A self-controlled case series study to measure the risk of SARS-CoV-2 infection associated with attendance at sporting and cultural events: the UK Events Research Programme events.

BACKGROUND: In 2021, whilst societies were emerging from major social restrictions during the SARS-CoV-2 pandemic, the UK government instigated an Events Research Programme to examine the risk of COVID-19 transmission from attendance at cultural events and explore ways to enable people to attend a range of events whilst minimising risk of transmission. We aimed to measure any impact on risk of COVID-19 transmission from attendance at events held at or close to commercially viable capacity using routinely collected data. METHODS: Data were obtained on attendees at Phase 3 Events Research Programme events, for which some infection risk mitigation measures were in place (i.e. evidence of vaccination or a negative lateral flow test). Attendance data were linked with COVID-19 test result data from the UK Test and Trace system. Using a self-controlled case series design, we measured the within person incidence rate ratio for testing positive for COVID-19, comparing the rate in days 3 to 9 following event attendance (high risk period) with days 1 and 2 and 10-16 (baseline period). Rate ratios were adjusted for estimates of underlying regional COVID-19 prevalence to account for population level fluctuations in infection risk, and events were grouped into broadly similar types. RESULTS: From attendance data available for 188,851 attendees, 3357 people tested positive for COVID-19 during the observation period. After accounting for total testing trends over the period, incidence rate ratios and 95% confidence intervals for positive tests were 1.16 (0.53-2.57) for indoor seated events, 1.12 (0.95-1.30) for mainly outdoor seated events, 0.65 (0.51-0.83) for mainly outdoor partially seated events, and 1.70 (1.52-1.89) for mainly outdoor unseated multi-day events. CONCLUSIONS: For the majority of event types studied in the third phase of the UK Events Research Programme, we found no evidence of an increased risk of COVID-19 transmission associated with event attendance. However, we found a 70% increased risk of infection associated with attendance at mainly outdoor unseated multi-day events. We have also demonstrated a novel use for self-controlled case series methodology in monitoring infection risk associated with event attendance.

Urticaria and the risk of cancer: a Danish population-based cohort study.

BACKGROUND: Urticaria has been tentatively linked to cancer, but epidemiological evidence supporting this link is sparse and conflicting. We therefore conducted a population-based cohort study using healthcare databases of the Danish population (January 1980-December 2022). We followed 87,507 people for a median of 10.1 years after first hospital contact for urticaria. OBJECTIVES: To examine associations of a hospital diagnosis of urticaria with incident cancer. METHODS: We computed absolute risk of cancer and standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) standardized to Danish national cancer rates. In a cross-sectional analysis, we examined whether the extent of cancer spread differed between people with vs. without a previous urticaria diagnosis. RESULTS: The overall SIR for all types of cancer was 1.09 (95% CI, 1.06-1.11) based on 7,788 observed vs. 7,161 expected cases. The risk for any cancer was 0.7% (95% CI, 0.6-0.7) for the first year of follow-up. Cancer was diagnosed in 588 people with urticaria during the first year of follow-up (SIR 1.49, 95% CI, 1.38-1.62) and in 7,200 people thereafter (SIR 1.06, 95% CI, 1.04-1.09). During the first year of follow-up, we found strong associations with hematological cancers (e.g., non-Hodgkin lymphoma SIR 2.91, 95% CI, 1.92-4.23). Cancer stage was similar in people with vs. without previous urticaria diagnosis. CONCLUSIONS: At the time of urticaria diagnosis, or in the first year afterwards, we found a large increase in the risk for cancer. In subsequent years, a persistent 6% increase in risk remained. Diagnostic efforts may partly explain the elevated short-term risk, but occult cancer may promote urticaria, or cancer and urticaria share common risk factors.

Common mental health disorders in adults with inflammatory skin conditions: nationwide population-based matched cohort studies in the UK.

