Females were excluded if they had a previous cancer diagnosis (except nonmelanoma skin cancer). Data analysis was performed between August 2022 and August 2023. EXPOSURE: Use of vaginal estrogen therapy, including vaginal tablets and creams, was ascertained from pharmacy dispensing records of the Prescribing Information System for the Scotland cohort and from general practice prescription records for the Wales cohort. MAIN OUTCOMES AND MEASURES: The primary outcome was time to breast cancer–specific mortality, which was obtained from national mortality records. Time-dependent Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% CIs for breast cancer–specific mortality, comparing vaginal estrogen therapy users with HRT nonusers and adjusting for confounders, including cancer stage and grade. RESULTS: The 2 cohorts comprised 49 237 females with breast cancer (between 40 and 79 years of age) and 5795 breast cancer–specific deaths. Five percent of patients with breast cancer used vaginal estrogen therapy after breast cancer diagnosis. In vaginal estrogen therapy users compared with HRT nonusers, there was no evidence of a higher risk of breast cancer–specific mortality in the pooled fully adjusted model (HR, 0.77; 95% CI, 0.63-0.94). CONCLUSIONS AND RELEVANCE: Results of this study showed no evidence of increased early breast cancer–specific mortality in patients who used vaginal estrogen therapy compared with patients who did not use HRT. This finding may provide some reassurance to prescribing clinicians and support the guidelines suggesting that vaginal estrogen therapy can be considered in patients with breast cancer and genitourinary symptoms.

Lung cancer is the second most common cancer in incidence and the leading cause of cancer deaths worldwide. Meanwhile, lung cancer screening with low-dose CT can reduce mortality. The UK National Screening Committee recommended targeted lung cancer screening on Sept 29, 2022, and asked for more modelling work to be done to help refine the recommendation. This study aims to develop and validate a risk prediction model—the CanPredict (lung) model—for lung cancer screening in the UK and compare the model performance against seven other risk prediction models.

BackgroundInjuries in children aged under 5 years most commonly occur in the home and disproportionately affect those living in the most disadvantaged communities. The ‘Safe at Home’ (SAH) national home safety equipment scheme, which ran in England between 2009 and 2011, has been shown to reduce injury-related hospital admissions, but there is little evidence of cost-effectiveness.Materials and methodsCost-effectiveness analysis from a health and local government perspective. Measures were the incremental cost-effectiveness ratio per hospital admission averted (ICER) and cost-offset ratio (COR), comparing SAH expenditure to savings in admission expenditure. The study period was split into three periods: T1 (years 0–2, implementation); T2 (years 3–4) and T3 (years 5–6). Analyses were conducted for T2 versus T1 and T3 versus T1.ResultsTotal cost of SAH was £9 518 066. 202 223 hospital admissions in the children occurred during T1-3, costing £3 320 000. Comparing T3 to T1 SAH reduced admission expenditure by £924 per month per local authority and monthly admission rates by 0.5 per local authority per month compared with control areas. ICER per admission averted was £4209 for T3 versus T1, with a COR of £0.29, suggesting that 29p was returned in savings on admission expenditure for every pound spent on SAH.ConclusionSAH was effective at reducing hospital admissions due to injury and did result in some cost recovery when taking into admissions only. Further analysis of its cost-effectiveness, including emergency healthcare, primary care attendances and wider societal costs, is likely to improve the return on investment further.

ObjectivePrior studies identified clinical factors associated with increased risk of pancreatic ductal adenocarcinoma (PDAC). However, little is known regarding their time-varying nature, which could inform earlier diagnosis. This study assessed temporality of body mass index (BMI), blood-based markers, comorbidities and medication use with PDAC risk .DesignWe performed a population-based nested case–control study of 28 137 PDAC cases and 261 219 matched-controls in England. We described the associations of biomarkers with risk of PDAC using fractional polynomials and 5-year time trends using joinpoint regression. Associations with comorbidities and medication use were evaluated using conditional logistic regression.ResultsRisk of PDAC increased with raised HbA1c, liver markers, white blood cell and platelets, while following a U-shaped relationship for BMI and haemoglobin. Five-year trends showed biphasic BMI decrease and HbA1c increase prior to PDAC; early-gradual changes 2–3 years prior, followed by late-rapid changes 1–2 years prior. Liver markers and blood counts (white blood cell, platelets) showed monophasic rapid-increase approximately 1 year prior. Recent diagnosis of pancreatic cyst, pancreatitis, type 2 diabetes and initiation of certain glucose-lowering and acid-regulating therapies were associated with highest risk of PDAC.ConclusionRisk of PDAC increased with raised HbA1c, liver markers, white blood cell and platelets, while followed a U-shaped relationship for BMI and haemoglobin. BMI and HbA1c derange biphasically approximately 3 years prior while liver markers and blood counts (white blood cell, platelets) derange monophasically approximately 1 year prior to PDAC. Profiling these in combination with their temporality could inform earlier PDAC diagnosis.

Peptic ulcers in patients receiving aspirin are associated with Helicobacter pyloriinfection. We aimed to investigate whether H pylorieradication would protect against aspirin-associated ulcer bleeding.

