Drug-induced orthostatic hypotension: Cluster analysis of co-prescription patterns in older people in UK primary care.

PURPOSE: Over 250 medications are reported to cause orthostatic hypotension, associated with serious adverse outcomes in older adults. Studies suggest a harmful cumulative risk of orthostatic hypotension with multiple medication use. However, there is limited evidence on the potential for harm in practice, particularly which drugs is co-prescribed and may increase risk of orthostatic hypotension. METHODS: Retrospective cohort study and cluster analysis using general practice data from IQVIA Medical Research Data (IMRD) in patients aged ≥50 contributing data between 1 January 2018 and 31 December 2018. Thirteen drug groups known to be associated with orthostatic hypotension by mechanism, were analyzed and clusters generated by sex and age-band. RESULTS: A total of 602 713 individuals aged ≥50 with 283 912 (47%) men and 318 801 (53%) women were included. The most prevalent prescriptions that might contribute to orthostatic hypotension were ACE inhibitors, calcium-channel blockers, beta-blockers, selective serotonin reuptake inhibitors and uroselective alpha-blockers. We identified distinct clusters of cardiovascular system (cardiovascular system) drugs in men and women at all ages. cardiovascular system plus psychoactive drug clusters were common in women at all ages, and in men aged ≤70. cardiovascular system plus uroselective alpha-blockers were identified in men aged ≥70. CONCLUSIONS: Distinct clusters of drugs associated with orthostatic hypotension exist in practice, which change over the life course. Our findings highlight potentially harmful drug combinations that may cause cumulative risk of orthostatic hypotension in older people. This may guide clinicians about the potential of synergistic harm and to monitor for orthostatic hypotension if using combinations of cardiovascular system drugs, cardiovascular system plus psychoactive drugs and/or alpha-blockers-particularly in patients aged ≥70 or at high-risk due to comorbidity. Future research should consider quantifying the risk of drug-induced orthostatic hypotension with such drug combinations.

Trends in incidence of recorded diagnosis of osteoporosis, osteopenia, and fragility fractures in people aged 50 years and above: retrospective cohort study using UK primary care data.

This study used primary care data to estimate the incidence of recorded diagnosis of osteoporosis, osteopenia, and fragility fracture in the UK during 2000-2018 accounting for age, sex, calendar year and social deprivation. More than 3 million people aged 50-99 years were included. We found that men living in the most deprived areas had a 45% higher risk of being diagnosed with osteoporosis and 50% higher risk of fragility fracture compared to men living in the least deprived areas. PURPOSE: a) To estimate the incidence trends of a recorded diagnosis of osteoporosis, osteopenia, and fragility fracture in the UK over time; b) to describe differences according to age, sex, and social deprivation. METHODS: This is a longitudinal population-based cohort study using routinely collected primary care data obtained via IQVIA Medical Research Database (IMRD). All patients aged 50-99 years registered with a practice participating in THIN (The Health Improvement Network) between 2000-2018 were included. The first recorded diagnosis of osteoporosis, osteopenia, or fragility fracture was used to estimate incidence rates (IR) per 10,000 person-years at risk. Poisson regression was used to provide Incidence Rate Ratios (IRR) adjusted by age, sex, social deprivation, calendar year, and practice effect. RESULTS: The year-specific adjusted IRR of recorded osteoporosis was highest in 2009 in women [IRR 1.44(95%CI 1.38-1.50)], whereas in men it was highest in 2013-2014 [IRR 1.94(95%CI 1.72-2.18)] compared to 2000. The year-specific adjusted IRR of fragility fracture was highest in 2012 in women [IRR 1.77(95%CI 1.69-1.85)], whereas in men it was highest in 2013 [IRR 1.64(95%CI 1.51-1.78)] compared to 2000. Men in the most deprived areas had a higher risk of being diagnosed with osteoporosis [IRR 1.45(95%CI 1.38-1.53)], osteopenia [IRR 1.17(95%CI 1.09-1.26)], and fragility fracture [IRR 1.50(95%CI 1.44-1.56)] compared to those living in the least deprived areas, but smaller differences were seen in women. CONCLUSION: Use of fracture risk assessment tools may enhance the detection of osteoporosis cases in primary care. Further research is needed on the effect of social deprivation on diagnosis of osteoporosis and fractures.

In utero or early in life exposure to antibiotics and the risk of childhood atopic dermatitis, a population-based cohort study.