BACKGROUND: Psoriasis and atopic eczema are common inflammatory skin diseases. Existing research has identified increased risks of common mental disorders (anxiety, depression) in people with eczema and psoriasis; however, explanations for the associations remain unclear. We aimed to establish the risk factors for mental illness in those with eczema or psoriasis and identify the population groups most at risk. METHODS: We used routinely collected data from the UK Clinical Practice Research Datalink (CPRD) GOLD. Adults registered with a general practice in CPRD (1997-2019) were eligible for inclusion. Individuals with eczema/psoriasis were matched (age, sex, practice) to up to five adults without eczema/psoriasis. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for hazards of anxiety or depression in people with eczema/psoriasis compared to people without. We adjusted for known confounders (deprivation, asthma [eczema], psoriatic arthritis [psoriasis], Charlson comorbidity index, calendar period) and potential mediators (harmful alcohol use, body mass index [BMI], smoking status, and, in eczema only, sleep quality [insomnia diagnoses, specific sleep problem medications] and high-dose oral glucocorticoids). RESULTS: We identified two cohorts with and without eczema (1,032,782, matched to 4,990,125 without), and with and without psoriasis (366,884, matched to 1,834,330 without). Sleep quality was imbalanced in the eczema cohorts, twice as many people with eczema had evidence of poor sleep at baseline than those without eczema, including over 20% of those with severe eczema. After adjusting for potential confounders and mediators, eczema and psoriasis were associated with anxiety (adjusted HR [95% CI]: eczema 1.14 [1.13-1.16], psoriasis 1.17 [1.15-1.19]) and depression (adjusted HR [95% CI]: eczema 1.11 [1.1-1.12], psoriasis 1.21 [1.19-1.22]). However, we found evidence that these increased hazards are unlikely to be constant over time and were especially high 1-year after study entry. CONCLUSIONS: Atopic eczema and psoriasis are associated with increased incidence of anxiety and depression in adults. These associations may be mediated through known modifiable risk factors, especially sleep quality in people with eczema. Our findings highlight potential opportunities for the prevention of anxiety and depression in people with eczema/psoriasis through treatment of modifiable risk factors and enhanced eczema/psoriasis management.

The risk of acute kidney injury in colorectal cancer survivors: an english population-based matched cohort study.

BACKGROUND: Colorectal cancer survival has improved in recent decades but there are concerns that survivors may develop kidney problems due to adverse effects of cancer treatment or complications of the cancer itself. We quantified the risk of acute kidney injury (AKI) in colorectal cancer survivors compared to people with no prior cancer. METHODS: Retrospective matched cohort study using electronic health record primary care data from the Clinical Practice Research Datalink GOLD linked to hospital data in England (HES-APC). Individuals with colorectal cancer between 1997-2018 were individually matched on age, sex, and GP practice to people with no prior cancer. We used Cox models to estimate hazard ratios for an incident hospital diagnosis of AKI in colorectal cancer survivors compared to individuals without cancer, overall and stratified by time since diagnosis adjusted for other individual-level factors (adj-HR). RESULTS: Twenty thousand three hundred forty colorectal cancer survivors were matched to 100,058 cancer-free individuals. Colorectal cancer survivors were at increased risk of developing AKI compared to people without cancer (adj-HR = 2.16; 95%CI 2.05-2.27). The HR was highest in the year after diagnosis (adj-HR 7.47, 6.66-8.37), and attenuated over time, but there was still increased AKI risk > 5 years after diagnosis (adj-HR = 1.26, 1.17-1.37). The association between colorectal cancer and AKI was greater for younger people, men, and those with pre-existing chronic kidney disease. CONCLUSIONS: Colorectal cancer survivors were at increased risk of AKI for several years after cancer diagnosis, suggesting a need to prioritise monitoring, prevention, and management of kidney problems in this group of cancer survivors.

Factors associated with depression, anxiety and severe mental illness among adults with atopic eczema or psoriasis: a systematic review and meta-analysis.