Background: Previous studies have shown an association between acute myocardial infarction and preceding respiratory infection. Contradictory evidence exists on the influence of influenza vaccination and pneumococcal vaccination in preventing cardiovascular disease. We aimed to investigate the possible association of influenza vaccination and pneumococcal vaccination with acute myocardial infarction. Methods: We used a matched case-control design with data from the United Kingdom General Practice Research Database. Cases were patients who were at least 40 years of age at diagnosis of first acute myocardial infarction recorded from Nov. 1, 2001, to May 31, 2007, and were matched for sex, general practice, age and calendar time (i.e., month corresponding to index date of acute myocardial infarction), with up to four controls each. Data were analyzed using conditional logistic regression, adjusted for vaccination target groups, cardiovascular risk factors, treatment medications and attendances at a general practice. Results: We included 78 706 patients, of whom 16 012 were cases and 62 694 were matched controls. Influenza vaccination had been received in the previous year by 8472 cases (52.9%) and 32 081 controls (51.2%) and was associated with a 19% reduction in the rate of acute myocardial infarction (adjusted odds ratio [OR] 0.81, 95% confidence interval [CI] 0.77-0.85). Early seasonal influenza vaccination was associated with a lower rate of acute myocardial infarction (adjusted OR 0.79, 95% CI 0.75-0.83) than vaccination after mid-November (adjusted OR 0.88, 95% CI 0.79-0.97). Pneumococcal vaccination was not associated with a reduction in the rate of acute myocardial infarction (adjusted OR 0.96, 95% CI 0.91-1.02). Interpretation: Influenza vaccination but not pneumococcal vaccination is associated with a reduced rate of first acute myocardial infarction. This association and the potential benefit of early seasonal vaccination need to be considered in future experimental studies., Winter peaks in incidence of acute myocardial infarction have been linked to climate, (1) metabolic factors (2) and infection. (3) Because known risk factors do not fully account for cases [...]

A high BMI has been associated with a reduced immune response to vaccination against influenza. We aimed to investigate the association between BMI and COVID-19 vaccine uptake, vaccine effectiveness, and risk of severe COVID-19 outcomes after vaccination by using a large, representative population-based cohort from England.

Abstract Objectives To determine whether paperless medical records contained less information than paper based medical records and whether that information was harder to retrieve. Design Cross sectional study with review [...]

Abstract Objective To compare the effectiveness of lipid lowering drugs in lowering serum cholesterol concentrations. Design Cross sectional study. Setting 17 practices within 17 primary care groups in Trent region, [...]

Although myocarditis and pericarditis were not observed as adverse events in coronavirus disease 2019 (COVID-19) vaccine trials, there have been numerous reports of suspected cases following vaccination in the general population. We undertook a self-controlled case series study of people aged 16 or older vaccinated for COVID-19 in England between 1 December 2020 and 24 August 2021 to investigate hospital admission or death from myocarditis, pericarditis and cardiac arrhythmias in the 1–28 days following adenovirus (ChAdOx1, n= 20,615,911) or messenger RNA-based (BNT162b2, n= 16,993,389; mRNA-1273, n= 1,006,191) vaccines or a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive test (n= 3,028,867). We found increased risks of myocarditis associated with the first dose of ChAdOx1 and BNT162b2 vaccines and the first and second doses of the mRNA-1273 vaccine over the 1–28 days postvaccination period, and after a SARS-CoV-2 positive test. We estimated an extra two (95% confidence interval (CI) 0, 3), one (95% CI 0, 2) and six (95% CI 2, 8) myocarditis events per 1 million people vaccinated with ChAdOx1, BNT162b2 and mRNA-1273, respectively, in the 28 days following a first dose and an extra ten (95% CI 7, 11) myocarditis events per 1 million vaccinated in the 28 days after a second dose of mRNA-1273. This compares with an extra 40 (95% CI 38, 41) myocarditis events per 1 million patients in the 28 days following a SARS-CoV-2 positive test. We also observed increased risks of pericarditis and cardiac arrhythmias following a positive SARS-CoV-2 test. Similar associations were not observed with any of the COVID-19 vaccines, apart from an increased risk of arrhythmia following a second dose of mRNA-1273. Subgroup analyses by age showed the increased risk of myocarditis associated with the two mRNA vaccines was present only in those younger than 40.

IntroductionMental health conditions are a major contributor to productivity loss and are common after injury. This study quantifies postinjury productivity loss and its association with preinjury and postinjury mental health, injury, demographic, health, social and other factors.MethodsMulticentre, longitudinal study recruiting hospitalised employed individuals aged 16–69 years with unintentional injuries, followed up at 1, 2, 4 and 12 months. Participants completed questionnaires on injury, demographic factors, health (including mental health), social factors, other factors and on-the-job productivity upon return to work (RTW). ORs were estimated for above median productivity loss using random effects logistic regression.Results217 adults had made an RTW at 2, 4 or 12 months after injury: 29% at 2 months, 66% at 4 months and 83% at 12 months. Productivity loss reduced over time: 3.3% of working time at 2 months, 1.7% at 4 months, 1% at 12 months. Significantly higher productivity loss was associated with preinjury psychiatric conditions (OR 21.40, 95% CI 3.50 to 130.78) and post-traumatic stress avoidance symptoms at 1 month (OR for 1-unit increase in score 1.15, 95% CI 1.07 to 1.22). Significantly lower productivity loss was associated with male gender (OR 0.32, 95% CI 0.14 to 0.74), upper and lower limb injuries (vs other body regions, OR 0.15, 95% CI 0.03 to 0.81) and sports injuries (vs home, OR 0.18, 95% CI 0.04 to 0.78). Preinjury psychiatric conditions and gender remained significant in analysis of multiply imputed data.ConclusionsUnintentional injury results in substantial productivity loss. Females, those with preinjury psychiatric conditions and those with post-traumatic stress avoidance symptoms experience greater productivity loss and may require additional support to enable successful RTW.