BACKGROUND: Atopic dermatitis (AD) is a common inflammatory disease of the skin that begins early in life and can be lifelong. The purpose of our study was to evaluate whether fetal exposure and/or early life exposure of a child to antibiotics increases the risk of early onset AD. OBJECTIVE: We hypothesize that antibiotic exposure in utero or early in life (e.g., first 90 days) increases the likelihood that children develop AD. METHODS: Utilizing a large prospectively collected electronic medical records database, we studied the association of antibiotic exposure received in utero or very early in life and the relative risk of onset of AD in a population-based cohort study. Associations were estimated using proportional hazards models as hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: The risk of AD in childhood was increased after in utero or early life antibiotic exposure. For any in utero AB exposure the HR was 1.38 (1.36,1.39). However, penicillin demonstrated the strongest association with AD for both in utero exposure, 1.43 (1.41,1.44), and for childhood exposure, 1.81(1.79,1.82). HRs were higher in children born to mothers without AD than those with AD pointing to effect modification by maternal AD status. CONCLUSION: Children born to mothers exposed to antibiotics while in utero had, depending on the mother's history of AD, approximately a 20 to 40% increased risk of developing AD. Depending on the antibiotic, children who received antibiotics early-in-life had a 40 to 80% increased risk of developing AD. Our study, supports and refines the association between incident AD and antibiotic administration. It also adds population-based support to therapeutic attempts to treat AD by modifying skin microbiome.

Stoma Formation in Crohn's Disease and the Likelihood of Antidepressant Use: A Population-Based Cohort Study.

BACKGROUND & AIMS: The impact of a temporary or permanent stoma on mental health in Crohn's Disease (CD) is unknown. The aim was to examine the association between intestinal surgery and stoma formation and subsequent antidepressant medication (ADM) use. METHODS: Using the Clinical Practice Research Datalink, we identified individuals with CD who underwent intestinal surgery between 1998-2018. We excluded individuals with a prescription for an ADM in the 6 months before surgery. Individuals were stratified into three groups: no stoma, temporary stoma, and permanent stoma. We used Kaplan-Meier curves to examine initiation of ADM after intestinal surgery and Cox regression to identify risk factors for ADM use after intestinal surgery. RESULTS: We identified 1,272 cases of CD undergoing their first intestinal surgery. Of these, 871 (68.5%) had no stoma, 191 (15.0%) had a temporary stoma and 210 (16.5%) had a permanent stoma. The 10-year cumulative incidence of ADM use was 26.4%, 33.4% and 37.3% respectively. Individuals with a permanent stoma were 71% more likely to receive an ADM than those with no stoma (HR 1.71, 95% CI 1.20-2.44). Individuals with a temporary stoma reversed within 12 months had a similar likelihood of ADM use to those without stoma formation (HR 0.99, 95% CI 0.64-1.53) whereas temporary stoma formation with late reversal after 12 months was associated with significantly greater likelihood of ADM use (HR 1.85, 95% CI 1.15-2.96). CONCLUSIONS: Permanent stomas and temporary stomas with late reversal surgery are associated with increased ADM use after intestinal surgery, likely associated with increased anxiety and depression.

Initiation of antidepressant medication in people with type 2 diabetes living in the United Kingdom-A retrospective cohort study.

INTRODUCTION: Depression is a common comorbidity in people with type 2 diabetes and it is associated with poorer outcomes. There is limited data on the treatments used for depression in this population. The aim of this study was to explore the rates of initiation of antidepressant prescriptions in people with type 2 diabetes in the UK and identify those most at risk of needing such treatment. RESEARCH DESIGN AND METHODS: This was a retrospective cohort study using data from IQVIA Medical Research Data (IMRD)-UK data. Data from general practices in IMRD-UK between January 2008 and December 2017 were used for this study. RESULTS: The overall rates of antidepressant prescribing were stable over the study period. The rate of initiation of antidepressant medication in people with type 2 diabetes was 22.93 per 1000 person years at risk (PYAR) with a 95%CI 22.48 to 23.39 compared to 16.89 per 1000 PYAR (95%CI 16.77 to 17.01) in an age and gender matched cohort. The risk of being prescribed antidepressant medication with age had a U-shaped distribution with the lowest risk in the 65-69 age group. The peak age for antidepressant initiation in men and women was 40-44, with a rate in men of 32.78 per 1000 PYAR (95% CI 29.57 to 36.34) and a rate in women of 46.80 per 1000 PYAR (95% CI 41.90 to 52.26). People with type 2 diabetes with in the least deprived quintile had an initiation rate of 19.66 per 1000 PYAR (95%CI 18.67 to 20.70) compared to 27.19 per 1000 PYAR (95%CI 25.50 to 28.93) in the most deprived quintile, with a 32% increase in the risk of starting antidepressant medication (95%CI 1.22 to 1.43). CONCLUSIONS: People with type 2 diabetes were 30% more likely to be started on antidepressant medication than people without type 2 diabetes. Women with type 2 diabetes were 35% more likely than men to be prescribed antidepressants and the risks increased with deprivation and in younger or older adults, with the lowest rates in the 65-69 year age band. The rates of antidepressant prescribing were broadly stable over the 10-year period in this study. The antidepressant medications prescribed changed slightly over time with sertraline becoming more widely used and fewer prescriptions of citalopram.