BACKGROUND: Evidence suggests an association between atopic eczema (AE) or psoriasis and mental illness; however, the factors associated with mental illness are unclear. OBJECTIVES: To synthesize and evaluate all available evidence on factors associated with depression, anxiety and severe mental illness (SMI) among adults with AE or psoriasis. METHODS: We searched electronic databases, grey literature databases and clinical trial registries from inception to February 2022 for studies of adults with AE or psoriasis. Eligible studies included randomized controlled trials (RCTs), cohort, cross-sectional or case-control studies where effect estimates of factors associated with depression, anxiety or SMI were reported. We did not apply language or geographical restrictions. We assessed risk of bias using the Quality in Prognosis Studies tool. We synthesized results narratively, and if at least two studies were sufficiently homogeneous, we pooled effect estimates in a random effects meta-analysis. RESULTS: We included 21 studies (11 observational, 10 RCTs). No observational studies in AE fulfilled our eligibility criteria. Observational studies in people with psoriasis mostly investigated factors associated with depression or anxiety - one cross-sectional study investigated factors associated with schizophrenia. Pooled effect estimates suggest that female sex and psoriatic arthritis were associated with depression [female sex: odds ratio (OR) 1.62, 95% confidence interval (CI) 1.09-2.40, 95% prediction intervals (PIs) 0.62-4.23, I2 = 24.90%, τ2 = 0.05; psoriatic arthritis: OR 2.26, 95% CI 1.56-3.25, 95% PI 0.21-24.23, I2 = 0.00%, τ2 = 0.00] and anxiety (female sex: OR 2.59, 95% CI 1.32-5.07, 95% PI 0.00-3956.27, I2 = 61.90%, τ2 = 0.22; psoriatic arthritis: OR 1.98, 95% CI 1.33-2.94, I2 = 0.00%, τ2 = 0.00). Moderate/severe psoriasis was associated with anxiety (OR 1.14, 95% CI 1.05-1.25, I2 0.00%, τ2 = 0.00), but not depression. Evidence from RCTs suggested that adults with AE or psoriasis given placebo had higher depression and anxiety scores compared with comparators given targeted treatment (e.g. biologic agents). CONCLUSIONS: Our review highlights limited existing research on factors associated with depression, anxiety and SMI in adults with AE or psoriasis. Observational evidence on factors associated with depression or anxiety in people with psoriasis was conflicting or from single studies, but some identified factors were consistent with those in the general population. Evidence on factors associated with SMIs in people with AE or psoriasis was particularly limited. Evidence from RCTs suggested that AE and psoriasis treated with placebo was associated with higher depression and anxiety scores compared with skin disease treated with targeted therapy; however, follow-up was limited. Therefore, long-term effects on mental health are unclear.

Long-term oral antibiotic use in people with acne vulgaris in UK primary care: a drug utilization study.

BACKGROUND: The inappropriate use of antibiotics is understood to contribute to antimicrobial resistance. Oral antibiotics are regularly used to treat moderate-to-severe acne vulgaris. In practice, we do not know the typical length of oral antibiotic treatment courses for acne in routine primary care and what proportion of people receive more than one course of treatment following a new acne diagnosis. OBJECTIVES: To describe how oral antibiotics are prescribed for acne over time in UK primary care. METHODS: We conducted a descriptive longitudinal drug utilization study using routinely collected primary care data from the Clinical Practice Research Datalink GOLD (2004-2019). We included individuals (8-50 years) with a new acne diagnosis recorded between 1 January 2004 and 31 July 2019. RESULTS: We identified 217 410 people with a new acne diagnosis. The median age was 17 years [interquartile range (IQR) 15-25] and median follow-up was 4.3 years (IQR 1.9-7.6). Among people with a new acne diagnosis, 96 703 (44.5%) received 248 560 prescriptions for long-term oral antibiotics during a median follow-up of 5.3 years (IQR 2.8-8.5). The median number of continuous courses of antibiotic therapy (≥ 28 days) per person was four (IQR 2-6). The majority (n = 59 010, 61.0%) of first oral antibiotic prescriptions in those with a recorded acne diagnosis were between the ages of 12 and 18. Most (n = 71 544, 74.0%) first courses for oral antibiotics were for between 28 and 90 days. The median duration of the first course of treatment was 56 days (IQR 50-93 days) and 18 127 (18.7%) of prescriptions of ≥ 28 days were for < 6 weeks. Among people who received a first course of oral antibiotic for ≥ 28 days, 56 261 (58.2%) received a second course after a treatment gap of ≥ 28 days. The median time between first and second courses was 135 days (IQR 67-302). The cumulative duration of exposure to oral antibiotics during follow-up was 255 days (8.5 months). CONCLUSIONS: Further work is needed to understand the consequences of using antibiotics for shorter periods than recommended. Suboptimal treatment duration may result in reduced clinical effectiveness or repeated exposures, potentially contributing to antimicrobial resistance.

The association between atopic eczema and lymphopenia: Results from a UK cohort study with replication in US survey data.