BackgroundConflicting evidence has emerged regarding the relevance of smoking on risk of COVID-19 and its severity.MethodsWe undertook large-scale observational and Mendelian randomisation (MR) analyses using UK Biobank. Most recent smoking status was determined from primary care records (70.8%) and UK Biobank questionnaire data (29.2%). COVID-19 outcomes were derived from Public Health England SARS-CoV-2 testing data, hospital admissions data, and death certificates (until 18 August 2020). Logistic regression was used to estimate associations between smoking status and confirmed SARS-CoV-2 infection, COVID-19-related hospitalisation, and COVID-19-related death. Inverse variance-weighted MR analyses using established genetic instruments for smoking initiation and smoking heaviness were undertaken (reported per SD increase).ResultsThere were 421 469 eligible participants, 1649 confirmed infections, 968 COVID-19-related hospitalisations and 444 COVID-19-related deaths. Compared with never-smokers, current smokers had higher risks of hospitalisation (OR 1.80, 95% CI 1.26 to 2.29) and mortality (smoking 1–9/day: OR 2.14, 95% CI 0.87 to 5.24; 10–19/day: OR 5.91, 95% CI 3.66 to 9.54; 20+/day: OR 6.11, 95% CI 3.59 to 10.42). In MR analyses of 281 105 White British participants, genetically predicted propensity to initiate smoking was associated with higher risks of infection (OR 1.45, 95% CI 1.10 to 1.91) and hospitalisation (OR 1.60, 95% CI 1.13 to 2.27). Genetically predicted higher number of cigarettes smoked per day was associated with higher risks of all outcomes (infection OR 2.51, 95% CI 1.20 to 5.24; hospitalisation OR 5.08, 95% CI 2.04 to 12.66; and death OR 10.02, 95% CI 2.53 to 39.72).InterpretationCongruent results from two analytical approaches support a causal effect of smoking on risk of severe COVID-19.

BackgroundUnintentional home injuries are a leading cause of preventable death in young children. Safety education and equipment provision improve home safety practices, but their impact on injuries is less clear. Between 2009 and 2011, a national home safety equipment scheme was implemented in England (Safe At Home), targeting high-injury-rate areas and socioeconomically disadvantaged families with children under 5. This provided a ‘natural experiment’ for evaluating the scheme’s impact on hospital admissions for unintentional injuries.MethodsControlled interrupted time series analysis of unintentional injury hospital admission rates in small areas (Lower Layer Super Output Areas (LSOAs)) in England where the scheme was implemented (intervention areas, n=9466) and matched with LSOAs in England and Wales where it was not implemented (control areas, n=9466), with subgroup analyses by density of equipment provision.Results57 656 homes receiving safety equipment were included in the analysis. In the 2 years after the scheme ended, monthly admission rates declined in intervention areas (−0.33% (−0.47% to −0.18%)) but did not decline in control areas (0.04% (−0.11%–0.19%), p value for difference in trend=0.001). Greater reductions in admission rates were seen as equipment provision density increased. Effects were not maintained beyond 2 years after the scheme ended.ConclusionsA national home safety equipment scheme was associated with a reduction in injury-related hospital admissions in children under 5 in the 2 years after the scheme ended. Providing a higher number of items of safety equipment appears to be more effective in reducing injury rates than providing fewer items.

BackgroundStudies report an increased risk of self-harm or suicide in people prescribed mirtazapine compared with other antidepressants.ObjectivesTo compare the risk of serious self-harm in people prescribed mirtazapine versus other antidepressants as second-line treatments.Design and settingCohort study using anonymised English primary care electronic health records, hospital admission data and mortality data with study window 1 January 2005 to 30 November 2018.Participants24 516 people diagnosed with depression, aged 18–99 years, initially prescribed a selective serotonin reuptake inhibitor (SSRI) and then prescribed mirtazapine, a different SSRI, amitriptyline or venlafaxine.Main outcome measuresHospitalisation or death due to deliberate self-harm. Age–sex standardised rates were calculated and survival analyses were performed using inverse probability of treatment weighting to account for baseline covariates.ResultsStandardised rates of serious self-harm ranged from 3.8/1000 person-years (amitriptyline) to 14.1/1000 person-years (mirtazapine). After weighting, the risk of serious self-harm did not differ significantly between the mirtazapine group and the SSRI or venlafaxine groups (HRs (95% CI) 1.18 (0.84 to 1.65) and 0.85 (0.51 to 1.41) respectively). The risk was significantly higher in the mirtazapine than the amitriptyline group (3.04 (1.36 to 6.79)) but was attenuated after adjusting for dose.ConclusionsThere was no evidence for a difference in risk between mirtazapine and SSRIs or venlafaxine after accounting for baseline characteristics. The higher risk in the mirtazapine versus the amitriptyline group might reflect residual confounding if amitriptyline is avoided in people considered at risk of self-harm.Clinical implicationsAddressing baseline risk factors and careful monitoring might improve outcomes for people at risk of serious self-harm.