Impact of home healthcare on end-of-life outcomes for people with dementia: a systematic review.

BACKGROUND: Home healthcare (HHC) comprises clinical services provided by medical professionals for people living at home with various levels of care needs and health conditions. HHC may reduce care transitions from home to acute hospitals, but its long-term impact on homebound people living with dementia (PLWD) towards end-of-life remains unclear. We aim to describe the impact of HHC on acute healthcare utilization and end-of-life outcomes in PLWD. METHODS: Design: Systematic review of quantitative and qualitative original studies which examine the association between HHC and targeted outcomes. INTERVENTIONS: HHC. PARTICIPANTS: At least 80% of study participants had dementia and lived at home. MEASUREMENTS: Primary outcome was acute healthcare utilization in the last year of life. Secondary outcomes included hospice palliative care, advance care planning, continuity of care, and place of death. We briefly reviewed selected national policy to provide contextual information regarding these outcomes. RESULTS: From 6831 articles initially identified, we included five studies comprising data on 4493 participants from USA, Japan, and Italy. No included studies received a "high" quality rating. We synthesised core properties related to HHC at three implementational levels. Micro-level: HHC may be associated with a lower risk of acute healthcare utilization in the early period (e.g., last 90 days before death) and a higher risk in the late period (e.g. last 15 days) of the disease trajectory toward end-of-life in PLWD. HHC may increase palliative care referrals. Advance care planning was an important factor influencing end-of-life outcomes. Meso-level: challenges for HHC providers in medical decision-making and initiating palliative care for PLWD at the end-of-life may require further training and external support. Coordination between HHC and social care is highlighted but not well examined. Macro-level: reforms of national policy or financial schemes are found in some countries but the effects are not clearly understood. CONCLUSIONS: This review highlights the dearth of dementia-specific research regarding the impact of HHC on end-of-life outcomes. Effects of advance care planning during HHC, the integration between health and social care, and coordination between primary HHC and specialist geriatric/ palliative care services require further investigation.

Depression in individuals who subsequently develop inflammatory bowel disease: a population-based nested case-control study.

OBJECTIVE: Depression is a potential risk factor for developing IBD. This association may be related to GI symptoms occurring before diagnosis. We aimed to determine whether depression, adjusted for pre-existing GI symptoms, is associated with subsequent IBD. DESIGN: We conducted a nested case-control study using the Clinical Practice Research Datalink identifying incident cases of UC and Crohn's disease (CD) from 1998 to 2016. Controls without IBD were matched for age and sex. We measured exposure to prevalent depression 4.5-5.5 years before IBD diagnosis. We created two sub-groups with prevalent depression based on whether individuals had reported GI symptoms before the onset of depression. We used conditional logistic regression to derive ORs for the risk of IBD depending on depression status. RESULTS: We identified 10 829 UC cases, 4531 CD cases and 15 360 controls. There was an excess of prevalent depression 5 years before IBD diagnosis relative to controls (UC: 3.7% vs 2.7%, CD 3.7% vs 2.9%). Individuals with GI symptoms prior to the diagnosis of depression had increased adjusted risks of developing UC and CD compared with those without depression (UC: OR 1.47, 95% CI 1.21 to 1.79; CD: OR 1.41, 95% CI 1.04 to 1.92). Individuals with depression alone had similar risks of UC and CD to those without depression (UC: OR 1.13, 95% CI 0.99 to 1.29; CD: OR 1.12, 95% CI 0.91 to 1.38). CONCLUSIONS: Depression, in the absence of prior GI symptoms, is not associated with subsequent development of IBD. However, depression with GI symptoms should prompt investigation for IBD.

