The rising tide of dementia deaths: triangulation of data from three routine data sources using the Clinical Practice Research Datalink.

BACKGROUND: Dementia is currently the leading certified underlying cause of death in England. We assess how dementia recording on Office for National Statistics death certificates (ONS) corresponded to recording in general practice records (GP) and Hospital Episode Statistics (HES). METHODS: Retrospective study of deaths (2001-15) in 153 English General Practices contributing to the Clinical Practice Research Datalink, with linked ONS and HES records. RESULTS: Of 207,068 total deaths from any cause, 19,627 mentioned dementia on the death certificate with 10,253 as underlying cause; steady increases occurred from 2001 to 2015 (any mention 5.3 to 15.4 %, underlying cause 2.7 to 10 %). Including all data sources, recording of any dementia increased from 13.2 to 28.6 %. In 2015, only 53.8 % of people dying with dementia had dementia recorded on their death certificates. Among deaths mentioning dementia on the death certificate, the recording of a prior diagnosis of dementia in GP and HES rose markedly over the same period. In 2001, only 76.3 % had a prior diagnosis in GP and/or HES records; by 2015 this had risen to 95.7 %. However, over the same period the percentage of all deaths with dementia recorded in GP or HES but not mentioned on the death certificate rose from 7.9 to 13.3 %. CONCLUSIONS: Dementia recording in all data sources increased between 2001 and 2015. By 2015 the vast majority of deaths mentioning dementia had supporting evidence in primary and/or secondary care. However, death certificates were still providing an inadequate picture of the number of people dying with dementia.

Mortality and Morbidity Effects of Long-Term Exposure to Low-Level PM2.5, BC, NO2, and O3: An Analysis of European Cohorts in the ELAPSE Project.