Emerging reports of rare neurological complications associated with COVID-19 infection and vaccinations are leading to regulatory, clinical and public health concerns. We undertook a self-controlled case series study to investigate hospital admissions from neurological complications in the 28 days after a first dose of ChAdOx1nCoV-19 (n= 20,417,752) or BNT162b2 (n= 12,134,782), and after a SARS-CoV-2-positive test (n= 2,005,280). There was an increased risk of Guillain–Barré syndrome (incidence rate ratio (IRR), 2.90; 95% confidence interval (CI): 2.15–3.92 at 15–21 days after vaccination) and Bell’s palsy (IRR, 1.29; 95% CI: 1.08–1.56 at 15–21 days) with ChAdOx1nCoV-19. There was an increased risk of hemorrhagic stroke (IRR, 1.38; 95% CI: 1.12–1.71 at 15–21 days) with BNT162b2. An independent Scottish cohort provided further support for the association between ChAdOx1nCoV and Guillain–Barré syndrome (IRR, 2.32; 95% CI: 1.08–5.02 at 1–28 days). There was a substantially higher risk of all neurological outcomes in the 28 days after a positive SARS-CoV-2 test including Guillain–Barré syndrome (IRR, 5.25; 95% CI: 3.00–9.18). Overall, we estimated 38 excess cases of Guillain–Barré syndrome per 10 million people receiving ChAdOx1nCoV-19 and 145 excess cases per 10 million people after a positive SARS-CoV-2 test. In summary, although we find an increased risk of neurological complications in those who received COVID-19 vaccines, the risk of these complications is greater following a positive SARS-CoV-2 test.

Abstract Objective--To assess patient, doctor, practice, and process of care variables for their effect on glycaemic control in diabetes mellitus, and to quantify their relative effects. Design--Search of general practice [...]

IMPORTANCE: Although children mainly experience mild COVID-19 disease, hospitalization rates are increasing, with limited understanding of underlying factors. There is an established association between race and severe COVID-19 outcomes in adults in England; however, whether a similar association exists in children is unclear. OBJECTIVE: To investigate the association between race and childhood COVID-19 testing and hospital outcomes. DESIGN, SETTING, PARTICIPANTS: In this cohort study, children (0-18 years of age) from participating family practices in England were identified in the QResearch database between January 24 and November 30, 2020. The QResearch database has individually linked patients with national SARS-CoV-2 testing, hospital admission, and mortality data. EXPOSURES: The main characteristic of interest is self-reported race. Other exposures were age, sex, deprivation level, geographic region, household size, and comorbidities (asthma; diabetes; and cardiac, neurologic, and hematologic conditions). MAIN OUTCOMES AND MEASURES: The primary outcome was hospital admission with confirmed COVID-19. Secondary outcomes were SARS-CoV-2–positive test result and any hospital attendance with confirmed COVID-19 and intensive care admission. RESULTS: Of 2 576 353 children (mean [SD] age, 9.23 [5.24] years; 48.8% female), 410 726 (15.9%) were tested for SARS-CoV-2 and 26 322 (6.4%) tested positive. A total of 1853 children (0.07%) with confirmed COVID-19 attended hospital, 343 (0.01%) were admitted to the hospital, and 73 (0.002%) required intensive care. Testing varied across race. White children had the highest proportion of SARS-CoV-2 tests (223 701/1 311 041 [17.1%]), whereas Asian children (33 213/243 545 [13.6%]), Black children (7727/93 620 [8.3%]), and children of mixed or other races (18 971/147 529 [12.9%]) had lower proportions. Compared with White children, Asian children were more likely to have COVID-19 hospital admissions (adjusted odds ratio [OR], 1.62; 95% CI, 1.12-2.36), whereas Black children (adjusted OR, 1.44; 95% CI, 0.90-2.31) and children of mixed or other races (adjusted OR, 1.40; 95% CI, 0.93-2.10) had comparable hospital admissions. Asian children were more likely to be admitted to intensive care (adjusted OR, 2.11; 95% CI, 1.07-4.14), and Black children (adjusted OR, 2.31; 95% CI, 1.08-4.94) and children of mixed or other races (adjusted OR, 2.14; 95% CI, 1.25-3.65) had longer hospital admissions (≥36 hours). CONCLUSIONS AND RELEVANCE: In this large population-based study exploring the association between race and childhood COVID-19 testing and hospital outcomes, several race-specific disparities were observed in severe COVID-19 outcomes. However, ascertainment bias and residual confounding in this cohort study should be considered before drawing any further conclusions. Overall, findings of this study have important public health implications internationally.

Public policy measures and clinical risk assessments relevant to COVID-19 need to be aided by risk prediction models that are rigorously developed and validated. We aimed to externally validate a risk prediction algorithm (QCovid) to estimate mortality outcomes from COVID-19 in adults in England.

Abstract Objective To determine whether people whose marital partners have depression, diabetes, hypertension, ischaemic heart disease, stroke, hyperlipidaemia, peptic ulcer disease, or asthma or chronic obstructive pulmonary disease are at [...]

Abstract Objective To determine the relation between morbidity from injury and deprivation for different levels of injury severity and for different injury mechanisms for children aged 0-14 years. Design Cross [...]