Drug-induced orthostatic hypotension: A systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Drug-induced orthostatic hypotension (OH) is common, and its resulting cerebral hypoperfusion is linked to adverse outcomes including falls, strokes, cognitive impairment, and increased mortality. The extent to which specific medications are associated with OH remains unclear. METHODS AND FINDINGS: We conducted a systematic review and meta-analysis to evaluate the extent to which specific drug groups are associated with OH. EMBASE, MEDLINE, and Web of Science databases were searched from inception through 23 November 2020. Placebo-controlled randomised controlled trials (RCTs) on any drug reporting on OH as an adverse effect in adults (≥18 years) were eligible. Three authors extracted data on the drug, OH, dose, participant characteristics, and study setting. The revised Cochrane risk-of-bias tool for randomised trials (RoB 2) was used to appraise evidence. Summary odds ratios (ORs) were estimated for OH using fixed effects Mantel-Haenszel statistics. We conducted subgroup analysis on validity of OH measurement, drug dose, risk of bias, age, and comorbidity. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool was used to summarise the certainty of evidence. Of 36,940 citations, 69 eligible RCTs were included in the meta-analysis comprising 27,079 participants. Compared with placebo, beta-blockers and tricyclic antidepressants were associated with increased odds of OH (OR 7.76 [95% CI 2.51, 24.03]; OR 6.30 [95% CI 2.86, 13.91]). Alpha-blockers, antipsychotics, and SGLT-2 inhibitors were associated with up to 2-fold increased odds of OH, compared to placebo. There was no statistically significant difference in odds of OH with vasodilators (CCBs, ACE inhibitors/ARBs, SSRIs), compared to placebo. Limitations of this study are as follows: data limited to placebo-controlled studies, (excluding head-to-head trials), many RCTs excluded older participants; therefore results may be amplified in older patients in the clinical setting. The study protocol is publicly available on PROSPERO (CRD42020168697). CONCLUSIONS: Medications prescribed for common conditions (including depression, diabetes, and lower urinary tract symptoms) were associated with significantly increased odds of OH. Drugs causing sympathetic inhibition were associated with significantly increased odds of OH, while most vasodilators were associated with small nonsignificant differences in odds of OH, compared to placebo. Drugs targeting multiple parts of the orthostatic blood pressure (BP) reflex pathway (e.g. sympathetic inhibition, vasodilation, cardio-inhibitory effects) may carry cumulative risk, suggesting that individuals with polypharmacy could benefit from postural BP monitoring.

Fatal opioid overdoses during and shortly after hospital admissions in England: A case-crossover study.

BACKGROUND: Hospital patients who use illicit opioids such as heroin may use drugs during an admission or leave the hospital in order to use drugs. There have been reports of patients found dead from drug poisoning on the hospital premises or shortly after leaving the hospital. This study examines whether hospital admission and discharge are associated with increased risk of opioid-related death. METHODS AND FINDINGS: We conducted a case-crossover study of opioid-related deaths in England. Our study included 13,609 deaths between January 1, 2010 and December 31, 2019 among individuals aged 18 to 64. For each death, we sampled 5 control days from the period 730 to 28 days before death. We used data from the national Hospital Episode Statistics database to determine the time proximity of deaths and control days to hospital admissions. We estimated the association between hospital admission and opioid-related death using conditional logistic regression, with a reference category of time neither admitted to the hospital nor within 14 days of discharge. A total of 236/13,609 deaths (1.7%) occurred following drug use while admitted to the hospital. The risk during hospital admissions was similar or lower than periods neither admitted to the hospital nor recently discharged, with odds ratios 1.03 (95% CI 0.87 to 1.21; p = 0.75) for the first 14 days of an admission and 0.41 (95% CI 0.30 to 0.56; p < 0.001) for days 15 onwards. 1,088/13,609 deaths (8.0%) occurred in the 14 days after discharge. The risk of opioid-related death increased in this period, with odds ratios of 4.39 (95% CI 3.75 to 5.14; p < 0.001) on days 1 to 2 after discharge and 2.09 (95% CI 1.92 to 2.28; p < 0.001) on days 3 to 14. 11,629/13,609 deaths (85.5%) did not occur close to a hospital admission, and the remaining 656/13,609 deaths (4.8%) occurred in hospital following admission due to drug poisoning. Risk was greater for patients discharged from psychiatric admissions, those who left the hospital against medical advice, and those leaving the hospital after admissions of 7 days or more. The main limitation of the method is that it does not control for time-varying health or drug use within individuals; therefore, hospital admissions coinciding with high-risk periods may in part explain the results. CONCLUSIONS: Discharge from the hospital is associated with an acute increase in the risk of opioid-related death, and 1 in 14 opioid-related deaths in England happens in the 2 weeks after the hospital discharge. This supports interventions that prevent early discharge and improve linkage with community drug treatment and harm reduction services.

Predictive values for different cancers and inflammatory bowel disease of 6 common abdominal symptoms among more than 1.9 million primary care patients in the UK: A cohort study.