INTRODUCTION: Epidemiological cohort studies have consistently found associations between long-term exposure to outdoor air pollution and a range of morbidity and mortality endpoints. Recent evaluations by the World Health Organization and the Global Burden of Disease study have suggested that these associations may be nonlinear and may persist at very low concentrations. Studies conducted in North America in particular have suggested that associations with mortality persisted at concentrations of particulate matter with an aerodynamic diameter of less than 2.5 µm (PM2.5) well below current air quality standards and guidelines. The uncertainty about the shape of the concentration-response function at the low end of the concentration distribution, related to the scarcity of observations in the lowest range, was the basis of the current project. Previous studies have focused on PM2.5, but increasingly associations with nitrogen dioxide (NO2) are being reported, particularly in studies that accounted for the fine spatial scale variation of NO2. Very few studies have evaluated the effects of long-term exposure to low concentrations of ozone (O3). Health effects of black carbon (BC), representing primary combustion particles, have not been studied in most large cohort studies of PM2.5. Cohort studies assessing health effects of particle composition, including elements from nontailpipe traffic emissions (iron, copper, and zinc) and secondary aerosol (sulfur) have been few in number and reported inconsistent results. The overall objective of our study was to investigate the shape of the relationship between long-term exposure to four pollutants (PM2.5, NO2, BC, and O3) and four broad health effect categories using a number of different methods to characterize the concentration-response function (i.e., linear, nonlinear, or threshold). The four health effect categories were (1) natural- and cause-specific mortality including cardiovascular and nonmalignant as well as malignant respiratory and diabetes mortality; and morbidity measured as (2) coronary and cerebrovascular events; (3) lung cancer incidence; and (4) asthma and chronic obstructive pulmonary disease (COPD) incidence. We additionally assessed health effects of PM2.5 composition, specifically the copper, iron, zinc, and sulfur content of PM2,5. METHODS: We focused on analyses of health effects of air pollutants at low concentrations, defined as less than current European Union (EU) Limit Values, U.S. Environmental Protection Agency (U.S. EPA), National Ambient Air Quality Standards (NAAQS), and/or World Health Organization (WHO) Air Quality Guideline values for PM2.5, NO2, and O3. We address the health effects at low air pollution levels by performing new analyses within selected cohorts of the ESCAPE study (European Study of Cohorts for Air Pollution Effects; Beelen et al. 2014a) and within seven very large European administrative cohorts. By combining well-characterized ESCAPE cohorts and large administrative cohorts in one study the strengths and weaknesses of each approach can be addressed. The large administrative cohorts are more representative of national or citywide populations, have higher statistical power, and can efficiently control for area-level confounders, but have fewer possibilities to control for individual-level confounders. The ESCAPE cohorts have detailed information on individual confounders, as well as country-specific information on area-level confounding. The data from the seven included ESCAPE cohorts and one additional non-ESCAPE cohort have been pooled and analyzed centrally. More than 300,000 adults were included in the pooled cohort from existing cohorts in Sweden, Denmark, Germany, the Netherlands, Austria, France, and Italy. Data from the administrative cohorts have been analyzed locally, without transfer to a central database. Privacy regulations prevented transfer of data from administrative cohorts to a central database. More than 28 million adults were included from national administrative cohorts in Belgium, Denmark, England, the Netherlands, Norway, and Switzerland as well as an administrative cohort in Rome, Italy. We developed central exposure assessment using Europewide hybrid land use regression (LUR) models, which incorporated European routine monitoring data for PM2.5, NO2, and O3, and ESCAPE monitoring data for BC and PM2.5 composition, land use, and traffic data supplemented with satellite observations and chemical transport model estimates. For all pollutants, we assessed exposure at a fine spatial scale, 100 × 100 m grids. These models have been applied to individual addresses of all cohorts including the administrative cohorts. In sensitivity analyses, we applied the PM2.5 models developed within the companion HEI-funded Canadian MAPLE study (Brauer et al. 2019) and O3 exposures on a larger spatial scale for comparison with previous studies. Identification of outcomes included linkage with mortality, cancer incidence, hospital discharge registries, and physician-based adjudication of cases. We analyzed natural-cause, cardiovascular, ischemic heart disease, stroke, diabetes, cardiometabolic, respiratory, and COPD mortality. We also analyzed lung cancer incidence, incidence of coronary and cerebrovascular events, and incidence of asthma and COPD (pooled cohort only). We applied the Cox proportional hazard model with increasing control for individual- and area-level covariates to analyze the associations between air pollution and mortality and/or morbidity for both the pooled cohort and the individual administrative cohorts. Age was used as the timescale because of evidence that this results in better adjustment for potential confounding by age. Censoring occurred at the time of the event of interest, death from other causes, emigration, loss to follow-up for other reasons, or at the end of follow-up, whichever came first. A priori we specified three confounder models, following the modeling methods of the ESCAPE study. Model 1 included only age (time axis), sex (as strata), and calendar year of enrollment. Model 2 added individual-level variables that were consistently available in the cohorts contributing to the pooled cohort or all variables available in the administrative cohorts, respectively. Model 3 further added area-level socioeconomic status (SES) variables. A priori model 3 was selected as the main model. All analyses in the pooled cohort were stratified by subcohort. All analyses in the administrative cohorts accounted for clustering of the data in neighborhoods by adjusting the variance of the effect estimates. The main exposure variable we analyzed was derived from the Europewide hybrid models based on 2010 monitoring data. Sensitivity analyses were conducted using earlier time periods, time-varying exposure analyses, local exposure models, and the PM2.5 models from the Canadian MAPLE project. We first specified linear single-pollutant models. Two-pollutant models were specified for all combinations of the four main pollutants. Two-pollutant models for particle composition were analyzed with PM2.5 and NO2 as the second pollutant. We then investigated the shape of the concentration-response function using natural splines with two, three, and four degrees of freedom; penalized