BACKGROUND: Lymphocyte skin homing in atopic eczema (AE) may induce lymphopenia. OBJECTIVE: To determine if AE is associated with lymphopenia. METHODS: We used UK primary care electronic health records (Clinical Practice Research Datalink GOLD) for a matched cohort study in adults (18 years+) (1997-2015) with at least one recorded lymphocyte count. We matched people with AE to up to five people without. We used multivariable logistic regression to estimate the association between AE and lymphopenia (two low lymphocyte counts within 3 months) and linear mixed effects regression to estimate the association with absolute lymphocyte counts using all available counts. Cox proportional hazard models were used to investigate the effect of lymphopenia on common infections. We replicated the study using US survey data (National Health and Nutrition Examination Survey [NHANES]). RESULTS: Among 71,731 adults with AE and 126,349 adults without AE, we found an adjusted odds ratio (OR) for lymphopenia of 1.16 (95% CI: 1.09-1.23); the strength of association increased with increasing eczema severity. When comparing all recorded lymphocyte counts from adults with AE (n = 1,497,306) to those of people without AE (n = 4,035,870) we saw a lower mean lymphocyte (adjusted mean difference -0.047 × 109 /L [95% CI: -0.051 to -0.043]) in those with AE. The difference was larger for men, with increasing age, and with increasing AE severity and was present among people with AE not treated with immunosuppressive drugs. In NHANES (n = 22,624), the adjusted OR for lymphopenia in adults with AE was 1.30 (95% CI: 0.80-2.11), and the adjusted mean lymphocyte count difference was -0.03 × 109 /L (95% CI: -0.07 to 0.02). Despite having a lower lymphocyte count, adjusting for time with lymphopenia, did not alter risk estimates of infections. CONCLUSION: Atopic eczema, including increasing AE severity, is associated with a decreased lymphocyte count, regardless of immunosuppressive drug use. Whether the lower lymphocyte count has wider health implications for people with severe eczema warrants further investigation.

Atopic eczema in adulthood and mortality: UK population-based cohort study, 1998-2016.

BACKGROUND: Atopic eczema affects up to 10% of adults and is becoming more common globally. Few studies have assessed whether atopic eczema increases the risk of death. OBJECTIVE: We aimed to determine whether adults with atopic eczema were at increased risk of death overall and by specific causes and to assess whether the risk varied by atopic eczema severity and activity. METHODS: The study was a population-based matched cohort study using UK primary care electronic health care records from the Clinical Practice Research Datalink with linked hospitalization data from Hospital Episode Statistics and mortality data from the Office for National Statistics from 1998 to 2016. RESULTS: A total of 526,736 patients with atopic eczema were matched to 2,567,872 individuals without atopic eczema. The median age at entry was 41.8 years, and the median follow-up time was 4.5 years. There was limited evidence of increased hazard for all-cause mortality in those with atopic eczema (hazard ratio = 1.04; 99% CI = 1.03-1.06), but there were somewhat stronger associations (8%-14% increased hazard) for deaths due to infectious, digestive, and genitourinary causes. Differences on the absolute scale were modest owing to low overall mortality rates. Mortality risk increased markedly with eczema severity and activity. For example, patients with severe atopic eczema had a 62% increased hazard (hazard ratio = 1.62; 99% CI = 1.54-1.71) for mortality compared with those without eczema, with the strongest associations for infectious, respiratory, and genitourinary causes. CONCLUSION: The increased hazards for all-cause and cause-specific mortality were largely restricted to those with the most severe or predominantly active atopic eczema. Understanding the reasons for these increased hazards for mortality is an urgent priority.

The effect of initiation of renin-angiotensin system inhibitors on haemoglobin: A national cohort study.

AIMS: To determine whether initiation of treatment with angiotensin converting enzyme inhibitors or angiotensin II receptor blockers (ACEI/ARBs) is associated with a subsequent reduction in haemoglobin in the general population. METHODS: We undertook a national cohort study over a 13-year period (2004-2016), using routine primary healthcare data from the UK Clinical Practice Research Datalink. We compared ACEI/ARB initiation with calcium channel blocker (CCB) initiation, to minimise confounding by indication. We included all first ACEI/ARB or CCB prescriptions in adults with at least 1 haemoglobin result in the 12 months before and 6 months after drug initiation. Our primary outcome was a ≥1 g/dL haemoglobin reduction in the 6 months after drug initiation. RESULTS: We examined 146 610 drug initiation events in 136 655 patients. Haemoglobin fell by ≥1 g/dL after drug initiation in 19.5% (16 936/86 652) of ACEI/ARB initiators and 15.9% (9521/59 958) of CCB initiators. The adjusted odds ratio of a ≥1 g/dL haemoglobin reduction in ACEI/ARB initiators vs CCB initiators was 1.15 (95% confidence interval 1.12-1.19). CONCLUSION: ACEI/ARBs are associated with a modest increase in the risk of a haemoglobin reduction. For every 100 patients in our study that initiated a CCB, 16 experienced a ≥1 g/dL haemoglobin decline. If the effect is causal, 3 additional patients would have experienced this outcome if they had received an ACEI/ARB. This may have implications for drug choice and monitoring for many patients in primary care. Further research could identify patients at higher risk of this outcome, who may benefit from closer monitoring.

Proton pump inhibitors and risk of all-cause and cause-specific mortality: A cohort study.