BACKGROUND: The diagnostic assessment of abdominal symptoms in primary care presents a challenge. Evidence is needed about the positive predictive values (PPVs) of abdominal symptoms for different cancers and inflammatory bowel disease (IBD). METHODS AND FINDINGS: Using data from The Health Improvement Network (THIN) in the United Kingdom (2000-2017), we estimated the PPVs for diagnosis of (i) cancer (overall and for different cancer sites); (ii) IBD; and (iii) either cancer or IBD in the year post-consultation with each of 6 abdominal symptoms: dysphagia (n = 86,193 patients), abdominal bloating/distension (n = 100,856), change in bowel habit (n = 106,715), rectal bleeding (n = 235,094), dyspepsia (n = 517,326), and abdominal pain (n = 890,490). The median age ranged from 54 (abdominal pain) to 63 years (dysphagia and change in bowel habit); the ratio of women/men ranged from 50%:50% (rectal bleeding) to 73%:27% (abdominal bloating/distension). Across all studied symptoms, the risk of diagnosis of cancer and the risk of diagnosis of IBD were of similar magnitude, particularly in women, and younger men. Estimated PPVs were greatest for change in bowel habit in men (4.64% cancer and 2.82% IBD) and for rectal bleeding in women (2.39% cancer and 2.57% IBD) and lowest for dyspepsia (for cancer: 1.41% men and 1.03% women; for IBD: 0.89% men and 1.00% women). Considering PPVs for specific cancers, change in bowel habit and rectal bleeding had the highest PPVs for colon and rectal cancer; dysphagia for esophageal cancer; and abdominal bloating/distension (in women) for ovarian cancer. The highest PPVs of abdominal pain (either sex) and abdominal bloating/distension (men only) were for non-abdominal cancer sites. For the composite outcome of diagnosis of either cancer or IBD, PPVs of rectal bleeding exceeded the National Institute of Health and Care Excellence (NICE)-recommended specialist referral threshold of 3% in all age-sex strata, as did PPVs of abdominal pain, change in bowel habit, and dyspepsia, in those aged 60 years and over. Study limitations include reliance on accuracy and completeness of coding of symptoms and disease outcomes. CONCLUSIONS: Based on evidence from more than 1.9 million patients presenting in primary care, the findings provide estimated PPVs that could be used to guide specialist referral decisions, considering the PPVs of common abdominal symptoms for cancer alongside that for IBD and their composite outcome (cancer or IBD), taking into account the variable PPVs of different abdominal symptoms for different cancers sites. Jointly assessing the risk of cancer or IBD can better support decision-making and prompt diagnosis of both conditions, optimising specialist referrals or investigations, particularly in women.

Infections in temporal proximity to HPV vaccination and adverse effects following vaccination in Denmark: A nationwide register-based cohort study and case-crossover analysis.

BACKGROUND: Public trust in the human papilloma virus (HPV) vaccination programme has been challenged by reports of potential severe adverse effects. The reported adverse symptoms were heterogeneous and overlapping with those characterised as chronic fatigue syndrome (CFS) and have been described as CFS-like symptoms. Evidence suggests that CFS is often precipitated by an infection. The aim of the study was to examine if an infection in temporal proximity to HPV vaccination is a risk factor for suspected adverse effects following HPV vaccination. METHODS AND FINDINGS: The study was a nationwide register-based cohort study and case-crossover analysis. The study population consisted of all HPV vaccinated females living in Denmark, born between 1974 and 2006, and vaccinated between January 1, 2006 and December 31, 2017. The exposure was any infection in the period ± 1 month around time of first HPV vaccination and was defined as (1) hospital-treated infection; (2) redemption of anti-infective medication; or (3) having a rapid streptococcal test done at the general practitioner. The outcome was referral to a specialised hospital setting (5 national HPV centres opened June 1, 2015) due to suspected adverse effects following HPV vaccination. Multivariable logistic regression was used to estimate the association between infection and later HPV centre referral. The participants were 600,400 HPV-vaccinated females aged 11 to 44 years. Of these, 48,361 (9.7%) females had a hospital-treated infection, redeemed anti-infective medication, or had a rapid streptococcal test ± 1 month around time of first HPV vaccination. A total of 1,755 (0.3%) females were referred to an HPV centre. Having a hospital-treated infection in temporal proximity to vaccination was associated with significantly elevated risk of later referral to an HPV centre (odds ratio (OR) 2.75, 95% confidence interval (CI) 1.72 to 4.40; P < 0.001). Increased risk was also observed among females who redeemed anti-infective medication (OR 1.56, 95% CI 1.33 to 1.83; P < 0.001) or had a rapid streptococcal test (OR 1.45, 95% CI 1.10 to 1.93; P = 0.010). Results from a case-crossover analysis, which was performed to adjust for potential unmeasured confounding, supported the findings. A key limitation of the study is that the HPV centres did not open until June 1, 2015, which may have led to an underestimation of the risk of suspected adverse effects, but stratified analyses by year of vaccination yielded similar results. CONCLUSIONS: Treated infection in temporal proximity to HPV vaccination is associated with increased risk for later referral with suspected adverse vaccine effects. Thus, the infection could potentially be a trigger of the CFS-like symptoms in a subset of the referred females. To our knowledge, the study is the first to investigate the role of infection in the development of suspected adverse effects after HPV vaccination and replication of these findings are needed in other studies.

Long-term systemic glucocorticoid therapy and weight gain: a population-based cohort study.