splines with the degrees of freedom determined by the algorithm and shape-constrained health impact functions (SCHIF) using confounder model 3. Additionally, we specified linear models in subsets of the concentration range, defined by removing concentrations above a certain value from the analysis, such as for PM2.5 25 µg/m3 (EU limit value), 20, 15, 12 µg/m3 (U.S. EPA National Ambient Air Quality Standard), and 10 µg/m3 (WHO Air Quality Guideline value). Finally, threshold models were evaluated to investigate whether the associations persisted below specific concentration values. For PM2.5, we evaluated 10, 7.5, and 5 µg/m3 as potential thresholds. Performance of threshold models versus the corresponding no-threshold linear model were evaluated using the Akaike information criterion (AIC). RESULTS: In the pooled cohort, virtually all subjects in 2010 had PM2.5 and NO2 annual average exposures below the EU limit values (25 µg/m3 and 40 µg/m3, respectively). More than 50,000 had a residential PM2.5 exposure below the U.S. EPA NAAQS (12 µg/m3). More than 25,000 subjects had a residential PM2.5 exposure below the WHO guideline (10 µg/m3). We found significant positive associations between PM2.5, NO2, and BC and natural-cause, respiratory, cardiovascular, and diabetes mortality. In our main model, the hazard ratios (HRs) (95% [confidence interval] CI) were 1.13 (CI = 1.11, 1.16) for an increase of 5 µg/m3 PM2.5, 1.09 (CI = 1.07, 1.10) for an increase of 10 µg/m3 NO2, and 1.08 (CI = 1.06, 1.10) for an increase of 0.5 × 10-5/m BC for natural-cause mortality. The highest HRs were found for diabetes mortality. Associations with O3 were negative, both in the fine spatial scale of the main ELAPSE model and in large spatial scale exposure models. For PM2.5, NO2, and BC, we generally observed a supralinear association with steeper slopes at low exposures and no evidence of a concentration below which no association was found. Subset analyses further confirmed that these associations remained at low levels: below 10 µg/m3 for PM2.5 and 20 µg/m3 for NO2. HRs were similar to the full cohort HRs for subjects with exposures below the EU limit values for PM2.5 and NO2, the U.S. NAAQS values for PM2.5, and the WHO guidelines for PM2.5 and NO2. The mortality associations were robust to alternative specifications of exposure, including different time periods, PM2.5 from the MAPLE project, and estimates from the local ESCAPE model. Time-varying exposure natural spline analyses confirmed associations at low pollution levels. HRs in two-pollutant models were attenuated but remained elevated and statistically significant for PM2.5 and NO2. In two-pollutant models of PM2.5 and NO2 HRs for natural-cause mortality were 1.08 (CI = 1.05, 1.11) for PM2.5 and 1.05 (CI = 1.03, 1.07) for NO2. Associations with O3 were attenuated but remained negative in two-pollutant models with NO2, BC, and PM2.5. We found significant positive associations between PM2.5, NO2, and BC and incidence of stroke and asthma and COPD hospital admissions. Furthermore, NO2 was significantly related to acute coronary heart disease and PM2.5 was significantly related to lung cancer incidence. We generally observed linear to supralinear associations with no evidence of a threshold, with the exception of the association between NO2 and acute coronary heart disease, which was sublinear. Subset analyses documented that associations remained even with PM2.5 below 20 µg/m3 and possibly 12 µg/m3. Associations remained even when NO2 was below 30 µg/m3 and in some cases 20 µg/m3. In two-pollutant models, NO2 was most consistently associated with acute coronary heart disease, stroke, asthma, and COPD hospital admissions. PM2.5 was not associated with these outcomes in two-pollutant models with NO2. PM2.5 was the only pollutant that was associated with lung cancer incidence in two-pollutant models. Associations with O3 were negative though generally not statistically significant. In the administrative cohorts, virtually all subjects in 2010 had PM2.5 and NO2 annual average exposures below the EU limit values. More than 3.9 million subjects had a residential PM2.5 exposure below the U.S. EPA NAAQS (12 µg/m3) and more than 1.9 million had residential PM2.5 exposures below the WHO guideline (10 µg/m3). We found significant positive associations between PM2.5, NO2, and BC and natural-cause, respiratory, cardiovascular, and lung cancer mortality, with moderate to high heterogeneity between cohorts. We found positive but statistically nonsignificant associations with diabetes mortality. In our main model meta-analysis, the HRs (95% CI) for natural-cause mortality were 1.05 (CI = 1.02, 1.09) for an increase of 5 µg/m3 PM2.5, 1.04 (CI = 1.02, 1.07) for an increase of 10 µg/m3 NO2, and 1.04 (CI = 1.02, 1.06) for an increase of 0.5 × 10-5/m BC, and 0.95 (CI = 0.93, 0.98) for an increase of 10 µg/m3 O3. The shape of the concentration-response functions differed between cohorts, though the associations were generally linear to supralinear, with no indication of a level below which no associations were found. Subset analyses documented that these associations remained at low levels: below 10 µg/m3 for PM2.5 and 20 µg/m3 for NO2. BC and NO2 remained significantly associated with mortality in two-pollutant models with PM2.5 and O3. The PM2.5 HR attenuated to unity in a two-pollutant model with NO2. The negative O3 association was attenuated to unity and became nonsignificant. The mortality associations were robust to alternative specifications of exposure, including time-varying exposure analyses. Time-varying exposure natural spline analyses confirmed associations at low pollution levels. Effect estimates in the youngest participants (<65 years at baseline) were much larger than in the elderly (>65 years at baseline). Effect estimates obtained with the ELAPSE PM2.5 model did not differ from the MAPLE PM2.5 model on average, but in individual cohorts, substantial differences were found. CONCLUSIONS: Long-term exposure to PM2.5, NO2, and BC was positively associated with natural-cause and cause-specific mortality in the pooled cohort and the administrative cohorts. Associations were found well below current limit values and guidelines for PM2.5 and NO2. Associations tended to be supralinear, with steeper slopes at low exposures with no indication of a threshold. Two-pollutant models documented the importance of characterizing the ambient mixture with both NO2 and PM2.5. We mostly found negative associations with O3. In two-pollutant models with NO2, the negative associations with O3 were attenuated to essentially unity in the mortality analysis of the administrative cohorts and the incidence analyses in the pooled cohort. In the mortality analysis of the pooled cohort, significant negative associations with O3 remained in two-pollutant models. Long-term exposure to PM2.5, NO2, and BC was also positively associated with morbidity outcomes in the pooled cohort. For stroke, asthma, and COPD, positive associations were found for PM2.5, NO2, and BC. For acute coronary heart disease, an increased HR was observed for NO2. For lung cancer, an increased HR was found only for PM2.5. Associations mostly showed steeper slopes at low exposures with no indication of a threshold.