Osteoarthritis (OA) is a common chronic condition in older individuals, but its association with other chronic conditions is largely unknown. This study aimed to systematically review the literature on comorbidities in individuals with OAcompared to those without. We searched 4 databases for observational studies on comorbidities in individuals with OA. Studies of OAonly or in comparison with non‐OAcontrols were included. The risk of bias and study quality were assessed using the Newcastle‐Ottawa Scale. The prevalence of comorbidities in the OAgroup and the prevalence ratio (PR) and 95% confidence interval (95% CI) between OAand non‐OAgroups were calculated. In all, 42 studies from 16 countries (27 case‐only and 15 comparative studies) met the inclusion criteria. The mean age of participants varied from 51 to 76 years. The pooled prevalence of any comorbidity was 67% (95% CI57–74) in individuals with OAversus 56% (95% CI44–68) in individuals without OA. The pooled PRfor any comorbidity was 1.21 (95% CI1.02–1.45). The PRincreased from 0.73 (95% CI0.43–1.25) for 1 comorbidity to 1.58 (95% CI1.03–2.42) for 2, and to 1.94 (95% CI1.45–2.59) for ≥3 comorbidities. The key comorbidities associated with OAwere stroke (PR2.61 [95% CI2.13–3.21]), peptic ulcer (PR2.36 [95% CI1.71–3.27]), and metabolic syndrome (PR1.94 [95% CI1.21–3.12]). Individuals with OAare more likely to have other chronic conditions. The association is dose‐dependent in terms of the number of comorbidities, suggesting multimorbidities. Further studies on the causality of this association and clinical implications are needed.

BackgroundThere is uncertainty about the associations of angiotensive enzyme (ACE) inhibitor and angiotensin receptor blocker (ARB) drugs with COVID-19 disease. We studied whether patients prescribed these drugs had altered risks of contracting severe COVID-19 disease and receiving associated intensive care unit (ICU) admission.MethodsThis was a prospective cohort study using routinely collected data from 1205 general practices in England with 8.28 million participants aged 20–99 years. We used Cox proportional hazards models to derive adjusted HRs for exposure to ACE inhibitor and ARB drugs adjusted for sociodemographic factors, concurrent medications and geographical region. The primary outcomes were: (a) COVID-19 RT-PCR diagnosed disease and (b) COVID-19 disease resulting in ICU care.FindingsOf 19 486 patients who had COVID-19 disease, 1286 received ICU care. ACE inhibitors were associated with a significantly reduced risk of COVID-19 disease (adjusted HR 0.71, 95% CI 0.67 to 0.74) but no increased risk of ICU care (adjusted HR 0.89, 95% CI 0.75 to 1.06) after adjusting for a wide range of confounders. Adjusted HRs for ARBs were 0.63 (95% CI 0.59 to 0.67) for COVID-19 disease and 1.02 (95% CI 0.83 to 1.25) for ICU care.There were significant interactions between ethnicity and ACE inhibitors and ARBs for COVID-19 disease. The risk of COVID-19 disease associated with ACE inhibitors was higher in Caribbean (adjusted HR 1.05, 95% CI 0.87 to 1.28) and Black African (adjusted HR 1.31, 95% CI 1.08 to 1.59) groups than the white group (adjusted HR 0.66, 95% CI 0.63 to 0.70). A higher risk of COVID-19 with ARBs was seen for Black African (adjusted HR 1.24, 95% CI 0.99 to 1.58) than the white (adjusted HR 0.56, 95% CI 0.52 to 0.62) group.InterpretationACE inhibitors and ARBs are associated with reduced risks of COVID-19 disease after adjusting for a wide range of variables. Neither ACE inhibitors nor ARBs are associated with significantly increased risks of receiving ICU care. Variations between different ethnic groups raise the possibility of ethnic-specific effects of ACE inhibitors/ARBs on COVID-19 disease susceptibility and severity which deserves further study.

BackgroundUnintentional injuries in children under the age of 5 years commonly occur in the home and disproportionately affect those living in disadvantaged circumstances. Targeted home safety promotion should be offered to families most at risk but there is a paucity of standardised evidence-based resources available for use across family-support practitioners.ObjectiveTo assess the effectiveness, implementation and cost-effectiveness of a 2-year home safety programme (Stay One Step Ahead) developed by parents, practitioners and researchers, and delivered by a range of family support providers in inner-city localities, compared with usual care in matched control localities.MethodsParents of children aged 0 to 7 months will be recruited to a controlled before and after observational study. The primary outcome is home safety assessed by the proportion of families with a fitted and working smoke alarm, safety gate on stairs (where applicable) and poisons stored out of reach, assessed using parent-administered questionnaires at baseline, 12 and 24 months.Secondary outcomes include: the impact on other parent-reported safety behaviours, medically-attended injuries, self-efficacy for home safety and knowledge of child development and injury risk using questionnaires and emergency department attendance data; implementation (reach, acceptability, barriers, facilitators) of home safety promotion assessed through interviews and observations; and cost-effectiveness using medically-attended injury costs ascertained from healthcare records.ConclusionIf shown to be effective and cost-effective this study will provide a practical resource to underpin national guidance. The study could inform public health prevention strategies to reduce home injury in children most at risk, while delivering cost savings to health and care services.Trial registration numberISRCTN31210493; Pre result.