AIM: To investigate the association between proton pump inhibitors (PPIs) and both all-cause and cause-specific mortality. METHODS: We conducted a cohort study using the UK Clinical Practice Research Datalink GOLD database. We compared 733 885 new users of PPIs to 124 410 new users of H2 receptor antagonists (H2Ras). In a secondary analysis we compared 689 602 PPI new users to 1 361 245 nonusers of acid suppression therapy matched on age, sex and calendar year. Hazard ratios for all-cause and cause-specific mortality were estimated using propensity score (PS) weighted Cox models. RESULTS: PPI prescription was associated with increased risk of all-cause mortality, with hazard ratios decreasing considerably by increasing adjustment (unadjusted hazard ratio [HR] 1.65, 95% confidence interval [CI] 1.62-1.69; PS-weighted HR 1.38, 95% CI 1.33-1.44; high-dimensional PS-weighted HR 1.31, 95% CI 1.26-1.37). Short-term associations were observed with mortality from causes where a causal short-term association is unexpected (eg, lung cancer mortality: PS-weighted HR at 6 months 1.77, 95% CI 1.39-2.25). Adjusted hazard ratios were substantially higher when compared to nonusers (PS-weighted HR all-cause mortality 1.96, 95% CI 1.94-1.99) rather than H2RA users. CONCLUSIONS: PPI prescription was strongly associated with all-cause and cause-specific mortality. However, the change in hazard ratios (a) by increasing adjustment and (b) between comparator groups indicates that residual confounding is likely to explain the association between poor health outcomes and PPI use, and fully accounting for this using observational data may not be possible.

UK prevalence of underlying conditions which increase the risk of severe COVID-19 disease: a point prevalence study using electronic health records.

BACKGROUND: Characterising the size and distribution of the population at risk of severe COVID-19 is vital for effective policy and planning. Older age, and underlying health conditions, are associated with higher risk of death from COVID-19. This study aimed to describe the population at risk of severe COVID-19 due to underlying health conditions across the United Kingdom. METHODS: We used anonymised electronic health records from the Clinical Practice Research Datalink GOLD to estimate the point prevalence on 5 March 2019 of the at-risk population following national guidance. Prevalence for any risk condition and for each individual condition is given overall and stratified by age and region with binomial exact confidence intervals. We repeated the analysis on 5 March 2014 for full regional representation and to describe prevalence of underlying health conditions in pregnancy. We additionally described the population of cancer survivors, and assessed the value of linked secondary care records for ascertaining COVID-19 at-risk status. RESULTS: On 5 March 2019, 24.4% of the UK population were at risk due to a record of at least one underlying health condition, including 8.3% of school-aged children, 19.6% of working-aged adults, and 66.2% of individuals aged 70 years or more. 7.1% of the population had multimorbidity. The size of the at-risk population was stable over time comparing 2014 to 2019, despite increases in chronic liver disease and diabetes and decreases in chronic kidney disease and current asthma. Separately, 1.6% of the population had a new diagnosis of cancer in the past 5 y. CONCLUSIONS: The population at risk of severe COVID-19 (defined as either aged ≥70 years, or younger with an underlying health condition) comprises 18.5 million individuals in the UK, including a considerable proportion of school-aged and working-aged individuals. Our national estimates broadly support the use of Global Burden of Disease modelled estimates in other countries. We provide age- and region- stratified prevalence for each condition to support effective modelling of public health interventions and planning of vaccine resource allocation. The high prevalence of health conditions among older age groups suggests that age-targeted vaccination strategies may efficiently target individuals at higher risk of severe COVID-19.

Atopic eczema and fracture risk in adults: A population-based cohort study.

BACKGROUND: Limited evidence suggests increased fracture risk in people with atopic eczema. Any link could have substantial effect; atopic eczema is common, and fractures have associated morbidity and mortality. OBJECTIVE: We sought to examine whether atopic eczema is associated with fracture and whether fracture risk varies with eczema severity. METHODS: We performed a matched cohort study set in primary care (Clinical Practice Research Datalink GOLD 1998-2016) and linked hospital admissions data (Hospital Episode Statistics), including adults (≥18 years old) with atopic eczema matched (by age, sex, general practice, and cohort entry date) with up to 5 individuals without eczema. We estimated hazard ratios (HRs) from stratified Cox regression comparing risk of major osteoporotic (hip, pelvis, spine, wrist, and proximal humerus) fractures individually and any fracture in those with and without atopic eczema. RESULTS: We identified 526,808 people with atopic eczema and 2,569,030 people without atopic eczema. Those with eczema had increased risk of hip (HR, 1.10; 99% CI, 1.06-1.14), pelvic (HR, 1.10; 99% CI, 1.02-1.19), spinal (HR, 1.18; 99% CI, 1.10-1.27), and wrist (HR, 1.07; 99% CI, 1.03,-1.11) fractures. We found no evidence of increased proximal humeral (HR, 1.06; 99% CI, 0.97-1.15) fracture risk. Fracture risk increased with increasing eczema severity, with the strongest associations in people with severe eczema (compared with those without) for spinal (HR, 2.09; 99% CI, 1.66-2.65), pelvic (HR, 1.66; 99% CI, 1.26-2.20), and hip (HR, 1.50; 99% CI, 1.30-1.74) fractures. Associations persisted after oral glucocorticoid adjustment. CONCLUSIONS: People with atopic eczema have increased fracture risk, particularly major osteoporotic fractures.