Bariatric surgery for patients with type 2 diabetes mellitus requiring insulin: Clinical outcome and cost-effectiveness analyses.

BACKGROUND: Although bariatric surgery is well established as an effective treatment for patients with obesity and type 2 diabetes mellitus (T2DM), there exists reluctance to increase its availability for patients with severe T2DM. The aims of this study were to examine the impact of bariatric surgery on T2DM resolution in patients with obesity and T2DM requiring insulin (T2DM-Ins) using data from a national database and to develop a health economic model to evaluate the cost-effectiveness of surgery in this cohort when compared to best medical treatment (BMT). METHODS AND FINDINGS: Clinical data from the National Bariatric Surgical Registry (NBSR), a comprehensive database of bariatric surgery in the United Kingdom, were extracted to analyse outcomes of patients with obesity and T2DM-Ins who underwent primary bariatric surgery between 2009 and 2017. Outcomes for this group were combined with data sourced from a comprehensive literature review in order to develop a state-transition microsimulation model to evaluate cost-effectiveness of bariatric surgery versus BMT for patients over a 5-year time horizon. The main outcome measure for the clinical study was insulin cessation at 1-year post-surgery: relative risks (RR) summarising predictive factors were determined, unadjusted, and after adjusting for variables including age, initial body mass index (BMI), duration of T2DM, and weight loss. Main outcome measures for the economic evaluation were total costs, total quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER) at willingness-to-pay threshold of GBP£20,000. A total of 2,484 patients were eligible for inclusion, of which 1,847 had 1-year follow-up data (mean age of 51 years, mean initial BMI 47.2 kg/m2, and 64% female). 67% of patients no longer required insulin at 1-year postoperatively: these rates persisted for 4 years. Roux-en-Y gastric bypass (RYGB) was associated with a higher rate of insulin cessation (71.7%) than sleeve gastrectomy (SG; 64.5%; RR 0.92, confidence interval (CI) 0.86-0.99) and adjustable gastric band (AGB; 33.6%; RR 0.45, CI 0.34-0.60; p < 0.001). When adjusted for percentage total weight loss and demographic variables, insulin cessation following surgery was comparable for RYGB and SG (RR 0.97, CI 0.90-1.04), with AGB having the lowest cessation rates (RR 0.55, CI 0.40-0.74; p < 0.001). Over 5 years, bariatric surgery was cost saving compared to BMT (total cost GBP£22,057 versus GBP£26,286 respectively, incremental difference GBP£4,229). This was due to lower treatment costs as well as reduced diabetes-related complications costs and increased health benefits. Limitations of this study include loss to follow-up of patients within the NBSR dataset and that the time horizon for the economic analysis is limited to 5 years. In addition, the study reflects current medical and surgical treatment regimens for this cohort of patients, which may change. CONCLUSIONS: In this study, we observed that in patients with obesity and T2DM-Ins, bariatric surgery was associated with high rates of postoperative cessation of insulin therapy, which is, in turn, a major driver of overall reductions in direct healthcare cost. Our findings suggest that a strategy utilising bariatric surgery for patients with obesity and T2DM-Ins is cost saving to the national healthcare provider (National Health Service (NHS)) over a 5-year time horizon.

Development of a structured clinical pharmacology review for specialist support for management of complex polypharmacy in primary care.

AIMS: Polypharmacy is widespread and associated with medication-related harms, including adverse drug reactions, medication errors and poor treatment adherence. General practitioners and pharmacists cite limited time and training to perform effective medication reviews for patients with complex polypharmacy, yet no specialist referral mechanism exists. To develop a structured framework for specialist review of primary care patients with complex polypharmacy. METHODS: We developed the clinical pharmacology structured review (CPSR) and stopping by indication tool (SBIT). We tested these in an age-sex stratified sample of 100 people with polypharmacy aged 65-84 years from the Clinical Practice Research Datalink, an anonymised primary care database. Simulated medication reviews based on electronic records using the CPSR and SBIT were performed. We recommended medication changes or review to optimise treatment benefits, reduce risk of harm or reduce treatment burden. RESULTS: Recommendations were made for all patients, for almost half (4.8 ± 2.4) of existing medicines (9.8 ± 3.1), most commonly stopping a drug (1.7 ± 1.3/patient) or reviewing with the patient (1.4 ± 1.2/patient). At least 1 new medicine (0.7 ± 0.9) was recommended for 51% patients. Recommendations predominantly aimed to reduce harm (44%). There was no relationship between number of recommendations made and time since last primary care medication review. We identified a core set of clinical information and investigations (polypharmacy workup) that could inform a standard screen prior to specialist review. CONCLUSION: The CPSR, SBIT and polypharmacy workup could form the basis of a specialist review for patients with complex polypharmacy. Further research is needed to test this approach in patients in general practice.

Effect of pedometer-based walking interventions on long-term health outcomes: Prospective 4-year follow-up of two randomised controlled trials using routine primary care data.