OBJECTIVES: To describe the variation in weight gain in people chronically exposed to systemic glucocorticoids in primary care and to identify the risk factors for weight gain. METHODS: Data were analysed from the British database, The Health Improvement Network. Body weight variations of individuals prescribed systemic glucocorticoids for at least 3 months at a mean dose ≥10 mg/day were described. The risk factors associated with weight gain ≥10% of the usual weight were assessed. RESULTS: A total of 31 516 adults prescribed glucocorticoids and 26 967 controls were included in the study. During glucocorticoid exposure, only 12 475 (39.6%) individuals gained >2 kg compared with their usual weight. Younger women were more likely to gain weight (mean weight gain in 18-39-year-old glucocorticoid-exposed women: 3.6 kg (s.d. 8.6) compared with 2 kg (s.d. 7.3) in the control group; the absolute mean difference was 1.6 kg (95% CI 0.9, 2.2; P < 0.001). Weight gain ≥10% of the usual weight was observed in 10.2% (n = 3208) of those chronically exposed to glucocorticoids. Women, younger people, those living in areas of higher deprivation, smokers, those on higher doses of the drug and those previously exposed to glucocorticoids were at higher risk. The risk was lower in people prescribed glucocorticoids for an inflammatory condition when compared with asthma or chronic obstructive pulmonary disease. CONCLUSION: After taking into account usual weight rather than weight just before glucocorticoid initiation and the natural history of weight variation, the amount of weight gain induced by systemic glucocorticoids as prescribed in primary care is less than usually thought. CLINICAL TRIAL REGISTRATION: 18THIN081.

Cigarette smoking as a risk factor for schizophrenia or all non-affective psychoses.

BACKGROUND: Smoking tobacco is regarded as an epiphenomenon in patients with schizophrenia when it may be causal. We aimed to examine whether smoking status is related to the onset of schizophrenia or the broader diagnosis of non-affective psychosis, including schizophrenia. METHODS: We used data from The Health Improvement Network primary care database to identify people aged 15-24 between 1 January 2004 and 31 December 2009. We followed them until the earliest of: first diagnosis of schizophrenia (or psychosis), patient left the practice, practice left THIN, patient died or 31 December 2014. RESULTS: In men, incidence rates for schizophrenia per 100 000 person years at risk were higher in smoking initiators (non-smoker who became a smoker during the study) than in non-smokers (adjusted IRR 1.94; 95% CI 1.29-2.91) and higher still in smokers (adjusted IRR 3.32; 95% CI 2.67-4.14). Among women, the incidence rate of schizophrenia was higher in smokers than in non-smokers (adjusted IRR 1.50; 95% CI 1.06-2.12), but no higher in smoking initiators than non-smokers. For non-affective psychosis, the pattern was similar for men but more evident in women where psychosis incidence rates were higher in smoking initiators (adjusted IRR 1.90; 95% CI 1.40-2.56) and in smokers (adjusted IRR 2.13; 95% CI 1.76-2.57) than in non-smokers. CONCLUSIONS: We found an important and strong association between smoking and incidence of schizophrenia. Smoking may increase risk through as yet unknown pathways or smoking may share genetic risk with schizophrenia and non-affective psychoses.

Extreme diurnal temperature range and cardiovascular emergency hospitalisations in a Mediterranean region.

OBJECTIVES: The impact of extreme diurnal temperature range (DTR) on cardiovascular morbidity in Mediterranean regions remains uncertain. We aimed to analyse the impact of extreme low DTR (stable temperature) or high DTR (changeable temperature) on cardiovascular hospitalisations in Catalonia (Southern Europe). METHODS: We conducted a self-controlled case series study using whole-year data from the System for the Development of Research in Primary Care database and 153 weather stations from the Catalan Meteorological Service. The outcome was first emergency hospitalisation. Monthly DTR percentiles were used to define extreme DTR as low (DTR 95th percentile). We assessed two effects: same-day (1-day exposure, coinciding with the extreme DTR episode) and cumulative (3-day exposure, adding two subsequent days). Incidence rate ratios (IRR) were calculated adjusted by age, season and air pollution. Stratified analyses by gender, age or cardiovascular type and regions are provided. RESULTS: We computed 121 206 cardiovascular hospitalisations from 2006 to 2013. The IRR was 1.032 (95% CI 1.005 to 1.061) for same day and 1.024 (95% CI 1.006 to 1.042) for cumulative effects of extreme high DTR. The impact was significant for stroke and heart failure, but not for coronary heart disease. Conversely, extreme low DTR did not increase cardiovascular hospitalisations. CONCLUSIONS: Extreme high DTR increased the incidence of cardiovascular hospitalisations, but not extreme low DTR. Same-day effects of extreme high DTR were stronger than cumulative effects. These findings contribute to better understand the impact of outdoor temperature on health, and to help defining public health strategies to mitigate such impact.

How are people with mild cognitive impairment or subjective memory complaints managed in primary care? A systematic review.