Medium and long-term risks of specific cardiovascular diseases in survivors of 20 adult cancers: a population-based cohort study using multiple linked UK electronic health records databases.

BACKGROUND: The past few decades have seen substantial improvements in cancer survival, but concerns exist about long-term cardiovascular disease risk in survivors. Evidence is scarce on the risks of specific cardiovascular diseases in survivors of a wide range of cancers to inform prevention and management. In this study, we used large-scale electronic health records data from multiple linked UK databases to address these evidence gaps. METHODS: For this population-based cohort study, we used linked primary care, hospital, and cancer registry data from the UK Clinical Practice Research Datalink to identify cohorts of survivors of the 20 most common cancers who were 18 years or older and alive 12 months after diagnosis and controls without history of cancer, matched for age, sex, and general practice. We compared risks for a range of cardiovascular disease outcomes using crude and adjusted Cox models. We fitted interactions to investigate effect modification, and flexible parametric survival models to estimate absolute excess risks over time. FINDINGS: Between Jan 1, 1990, and Dec 31, 2015, 126 120 individuals with a diagnosis of a cancer of interest still being followed up at least 1 year later were identified and matched to 630 144 controls. After exclusions, 108 215 cancer survivors and 523 541 controls were included in the main analyses. Venous thromboembolism risk was elevated in survivors of 18 of 20 site-specific cancers compared with that of controls; adjusted hazard ratios (HRs) ranged from 1·72 (95% CI 1·57-1·89) in patients after prostate cancer to 9·72 (5·50-17·18) after pancreatic cancer. HRs decreased over time, but remained elevated more than 5 years after diagnosis. We observed increased risks of heart failure or cardiomyopathy in patients after ten of 20 cancers, including haematological (adjusted HR 1·94, 1·66-2·25, with non-Hodgkin lymphoma; 1·77, 1·50-2·09, with leukaemia; and 3·29, 2·59-4·18, with multiple myeloma), oesophageal (1·96, 1·46-2·64), lung (1·82, 1·52-2·17) kidney (1·73, 1·38-2·17) and ovarian (1·59, 1·19-2·12). Elevated risks of arrhythmia, pericarditis, coronary artery disease, stroke, and valvular heart disease were also observed for multiple cancers, including haematological malignancies. HRs for heart failure or cardiomyopathy and venous thromboembolism were greater in patients without previous cardiovascular disease and in younger patients. However, absolute excess risks were generally greater with increasing age. Increased risks of these outcomes seemed most pronounced in patients who had received chemotherapy. INTERPRETATION: Survivors of most site-specific cancers had increased medium-term to long-term risk for one or more cardiovascular diseases compared with that for the general population, with substantial variations between cancer sites. FUNDING: Wellcome Trust and Royal Society.

Stopping renin-angiotensin system blockers after acute kidney injury and risk of adverse outcomes: parallel population-based cohort studies in English and Swedish routine care.