BACKGROUND: Data are lacking from physical activity (PA) trials with long-term follow-up of both objectively measured PA levels and robust health outcomes. Two primary care 12-week pedometer-based walking interventions in adults and older adults (PACE-UP and PACE-Lift) found sustained objectively measured PA increases at 3 and 4 years, respectively. We aimed to evaluate trial intervention effects on long-term health outcomes relevant to walking interventions, using routine primary care data. METHODS AND FINDINGS: Randomisation was from October 2012 to November 2013 for PACE-UP participants from seven general (family) practices and October 2011 to October 2012 for PACE-Lift participants from three practices. We downloaded primary care data, masked to intervention or control status, for 1,001 PACE-UP participants aged 45-75 years, 36% (361) male, and 296 PACE-Lift participants, aged 60-75 years, 46% (138) male, who gave written informed consent, for 4-year periods following randomisation. The following new events were counted for all participants, including those with preexisting diseases (apart from diabetes, for which existing cases were excluded): nonfatal cardiovascular, total cardiovascular (including fatal), incident diabetes, depression, fractures, and falls. Intervention effects on time to first event post-randomisation were modelled using Cox regression for all outcomes, except for falls, which used negative binomial regression to allow for multiple events, adjusting for age, sex, and study. Absolute risk reductions (ARRs) and numbers needed to treat (NNTs) were estimated. Data were downloaded for 1,297 (98%) of 1,321 trial participants. Event rates were low (<20 per group) for outcomes, apart from fractures and falls. Cox hazard ratios for time to first event post-randomisation for interventions versus controls were nonfatal cardiovascular 0.24 (95% confidence interval [CI] 0.07-0.77, p = 0.02), total cardiovascular 0.34 (95% CI 0.12-0.91, p = 0.03), diabetes 0.75 (95% CI 0.42-1.36, p = 0.34), depression 0.98 (95% CI 0.46-2.07, p = 0.96), and fractures 0.56 (95% CI 0.35-0.90, p = 0.02). Negative binomial incident rate ratio for falls was 1.07 (95% CI 0.78-1.46, p = 0.67). ARR and NNT for cardiovascular events were nonfatal 1.7% (95% CI 0.5%-2.1%), NNT = 59 (95% CI 48-194); total 1.6% (95% CI 0.2%-2.2%), NNT = 61 (95% CI 46-472); and for fractures 3.6% (95% CI 0.8%-5.4%), NNT = 28 (95% CI 19-125). Main limitations were that event rates were low and only events recorded in primary care records were counted; however, any underrecording would not have differed by intervention status and so should not have led to bias. CONCLUSIONS: Routine primary care data used to assess long-term trial outcomes demonstrated significantly fewer new cardiovascular events and fractures in intervention participants at 4 years. No statistically significant differences between intervention and control groups were demonstrated for other events. Short-term primary care pedometer-based walking interventions can produce long-term health benefits and should be more widely used to help address the public health inactivity challenge. TRIAL REGISTRATIONS: PACE-UP isrctn.com ISRCTN98538934; PACE-Lift isrctn.com ISRCTN42122561.

Longitudinal exposure of English primary care patients to pharmacogenomic drugs: An analysis to inform design of pre-emptive pharmacogenomic testing.

AIMS: To investigate the longitudinal exposure of English primary care patients to pharmacogenomic drugs to inform design of pre-emptive testing. METHODS: Sixty-three drugs were identified with dosing guidelines based on variants of 19 pharmacogenes in the Pharmacogenomics Knowledgebase on 01 September 2018. Prescribing of these pharmacogenomic drugs between 1993 and 2017 was summarised for a sample of 648 141 English patients aged 50-99 years on 01 January 2013, registered with Clinical Practice Research Datalink practices during 2011-12. Exposure of patients to pharmacogenomic drugs retrospectively (2, 10, 20 y) and prospectively (5 y) was described. RESULTS: During 2011-12, 58% of patients were prescribed at least 1 pharmacogenomic drug, increasing to 80% over the previous 20 years. Multiple exposure was common, with 47% patients prescribed ≥2 pharmacogenomic drugs and 7% prescribed ≥5 pharmacogenomic drugs over the next 5 years. The likelihood of exposure to pharmacogenomic drugs increased with age, with 89% patients ≥70 years prescribed at least 1 pharmacogenomic drug over the previous 20 years. Even among those aged 50-59 years, 71% were prescribed at least 1 pharmacogenomic drug over the previous 20 years. The pharmacogenomic drugs prescribed to the most patients were for pain relief, gastroprotection, psychiatric and cardiovascular conditions. Three pharmacogenes (CYP2D6, CYP2C19 and SLCO1B1) accounted for >95% pharmacogenomic drugs prescribed. CONCLUSIONS: In primary care patients, exposure to pharmacogenomic drugs is extremely common, multiplicitous and has commenced by relatively early adulthood. A small number of pharmacogenes account for the majority of drugs prescribed. These findings could inform design of pre-emptive pharmacogenomic testing for implementation in primary care.

'I'm sure we made it a better study ': Experiences of adults with intellectual disabilities and parent carers of patient and public involvement in a health research study.