IntroductionClinical guidelines recommend antidepressants as the first line of treatment for adults with moderate-to-severe depression. Randomised trials provide the best evidence on the comparative effectiveness of antidepressants for depression, but are limited by a short follow-up and a highly selected population. We aim to conduct a cohort study on a large database to assess acceptability, efficacy, safety and tolerability of antidepressant monotherapy in people with depressive disorder in primary care.Methods and analysisThis is a protocol for a cohort study using data from the QResearch primary care research database, which is the largest general practice research database in the UK. We will include patients registered for at least 1 year from 1 January 1998, diagnosed with a new episode of depression and on antidepressant and a comparison group not on antidepressant. The exposure of interest will be treatment with antidepressant medications. Our outcomes will be acceptability (treatment discontinuation due to any cause), efficacy (clinical response and remission); safety (adverse events (AEs) and all-cause mortality); and tolerability (dropouts due to any AE) measured at 2 months, 6 months and 1 year. For each outcome, we will estimate the absolute risks for all antidepressants, and relative effects between antidepressants using Cox’s proportion hazards models. We will calculate HRs and 99.9% CIs for each outcome of interest.DiscussionThe main limitation is the observational nature of our study, while the major strengths include the large representative population contained in QResearch and the possibly high generalisability.

IMPORTANCE: Anticholinergic medicines have short-term cognitive adverse effects, but it is uncertain whether long-term use of these drugs is associated with an increased risk of dementia. OBJECTIVE: To assess associations between anticholinergic drug treatments and risk of dementia in persons 55 years or older. DESIGN, SETTING, AND PARTICIPANTS: This nested case-control study took place in general practices in England that contributed to the QResearch primary care database. The study evaluated whether exposure to anticholinergic drugs was associated with dementia risk in 58 769 patients with a diagnosis of dementia and 225 574 controls 55 years or older matched by age, sex, general practice, and calendar time. Information on prescriptions for 56 drugs with strong anticholinergic properties was used to calculate measures of cumulative anticholinergic drug exposure. Data were analyzed from May 2016 to June 2018. EXPOSURES: The primary exposure was the total standardized daily doses (TSDDs) of anticholinergic drugs prescribed in the 1 to 11 years prior to the date of diagnosis of dementia or equivalent date in matched controls (index date). MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) for dementia associated with cumulative exposure to anticholinergic drugs, adjusted for confounding variables. RESULTS: Of the entire study population (284 343 case patients and matched controls), 179 365 (63.1%) were women, and the mean (SD) age of the entire population was 82.2 (6.8) years. The adjusted OR for dementia increased from 1.06 (95% CI, 1.03-1.09) in the lowest overall anticholinergic exposure category (total exposure of 1-90 TSDDs) to 1.49 (95% CI, 1.44-1.54) in the highest category (>1095 TSDDs), compared with no anticholinergic drug prescriptions in the 1 to 11 years before the index date. There were significant increases in dementia risk for the anticholinergic antidepressants (adjusted OR [AOR], 1.29; 95% CI, 1.24-1.34), antiparkinson drugs (AOR, 1.52; 95% CI, 1.16-2.00), antipsychotics (AOR, 1.70; 95% CI, 1.53-1.90), bladder antimuscarinic drugs (AOR, 1.65; 95% CI, 1.56-1.75), and antiepileptic drugs (AOR, 1.39; 95% CI, 1.22-1.57) all for more than 1095 TSDDs. Results were similar when exposures were restricted to exposure windows of 3 to 13 years (AOR, 1.46; 95% CI, 1.41-1.52) and 5 to 20 years (AOR, 1.44; 95% CI, 1.32-1.57) before the index date for more than 1095 TSDDs. Associations were stronger in cases diagnosed before the age of 80 years. The population-attributable fraction associated with total anticholinergic drug exposure during the 1 to 11 years before diagnosis was 10.3%. CONCLUSIONS AND RELEVANCE: Exposure to several types of strong anticholinergic drugs is associated with an increased risk of dementia. These findings highlight the importance of reducing exposure to anticholinergic drugs in middle-aged and older people.

IntroductionIncreasing numbers of children and young people (CYP) are receiving prescriptions for antidepressants. This is the protocol of a study aiming to describe the trends and variation in antidepressant prescriptions in CYP in England, and to examine the indications for the prescriptions recorded and whether there was contact with secondary care specialists on or around the time of the first antidepressant prescription.Methods and analysisAll eligible CYP aged between 5 and 17 years in 1998–2017 from the QResearch primary care database will be included. Incidence and prevalence rates of any antidepressant prescription in each year will be calculated. We will examine four different antidepressant classes: selective serotonin reuptake inhibitors, tricyclic and related antidepressants, serotonin and norepinephrine reuptake inhibitors and other antidepressants, as well as for individual drugs. Linked primary and secondary care data (hospital episode statistics) in the year before and up to 6 months after the first antidepressant prescription will be examined for CYP whose first antidepressant prescription was in 2006–2017. Whether there were records of indications and being seen by psychiatric or paediatric specialists will be identified. Trends over time and differences by region, deprivation and ethnicity will be examined using Poisson regression.DiscussionThis large, population-based study will give an up-to-date picture of antidepressant prescribing in CYP and identify any variation. Understanding what indications are recorded when CYP are being prescribed antidepressants, and whether this was done in partnership with secondary care specialists, will provide evidence of whether appropriate guidelines are being followed.