BACKGROUND: Primary care is typically the first point of contact in the health care system for people raising concerns about their memory. However, there is still a lack of high-quality evidence and understanding about how primary care professionals (PCPs) currently manage people at higher risk of developing dementia. OBJECTIVES: To systematically review management strategies provided by PCPs to reduce cognitive decline in people with mild cognitive impairment and subjective memory complaints. METHOD: A systematic search for studies was conducted in December 2019 across five databases (EMBASE, Medline, PsycInfo, CINAHL and Web of Science). Methodological quality of included studies was independently assessed by two authors using the Mixed Methods Appraisal Tool. RESULTS: An initial 11 719 were found, 7250 were screened and 9 studies were included in the review. Most studies were self-reported behaviour surveys. For non-pharmacological strategies, the most frequent advice PCPs provided was to increase physical activity, cognitive stimulation, diet and social stimulation. For pharmacological strategies, PCPs would most frequently not prescribe any treatment. If PCPs did prescribe, the most frequent prescriptions targeted vascular risk factors to reduce the risk of further cognitive decline. CONCLUSION: PCPs reported that they are much more likely to provide non-pharmacological strategies than pharmacological strategies in line with guidelines on preventing the onset of dementia. However, the quality of evidence within the included studies is low and relies on subjective self-reported behaviours. Observational research is needed to provide an accurate reflection of how people with memory problems are managed in primary care.

People will typically go to their general practitioners, also known as primary care professionals (PCPs), to raise concerns about their memory. However, there is no clear understanding of what advice or treatment PCPs provide to people with memory concerns who are at high risk of dementia. This review aims to summarize the findings from research that studied what advice or treatments PCPs would give to a person with memory concerns. Nine studies were included in the review after screening through 11 719 studies. The current review found that PCPs were more likely to provide advice rather than prescribe any drug treatment. The most common advice that PCPs provided was to increase physical activity, cognitive stimulation and social stimulation. If PCPs decided to prescribe drugs, the most common prescriptions were to improve blood flow. Improving blood flow has been linked with reducing the risk of developing dementia. However, the quality of the studies included in this review is low because many relied on PCPs answering questionnaires on their intentions to manage people with memory concerns. Therefore, future research needs to observe PCPs' real-life practice to provide an accurate reflection of how people with memory problems are managed in primary care.

Hospital variation in the risk of infection after hip fracture surgery: a population-based cohort study including 29,598 patients from 2012-2017.

Background and purpose - Understanding the key drivers of hospital variation in postoperative infections after hip fracture surgery is important for directing quality improvements. Therefore, we investigated variation in the risk of any infection, and subgroups of infections including pneumonia and sepsis after hip fracture surgery.Methods - In this nationwide population-based cohort study, all Danish patients aged ≥ 65 undergoing surgery for an incident hip fracture from 2012 to 2017 were included. Risk of postoperative infections, based on data from hospital registration (hospital-treated infections) and antibiotic dispensing (community-treated infections), were calculated using multilevel Poisson regression analysis. Hospital variation was evaluated by intra-class coefficient (ICC) and median risk ratio (MRR).Results - The risk of hospital-treated infection was 15%. The risk of community-treated infection was 24%. The adjusted risk varied between hospitals from 7.8-25% for hospital-treated infection and 16-34% for community-treated infection. The ICC indicated that 19% of the adjusted variance was due to hospital level for hospital-treated infection. The ICC for community-treated infections was 13%. The MRR showed a 2-fold increased risk for the average patient acquiring a hospital-treated infection at the highest risk hospital compared with the lowest risk hospital. For community-treated infection, the MRR was 1.4.Interpretation - Our results suggest that 20% of infections could be reduced by applying the top performing hospitals' approach. Nearly a 5th of the variation was at the hospital level. This suggests a more standardized approach to avoid postoperative infection after hip fracture surgery.Hip fracture is a leading cause of hospital admission among the elderly. The 30-day mortality following hip fracture surgery has been approximately 10% during the last few years in Denmark (Pedersen et al. 2017). Higher mortality after hip fracture has been associated with a range of hospital factors (Kristensen et al. 2016, Sheehan et al. 2016) and patient factors in observational studies (Roche et al. 2005). Furthermore, variation in 30-day mortality after hip fracture surgery has been observed between Danish hospitals, but not fully explained (Kristensen et al. 2019).

Hospital Records of Pain, Fatigue, or Circulatory Symptoms in Girls Exposed to Human Papillomavirus Vaccination: Cohort, Self-Controlled Case Series, and Population Time Trend Studies.