Patient and public involvement is considered integral to health research in the United Kingdom; however, studies documenting the involvement of adults with intellectual disabilities and parent carers in health research studies are scarce. Through group interviews, this study explored the perspectives and experiences of a group of adults with intellectual disabilities and a group of parent carers about their collaborative/participatory involvement in a 3-year study which explored the effectiveness of annual health checks for adults with intellectual disabilities. Thematic analysis identified five key themes consistent across both groups; authenticity of participation, working together, generating new outcome measures, dissemination of findings and involvement in future research. Although reported anecdotally rather than originating from the analysis, increased self-confidence is also discussed. The groups' unique perspectives led to insights not previously considered by the research team which led to important recommendations to inform healthcare practice.

Interpreting population reach of a large, successful physical activity trial delivered through primary care.

BACKGROUND: Failure to include socio-economically deprived or ethnic minority groups in physical activity (PA) trials may limit representativeness and could lead to implementation of interventions that then increase health inequalities. Randomised intervention trials often have low recruitment rates and rarely assess recruitment bias. A previous trial by the same team using similar methods recruited 30% of the eligible population but was in an affluent setting with few non-white residents and was limited to those over 60 years of age. METHODS: PACE-UP is a large, effective, population-based walking trial in inactive 45-75 year-olds that recruited through seven London general practices. Anonymised practice demographic data were available for all those invited, enabling investigation of inequalities in trial recruitment. Non-participants were invited to complete a questionnaire. RESULTS: From 10,927 postal invitations, 1150 (10.5%) completed baseline assessment. Participation rate ratios (95% CI), adjusted for age and gender as appropriate, were lower in men 0.59 (0.52, 0.67) than women, in those under 55 compared with those ≥65, 0.60 (0.51, 0.71), in the most deprived quintile compared with the least deprived 0.52 (0.39, 0.70) and in Asian individuals compared with whites 0.62 (0.50, 0.76). Black individuals were equally likely to participate as white individuals. Participation was also associated with having a co-morbidity or some degree of health limitation. The most common reasons for non-participation were considering themselves as being too active or lack of time. CONCLUSIONS: Conducting the trial in this diverse setting reduced overall response, with lower response in socio-economically deprived and Asian sub-groups. Trials with greater reach are likely to be more expensive in terms of recruitment and gains in generalizability need to be balanced with greater costs. Differential uptake of successful trial interventions may increase inequalities in PA levels and should be monitored. TRIAL REGISTRATION: ISRCTN.com ISRCTN98538934 . Registered 2nd March 2012.

Preventable Emergency Hospital Admissions Among Adults With Intellectual Disability in England.

PURPOSE: Adults with intellectual disabilities experience poorer physical health and health care quality, but there is limited information on the potential for reducing emergency hospital admissions in this population. We describe overall and preventable emergency admissions for adults with vs without intellectual disabilities in England and assess differences in primary care management before admission for 2 common ambulatory care-sensitive conditions (ACSCs). METHODS: We used electronic records to study a cohort of 16,666 adults with intellectual disabilities and 113,562 age-, sex-, and practice-matched adults without intellectual disabilities from 343 English family practices. Incident rate ratios (IRRs) from conditional Poisson regression were analyzed for all emergency and preventable emergency admissions. Primary care management of lower respiratory tract infections and urinary tract infections, as exemplar ACSCs, before admission were compared in unmatched analysis between adults with and without intellectual disabilities. RESULTS: The overall rate for emergency admissions for adults with vs without intellectual disabilities was 182 vs 68 per 1,000 per year (IRR = 2.82; 95% CI, 2.66-2.98). ACSCs accounted for 33.7% of emergency admissions among the former compared with 17.3% among the latter (IRR = 5.62; 95% CI, 5.14-6.13); adjusting for comorbidity, smoking, and deprivation did not fully explain the difference (IRR = 3.60; 95% CI, 3.25-3.99). Although adults with intellectual disability were at nearly 5 times higher risk for admission for lower respiratory tract infections and urinary tract infections, they had similar primary care use, investigation, and management before admission as the general population. CONCLUSIONS: Adults with intellectual disabilities are at high risk for preventable emergency admissions. Identifying strategies for better detecting and managing ACSCs, including lower respiratory and urinary tract infections, in primary care could reduce hospitalizations.

Mortality Among Adults With Intellectual Disability in England: Comparisons With the General Population.

OBJECTIVES: To describe mortality among adults with intellectual disability in England in comparison with the general population. METHODS: We conducted a cohort study from 2009 to 2013 using data from 343 general practices. Adults with intellectual disability (n = 16 666; 656 deaths) were compared with age-, gender-, and practice-matched controls (n = 113 562; 1358 deaths). RESULTS: Adults with intellectual disability had higher mortality rates than controls (hazard ratio [HR] = 3.6; 95% confidence interval [CI] = 3.3, 3.9). This risk remained high after adjustment for comorbidity, smoking, and deprivation (HR = 3.1; 95% CI = 2.7, 3.4); it was even higher among adults with intellectual disability and Down syndrome or epilepsy. A total of 37.0% of all deaths among adults with intellectual disability were classified as being amenable to health care intervention, compared with 22.5% in the general population (HR = 5.9; 95% CI = 5.1, 6.8). CONCLUSIONS: Mortality among adults with intellectual disability is markedly elevated in comparison with the general population, with more than a third of deaths potentially amenable to health care interventions. This mortality disparity suggests the need to improve access to, and quality of, health care among people with intellectual disability.