BACKGROUND: The safety of restarting angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB) after acute kidney injury (AKI) is unclear. There is concern that previous users do not restart ACEI/ARB despite ongoing indications. We sought to determine the risk of adverse events after an episode of AKI, comparing prior ACEI/ARB users who stop treatment to those who continue. METHODS: We conducted two parallel cohort studies in English and Swedish primary and secondary care, 2006-2016. We used multivariable Cox regression to estimate hazard ratios (HR) for hospital admission with heart failure (primary analysis), AKI, stroke, or death within 2 years after hospital discharge following a first AKI episode. We compared risks of admission between people who stopped ACEI/ARB treatment to those who were prescribed ACEI/ARB within 30 days of AKI discharge. We undertook sensitivity analyses, including propensity score-matched samples, to explore the robustness of our results. RESULTS: In England, we included 7303 people with AKI hospitalisation following recent ACEI/ARB therapy for the primary analysis. Four thousand three (55%) were classified as stopping ACEI/ARB based on no prescription within 30 days of discharge. In Sweden, we included 1790 people, of whom 1235 (69%) stopped treatment. In England, no differences were seen in subsequent risk of heart failure (HR 1.10; 95% confidence intervals (CI) 0.93-1.30), AKI (HR 0.90; 95% CI 0.77-1.05), or stroke (HR 0.99; 95% CI 0.71-1.38), but there was an increased risk of death (HR 1.27; 95% CI 1.15-1.41) in those who stopped ACEI/ARB compared to those who continued. Results were similar in Sweden: no differences were seen in risk of heart failure (HR 0.91; 95% CI 0.73-1.13) or AKI (HR 0.81; 95% CI 0.54-1.21). However, no increased risk of death was seen (HR 0.94; 95% CI 0.78-1.13) and stroke was less common in people who stopped ACEI/ARB (HR 0.56; 95% CI 0.34-0.93). Results were similar across all sensitivity analyses. CONCLUSIONS: Previous ACEI/ARB users who continued treatment after an episode of AKI did not have an increased risk of heart failure or subsequent AKI compared to those who stopped the drugs.

Propensity scores using missingness pattern information: a practical guide.

Electronic health records are a valuable data source for investigating health-related questions, and propensity score analysis has become an increasingly popular approach to address confounding bias in such investigations. However, because electronic health records are typically routinely recorded as part of standard clinical care, there are often missing values, particularly for potential confounders. In our motivating study-using electronic health records to investigate the effect of renin-angiotensin system blockers on the risk of acute kidney injury-two key confounders, ethnicity and chronic kidney disease stage, have 59% and 53% missing data, respectively. The missingness pattern approach (MPA), a variant of the missing indicator approach, has been proposed as a method for handling partially observed confounders in propensity score analysis. In the MPA, propensity scores are estimated separately for each missingness pattern present in the data. Although the assumptions underlying the validity of the MPA are stated in the literature, it can be difficult in practice to assess their plausibility. In this article, we explore the MPA's underlying assumptions by using causal diagrams to assess their plausibility in a range of simple scenarios, drawing general conclusions about situations in which they are likely to be violated. We present a framework providing practical guidance for assessing whether the MPA's assumptions are plausible in a particular setting and thus deciding when the MPA is appropriate. We apply our framework to our motivating study, showing that the MPA's underlying assumptions appear reasonable, and we demonstrate the application of MPA to this study.

Estimating treatment effects with partially observed covariates using outcome regression with missing indicators.

Missing data is a common issue in research using observational studies to investigate the effect of treatments on health outcomes. When missingness occurs only in the covariates, a simple approach is to use missing indicators to handle the partially observed covariates. The missing indicator approach has been criticized for giving biased results in outcome regression. However, recent papers have suggested that the missing indicator approach can provide unbiased results in propensity score analysis under certain assumptions. We consider assumptions under which the missing indicator approach can provide valid inferences, namely, (1) no unmeasured confounding within missingness patterns; either (2a) covariate values of patients with missing data were conditionally independent of treatment or (2b) these values were conditionally independent of outcome; and (3) the outcome model is correctly specified: specifically, the true outcome model does not include interactions between missing indicators and fully observed covariates. We prove that, under the assumptions above, the missing indicator approach with outcome regression can provide unbiased estimates of the average treatment effect. We use a simulation study to investigate the extent of bias in estimates of the treatment effect when the assumptions are violated and we illustrate our findings using data from electronic health records. In conclusion, the missing indicator approach can provide valid inferences for outcome regression, but the plausibility of its assumptions must first be considered carefully.

Mood Disorders and Risk of Herpes Zoster in 2 Population-Based Case-Control Studies in Denmark and the United Kingdom.