BackgroundFalls in older people are a leading causes of unintentional injury. Due to an ageing population, injuries are likely to increase unless more is done to reduce older people’s falls risk. In clinical trials, the Falls Management Exercise (FaME) programme has reduced the rate of falls and falls-related injuries in community-dwelling older adults. However, the commissioning of FaME is inconsistent across England, potentially due to a lack of evidence that FaME can be delivered effectively in a ‘real world’ setting. The PHysical activity Implementation Study In Community-dwelling AduLts (PHISICAL) study is designed to study the implementation of FaME in a range of different settings in England.MethodsThe PHISICAL study will use a mixed-methods, triangulation, multilevel design to explore the implementation of FaME. Framework analysis of semistructured interviews with up to 90 stakeholders (exercise programme users, service providers, referrers and commissioners) and observational data from locally led communities of practice will identify the factors that influence FaME’s implementation. Quantitative, anonymised, routine service data from up to 650 exercise programme users, including measures of falls and physical activity, will allow assessment of whether the benefits of FaME reported in clinical trials translate to the ‘real world’ setting.ConclusionThe findings from this study will be used to develop a toolkit of resources and guidance to inform the commissioning and delivery of future FaME programmes. This study has the potential to inform public health prevention strategies, and in doing so may reduce the number of falls in the older population while delivering cost savings to health and social care services.

Abstract Objectives To determine whether antidepressants are a risk factor for ischaemic heart disease and to compare the risk for different subgroups of antidepressants and individual antidepressants. Design Case-control study. [...]

Abstract Objectives To determine whether there are important differences in performance between group practices and singlehanded general practitioners and the extent to which any differences are explained by practice characteristics [...]

To investigate the causal association between Osteoarthritis (OA) and five comorbidities: depression, tiredness, multisite chronic pain, irritable bowel syndrome (IBS) and gout.

Background: Up to 3 years of treatment with alendronate, 5 mg/d, prevents postmenopausal bone loss. Objective: To determine whether the effect of alendronate is sustained at 4 years of treatment and persists after treatment is discontinued. Design: Randomized, controlled trial. Setting: United States and Europe. Participants: 1609 postmenopausal women 45 to 59 years of age. Intervention: Participants were randomly assigned to receive oral alendronate, 5 mg/d or 2.5 mg/d; placebo; or open-label estrogen-progestin. Women in the alendronate groups received alendronate for the first 2 years of the study. Treatment was then continued without change or replaced with placebo for the last 2 years of the study. Measurements: Annual measurement of bone mineral density. Results: By year 4, the bone mineral density of participants in the placebo group had decreased by 1% to 6% (P [is less than] 0.001). Four years of treatment with 5 mg of alendronate per day increased bone mineral density at the spine (mean change [[+ or -] SE], 3.8% [+ or -] 0.3%), hip (mean, 2.9% [+ or -] 0.2%), and total body (mean, 0.9% [+ or -] 0.2%) (P [is less than] 0.001 overall). By year 4, bone mineral density at most skeletal sites was greater in participants who switched from alendronate to placebo than in those who continuously received placebo. In years 3 and 4, bone loss in participants who switched from alendronate to placebo was similar to that seen during years 1 and 2 in those who continuously received placebo. Compared with 5 mg of alendronate per day, estrogen-medroxyprogesterone acetate produced similar increases in bone mineral density and estradiol-norethisterone acetate produced increases that were substantially greater. Conclusions: Four years of treatment with alendronate or estrogen-progestin prevented postmenopausal bone loss. A residual effect was seen 2 years after alendronate therapy was stopped; however, continuous alendronate treatment was more effective in preventing postmenopausal bone loss than 2 years of alendronate followed by 2 years of placebo., Postmenopausal women who take the drug alendronate may need to take it for many years. Alendronate is used to prevent osteoporosis. Researchers randomly assigned 1,609 postmenopausal women to take alendronate or placebo for two years. Then some women continued to take alendronate while others switched to a placebo for an additional two years. By the fourth year, women who took a placebo all four years had lost bone density. Women who took alendronate all four years had increased bone density. Women who switched after two years had smaller increases in bone density.

Unintentional injury is the leading cause of death in children aged 1 to 15, and two thirds of fatal injuries in schoolchildren result from road traffic crashes. (1) More than [...]

Cycling can improve health and well-being by reducing inactivity. Concern about collision crashes may be a barrier to participation since collision crashes can lead to significant mortality and morbidity. The conspicuity of cyclists may be a contributory factor in some collision crashes. This study investigated whether increased conspicuity aid use (such as reflective or fluorescent clothing) is associated with a reduced risk of collision crashes for cyclists in a UK city.