The mental health and mortality impact of death of a partner with dementia.

OBJECTIVE: Caring for a partner with dementia and partner bereavement are independently associated with poor health. An understanding of the health effects of living with a partner dying with dementia can help optimise support. We describe health in the year before and after loss of a partner with dementia compared with other bereavements. METHODS: In a UK primary care database, 2624 older individuals whose partner died with dementia during 2005-2012 were matched with 7512 individuals experiencing bereavement where the deceased partner had no dementia recorded. RESULTS: Prior to bereavement, partners of the deceased with dementia were more likely to be diagnosed with depression (OR 2.31, 1.69-3.14) and receive psychotropic medication (OR 1.34, 1.21-1.49) than partners from bereavements without dementia. In contrast, psychotropic medication initiation two months after dementia bereavement was lower (HR 0.69, 0.56-0.85). Compared with other bereaved individuals, mortality after bereavement was lower in men experiencing a dementia bereavement (HR 0.68, 0.49-0.94) but similar in women (HR 1.02, 0.75-1.38). Prior to bereavement, those who died with dementia were less likely to receive palliative care (OR 0.47, 0.41-0.54). CONCLUSION: In the year before bereavement, partners of individuals dying with dementia experience poorer mental health than those facing bereavement from other causes, and their partner is less likely to receive palliative care. In the year after, individuals whose partner died with dementia experience some attenuation of the adverse health effects of bereavement. Services need to address the needs of carers for individuals dying with dementia and improve access to palliative care. Copyright © 2016 John Wiley & Sons, Ltd.

Impact of partner bereavement on quality of cardiovascular disease management.

BACKGROUND: Bereavement is a period of increased risk of cardiovascular death. There is limited understanding of the potential contribution of quality of cardiovascular disease management to this increased risk. METHODS AND RESULTS: In a UK primary-care database, 12 722 older individuals with preexisting cardiovascular disease (coronary heart disease, hypertension, diabetes mellitus, stroke) and a partner bereavement were matched with a non-bereaved control group (n=33 911). We examined key routine annual process measures of care in the year before and after bereavement and cardiovascular medication prescribing (lipid-lowering, antiplatelet, renin-angiotensin system drugs). Odds ratios for change after bereavement compared with the change in non-bereaved matched controls are presented. In the bereaved, uptake of all annual measures was lower in the year before bereavement, with improvement in the year after, whereas in the controls, uptake was relatively stable. The odds ratio for change was 1.30 (95% confidence interval, 1.15-1.46) for cholesterol measurement and 1.40 (95% confidence interval, 1.22-1.61) for blood pressure measurement. For all medication, there was a transient fall in prescribing in the peri-bereavement period lasting until about 3 months after bereavement. The odds ratio for at least 80% prescription coverage in the 30 days after bereavement was 0.80 (95% confidence interval, 0.73-0.88) for lipid-lowering medication and 0.82 (95% confidence interval, 0.74-0.91) for antiplatelet medication compared with the change in non-bereaved individuals. CONCLUSIONS: Lower uptake of key cardiovascular care measures in the year before bereavement and reduced medication coverage after bereavement may contribute to increased cardiovascular risk. Clinicians need to ensure that quality of cardiovascular care is maintained in the pre- and post-bereavement periods.

Mortality associations with long-term exposure to outdoor air pollution in a national English cohort.

RATIONALE: Cohort evidence linking long-term exposure to outdoor particulate air pollution and mortality has come largely from the United States. There is relatively little evidence from nationally representative cohorts in other countries. OBJECTIVES: To investigate the relationship between long-term exposure to a range of pollutants and causes of death in a national English cohort. METHODS: A total of 835,607 patients aged 40-89 years registered with 205 general practices were followed from 2003-2007. Annual average concentrations in 2002 for particulate matter with a median aerodynamic diameter less than 10 (PM(10)) and less than 2.5 µm (PM(2.5)), nitrogen dioxide (NO(2)), ozone, and sulfur dioxide (SO(2)) at 1 km(2) resolution, estimated from emission-based models, were linked to residential postcode. Deaths (n = 83,103) were ascertained from linkage to death certificates, and hazard ratios (HRs) for all- and cause-specific mortality for pollutants were estimated for interquartile pollutant changes from Cox models adjusting for age, sex, smoking, body mass index, and area-level socioeconomic status markers. MEASUREMENTS AND MAIN RESULTS: Residential concentrations of all pollutants except ozone were positively associated with all-cause mortality (HR, 1.02, 1.03, and 1.04 for PM(2.5), NO(2), and SO(2), respectively). Associations for PM(2.5), NO(2), and SO(2) were larger for respiratory deaths (HR, 1.09 each) and lung cancer (HR, 1.02, 1.06, and 1.05) but nearer unity for cardiovascular deaths (1.00, 1.00, and 1.04). CONCLUSIONS: These results strengthen the evidence linking long-term ambient air pollution exposure to increased all-cause mortality. However, the stronger associations with respiratory mortality are not consistent with most US studies in which associations with cardiovascular causes of death tend to predominate.