We examined the association between mood disorders and risk of herpes zoster in two case-control studies using data from nationwide Danish registries and practices in the UK Clinical Practice Research Datalink. We included incident zoster cases diagnosed in general practice (using systemic antivirals as a proxy in Denmark) or hospital during 1997-2013 in Denmark (n = 190,671) and during 2000-2013 in the United Kingdom (n = 177,361). We risk-set sampled 4 matched population controls per case. Conditional logistic regression analyses adjusting for zoster risk factors showed that the odds ratios for previous mood disorder among cases versus controls were 1.15 (99% confidence interval (CI): 1.12, 1.19; prevalence 7.1% vs. 6.0%) in Denmark and 1.12 (99% CI: 1.11, 1.14; prevalence 31.6% vs. 29.2%) in the United Kingdom. In Denmark, odds ratios were higher for anxiety (1.23; 99% CI: 1.17, 1.30) and severe stress and adjustment disorder (1.24; 99% CI: 1.18, 1.30) than for depression (1.11; 99% CI: 1.07, 1.14). In the United Kingdom, odds ratios for these conditions were similar: 1.12 (99% CI: 1.10, 1.13), 1.12 (99% CI: 1.10, 1.14), and 1.14 (99% CI: 1.10, 1.19) for depression, anxiety, and severe stress and adjustment disorder, respectively. In conclusion, mood disorders were associated with an increased risk of zoster.

Gastrointestinal bleeding risk of selective serotonin reuptake inhibitors by level of kidney function: A population-based cohort study.

AIM: To estimate the risk of gastrointestinal (GI) bleeding associated with serotonin reuptake inhibitors (SSRIs) by level of kidney function. METHODS: We conducted a cohort study using the Clinical Practice Research Datalink linked to Hospital Episode Statistics. We identified patients with chronic kidney disease (CKD; estimated glomerular filtration rate <60 ml min-1  1.73 m-2 for ≥3 months), and a comparison group of patients without it. Patients with CKD were further classified as stage 3a (eGFR 45-59 ml min-1  1.73 m-2 ), 3b (30-44 ml min-1  1.73 m-2 ) and 4/5 (<30 ml min-1  1.73 m-2 ). We excluded prevalent SSRI users at cohort entry. Exposure was time-dependent SSRI prescription and outcome was first hospitalization for GI bleeding. We estimated adjusted rate ratio (aRR) and rate difference (aRD) of GI bleeding comparing periods with and without SSRI prescription at each level of kidney function. RESULTS: The aRRs and aRDs were: (i) no CKD (n = 202 121) aRR: 1.66 (95%CI 1.37-2.01), aRD: 2.0/1000 person-years (5.5 vs. 3.5/1000 person-years in period with and without SSRIs); (ii) CKD stage 3a (n = 153 316) aRR: 1.86 (1.62-2.15), aRD: 4.2/1000 person-years (8.3 vs. 4.1/1000 person-years); (iii) CKD stage 3b (n = 46 482) aRR: 1.61 (1.27-2.04), aRD: 4.8/1000 person-years (9.9 vs. 5.1/1000 person-years); and (iv) CKD stage 4/5 (n = 11 197) aRR: 1.84 (1.14-2.96), aRD: 7.9/1000 person-years (15.3 vs. 7.4/1000 person-years). While there was no evidence of increase in the aRR (P = 0.922), there was strong evidence that the aRD increased as kidney function deteriorated (P = 0.001). CONCLUSIONS: While the relative risk was constant, the excess risk of GI bleeding associated with SSRIs markedly increased among patients with decreased kidney function.

Partner Bereavement and Risk of Herpes Zoster: Results from Two Population-Based Case-Control Studies in Denmark and the United Kingdom.

Background: Psychological stress is commonly thought to increase the risk of herpes zoster by causing immunosuppression. However, epidemiological studies on the topic are sparse and inconsistent. We conducted 2 parallel case-control studies of the association between partner bereavement and risk of zoster using electronic healthcare data covering the entire Danish population and general practices in the UK Clinical Practice Research Datalink. Methods: We included patients with a zoster diagnosis from the primary care or hospital-based setting in 1997-2013 in Denmark (n = 190671) and 2000-2013 in the United Kingdom (n = 150207). We matched up to 4 controls to each case patient by age, sex, and general practice (United Kingdom only) using risk-set sampling. The date of diagnosis was the index date for case patients and their controls. We computed adjusted odds ratios with 99% confidence intervals for previous bereavement among case patients versus controls using conditional logistic regression with results from the 2 settings pooled using random-effects meta-analysis. Results: Overall, the adjusted odds ratios for the association between partner bereavement and zoster were 1.05 (99% confidence interval, 1.03-1.07) in Denmark and 1.01 (.98-1.05) in the United Kingdom. The pooled estimates were 0.72, 0.90, 1.10, 1.08, 1.02, 1.04, and 1.03 for bereavement within 0-7, 8-14, 15-30, 31-90, 91-365, 366-1095, and >1095 days before the index date, respectively. Conclusions: We found no consistent evidence of an increased risk of zoster after partner death. Initial fluctuations in estimates may be explained by delayed healthcare contact due to the loss.