Human papillomavirus (HPV) vaccination has been associated with subsequent diffuse symptoms in girls, reducing public confidence in the vaccine. We examined whether girls have nonspecific outcomes of HPV vaccination, using triangulation from cohort, self-controlled case series (SCCS), and population time trend analyses carried out in Denmark between 2000 and 2014. The study population consisted of 314,017 HPV-vaccinated girls and 314,017 age-matched HPV-unvaccinated girls (cohort analyses); 11,817 girls with hospital records (SCCS analyses); and 1,465,049 girls and boys (population time trend analyses). The main outcome measures were hospital records of pain, fatigue, or circulatory symptoms. The cohort study revealed no increased risk among HPV vaccine-exposed girls, with incidence rate ratios close to 1.0 for abdominal pain, nonspecific pain, headache, hypotension/syncope, tachycardia (including postural orthostatic tachycardia syndrome), and malaise/fatigue (including chronic fatigue syndrome). In the SCCS analyses, we observed no association between HPV vaccination and subsequent symptoms. In time trend analyses, we observed a steady increase in these hospital records in both girls and (HPV-unvaccinated) boys, with no relationship to the 2009 introduction of HPV vaccine to Denmark's vaccination program. This study, which had nationwide coverage, showed no evidence of a causal link between HPV vaccination and diffuse autonomic symptoms leading to hospital contact.

Social Inequalities in Life Expectancy and Mortality in People With Dementia in the United Kingdom.

INTRODUCTION: Inequalities in life expectancy and mortality by social deprivation in the general population of the United Kingdom are widening. For people with dementia, data on potential gradients in life expectancy and mortality by social deprivation are sparse. This study aimed to explore potential differentials in life expectancy and mortality in people with dementia according to social deprivation. METHODS: Using The Health Improvement Network (THIN) primary care database, we included people with a diagnosis of dementia in the United Kingdom in 2000 to 2016 and obtained data on age at death and mortality. Comparisons were made according to social deprivation quintiles adjusting for age at diagnosis. RESULTS: Among 166,268 people with dementia there were no differences in life expectancy and mortality in the most deprived compared with the least deprived. This pattern has been stable during the study period, as no increasing inequalities in life expectancy and mortality according to social deprivation were found. DISCUSSION: Contrary to the general population, there were limited inequalities in life expectancy and mortality according to social deprivation for people with dementia.

HOme-based Longitudinal Investigation of the multidiSciplinary Team Integrated Care (HOLISTIC): protocol of a prospective nationwide cohort study.

BACKGROUND: The use of home health care (HHC) is increasing worldwide. This may have an impact not only on patients and their caregivers' health but on care resource utilization and costs. We lack information on the impact of HHC on the broader dimensions of health status and care resource utilization. More understanding of the longitudinal HHC impact on HHC patients and caregivers is also needed. Moreover, we know little about the synergy between HHC and social care. Therefore, the present study aims to observe longitudinal changes in health, care resource utilization and costs and caregiving burden among HHC recipients and their caregivers in Taiwan. METHODS: A prospective cohort study "Home-based Longitudinal Investigation of the Multidisciplinary Team Integrated Care (HOLISTIC)" will be conducted and 600 eligible patient-caregiver dyads will be recruited and followed with comprehensive quantitative assessments during six home investigations over two years. The measurements include physical function, psychological health, cognitive function, wellbeing, shared decision making and advance care planning, palliative care and quality of dying, caregiving burden, continuity and coordination of care, care resource utilization, and costs. DISCUSSION: The HOLISTIC study offers the opportunity to comprehensively understand longitudinal changes in health conditions, care resource utilization and costs and caregiving burden among HHC patients and caregivers. It will provide new insights for clinical practitioners and policymakers. TRIAL REGISTRATION: ClinicalTrials.gov Identifier is NCT04250103 which has been registered on 31st January 2020.

Population-calibrated multiple imputation for a binary/categorical covariate in categorical regression models.

Multiple imputation (MI) has become popular for analyses with missing data in medical research. The standard implementation of MI is based on the assumption of data being missing at random (MAR). However, for missing data generated by missing not at random mechanisms, MI performed assuming MAR might not be satisfactory. For an incomplete variable in a given data set, its corresponding population marginal distribution might also be available in an external data source. We show how this information can be readily utilised in the imputation model to calibrate inference to the population by incorporating an appropriately calculated offset termed the "calibrated-δ adjustment." We describe the derivation of this offset from the population distribution of the incomplete variable and show how, in applications, it can be used to closely (and often exactly) match the post-imputation distribution to the population level. Through analytic and simulation studies, we show that our proposed calibrated-δ adjustment MI method can give the same inference as standard MI when data are MAR, and can produce more accurate inference under two general missing not at random missingness mechanisms. The method is used to impute missing ethnicity data in a type 2 diabetes prevalence case study using UK primary care electronic health records, where it results in scientifically relevant changes in inference for non-White ethnic groups compared with standard MI. Calibrated-δ adjustment MI represents a pragmatic approach for utilising available population-level information in a sensitivity analysis to explore potential departures from the MAR assumption.