IntroductionChildhood poisonings are common, placing a substantial burden on health services. Case–control studies have found inconsistent evidence about modifiable risk factors for poisonings among children aged 0–4 years. This study quantifies associations between poison prevention practices and medically attended poisonings in children aged 0–4 years.MethodsMulticentre case–control study conducted at hospitals, minor injury units and family practices from four study centres in England between 2010 and 2013. Participants comprised 567 children presenting with unintentional poisoning occurring at home and 2320 community control participants matched on age, sex, date of event and study centre. Parents/caregivers provided data on safety practices, safety equipment use, home hazards and potential confounders by means of self-completion questionnaires. Data were analysed using conditional logistic regression.ResultsCompared with community controls, parents of poisoned children were significantly more likely not to store medicines out of reach (adjusted OR (AOR) 1.59; 95% CI 1.21 to 2.09; population attributable fraction (PAF) 15%), not to store medicines safely (locked or out of reach (AOR 1.83; 95% CI 1.38 to 2.42; PAF 16%) and not to have put all medicines (AOR 2.11; 95% CI 1.54 to 2.90; PAF 20%) or household products (AOR 1.79, 95% CI 1.29 to 2.48; PAF 11%) away immediately after use.ConclusionsNot storing medicines out of reach or locked away and not putting medicines and household products away immediately after use increased the odds of secondary care attended poisonings in children aged 0–4 years. If associations are causal, implementing these poison prevention practices could each prevent between 11% and 20% of poisonings.

ObjectivesTo derive and validate risk prediction algorithms (QCOVID4) to estimate the risk of covid-19 related death and hospital admission in people with a positive SARS-CoV-2 test result during the period when the omicron variant of the virus was predominant in England, and to evaluate performance compared with a high risk cohort from NHS Digital.DesignCohort study.SettingQResearch database linked to English national data on covid-19 vaccinations, SARS-CoV-2 test results, hospital admissions, and cancer and mortality data, 11 December 2021 to 31 March 2022, with follow-up to 30 June 2022.Participants1.3 million adults in the derivation cohort and 0.15 million adults in the validation cohort, aged 18-100 years, with a positive test result for SARS-CoV-2 infection.Main outcome measuresPrimary outcome was covid-19 related death and secondary outcome was hospital admission for covid-19. Risk equations with predictor variables were derived from models fitted in the derivation cohort. Performance was evaluated in a separate validation cohort.ResultsOf 1 297 922 people with a positive test result for SARS-CoV-2 infection in the derivation cohort, 18 756 (1.5%) had a covid-19 related hospital admission and 3878 (0.3%) had a covid-19 related death during follow-up. The final QCOVID4 models included age, deprivation score and a range of health and sociodemographic factors, number of covid-19 vaccinations, and previous SARS-CoV-2 infection. The risk of death related to covid-19 was lower among those who had received a covid-19 vaccine, with evidence of a dose-response relation (42% risk reduction associated with one vaccine dose and 92% reduction with four or more doses in men). Previous SARS-CoV-2 infection was associated with a reduction in the risk of covid-19 related death (49% reduction in men). The QCOVID4 algorithm for covid-19 explained 76.0% (95% confidence interval 73.9% to 78.2%) of the variation in time to covid-19 related death in men with a D statistic of 3.65 (3.43 to 3.86) and Harrell’s C statistic of 0.970 (0.962 to 0.979). Results were similar for women. QCOVID4 was well calibrated. QCOVID4 was substantially more efficient than the NHS Digital algorithm for correctly identifying patients at high risk of covid-19 related death. Of the 461 covid-19 related deaths in the validation cohort, 333 (72.2%) were in the QCOVID4 high risk group and 95 (20.6%) in the NHS Digital high risk group.ConclusionThe QCOVID4 risk algorithm, modelled from data during the period when the omicron variant of the SARS-CoV-2 virus was predominant in England, now includes vaccination dose and previous SARS-CoV-2 infection, and predicted covid-19 related death among people with a positive test result. QCOVID4 more accurately identified individuals at the highest levels of absolute risk for targeted interventions than the approach adopted by NHS Digital. QCOVID4 performed well and could be used for targeting treatments for covid-19 disease.

BackgroundThere is an increasing demand for mental health services for young people, which may vary across the year.ObjectiveTo determine whether there are seasonal patterns in primary care antidepressant prescribing and mental health issues in adolescents and young adults.MethodsThis cohort study used anonymised electronic health records from general practices in England contributing to QResearch. It included 5 081 263 males and females aged 14–18 (adolescents), 19–23 and 24–28 years between 2006 and 2019. The incidence rates per 1000 person-years and the incidence rate ratios (IRRs) were calculated for the first records of a selective serotonin reuptake inhibitor (SSRI) prescription, depression, anxiety and self-harm. The IRRs were adjusted for year, region, deprivation, ethnic group and number of working days.FindingsThere was an increase in SSRI prescribing, depression and anxiety incidence in male and female adolescents in the autumn months (September–November) that was not seen in older age groups. The IRRs for SSRI prescribing for adolescents peaked in November (females: 1.75, 95% CI 1.67 to 1.83, p<0.001; males: 1.72, 95% CI 1.61 to 1.84, p<0.001, vs in January) and for depression (females: 1.29, 95% CI 1.25 to 1.33, p<0.001; males: 1.29, 95% CI 1.23 to 1.35, p<0.001). Anxiety peaked in November for females aged 14–18 years (1.17, 95% CI 1.13 to 1.22, p<0.001) and in September for males (1.19, 95% CI 1.12 to 1.27, p<0.001).ConclusionsThere were higher rates of antidepressant prescribing and consultations for depression and anxiety at the start of the school year among adolescents.Clinical implicationsSupport around mental health issues from general practitioners and others should be focused during autumn.