A matched cohort study evaluating the risks of infections in people with type 1 diabetes and their associations with glycated haemoglobin.

AIMS: People with type 1 diabetes (T1D) have raised infection rates compared to those without, but how these risks vary by age, sex and ethnicity, or by glycated haemoglobin (HbA1c), remain uncertain. METHODS: 33,829 patients with T1D in Clinical Practice Research Datalink on 01/01/2015 were age-sex-ethnicity matched to two non-diabetes patients. Infections were collated from primary care and linked hospitalisation records during 2015-2019, and incidence rate ratios (IRRs) were estimated versus non-diabetes. For 26,096 people with T1D, with ≥3 HbA1c measurements in 2012-2014, mean and coefficient of variation were estimated, and compared across percentiles. RESULTS: People with T1D had increased risk for infections presenting in primary care (IRR = 1.81, 95%CI 1.77-1.85) and hospitalisations (IRR = 3.37, 3.21-3.53) compared to non-diabetes, slightly attenuated after further adjustment. Younger ages and non-White ethnicities had greater relative risks, potentially explained by higher HbA1c mean and variability amongst people with T1D within these sub-groups. Both mean HbA1c and greater variability were strongly associated with infection risks, but the greatest associations were at the highest mean levels (hospitalisations IRR = 4.09, 3.64-4.59) for >97 versus ≤53 mmol/mol. CONCLUSIONS: Infections are a significant health burden in T1D. Improved glycaemic control may reduce infection risks, while prompter infection treatments may reduce hospital admissions.

Effects of long-term HbA1c variability on serious infection risks in patients with type 2 diabetes and the influence of age, sex and ethnicity: A cohort study of primary care data.

AIMS: Long-term HbA1c (glycated haemoglobin) variability is associated with micro- and macrovascular complications in Type 2 diabetes (T2D). We explored prospective associations between HbA1c variability and serious infections, and how these vary by HbA1c level, age, sex and ethnicity. METHODS: 411,963 T2D patients in England, aged 18-90, alive on 01/01/2015 in the Clinical Practice Research Datalink with ≥ 4 HbA1c measurements during 2011-14. Poisson regression estimated incidence rate ratios (IRRs) for infections requiring hospitalisation during 2015-19 by HbA1c variability score (HVS) and average level, adjusting for confounders, and stratified by age, sex, ethnicity and average level. Attributable risk fractions (AF) were calculated using reference categories for variability (HVS < 20) and average level (42-48 mmol/mol). RESULTS: An increased infection risk (IRR > 1.2) was seen with even modest variability (HVS ≥ 20, 73 % of T2D patients), but only at higher average levels (≥64 mmol/mol, 27 % patients). Estimated AFs were markedly greater for variability than average level (17.1 % vs. 4.1 %). Associations with variability were greater among older patients, and those with lower HbA1c levels, but not observed among Black ethnicities. CONCLUSIONS: HbA1c variability between T2D patients' primary care visits appears to be associated with more serious infections than average level overall. Well-designed trials could test whether these associations are causal.

Long-term exposure to outdoor air pollution and incidence of cardiovascular diseases.

BACKGROUND: Evidence based largely on US cohorts suggests that long-term exposure to fine particulate matter is associated with cardiovascular mortality. There is less evidence for other pollutants and for cardiovascular morbidity. By using a cohort of 836,557 patients age 40 to 89 years registered with 205 English general practices in 2003, we investigated relationships between ambient outdoor air pollution and incident myocardial infarction, stroke, arrhythmia, and heart failure over a 5-year period. METHODS: Events were identified from primary care records, hospital admissions, and death certificates. Annual average concentrations in 2002 for particulate matter with a median aerodynamic diameter <10 (PM10) and <2.5 microns, nitrogen dioxide (NO2), ozone, and sulfur dioxide at a 1 × 1 km resolution were derived from emission-based models and linked to residential postcode. Analyses were performed using Cox proportional hazards models adjusting for relevant confounders, including social and economic deprivation and smoking. RESULTS: While evidence was weak for relationships with myocardial infarction, stroke, or arrhythmia, we found consistent associations between pollutant concentrations and incident cases of heart failure. An interquartile range change in PM10 and in NO2 (3.0 and 10.7 µg/m, respectively) both produced a hazard ratio of 1.06 (95% confidence interval = 1.01-1.11) after adjustment for confounders. There was some evidence that these effects were greater in more affluent areas. CONCLUSIONS: This study of an English national cohort found evidence linking long-term exposure to particulate matter and NO2 with the development of heart failure. We did not, however, replicate associations for other cardiovascular outcomes that have been reported elsewhere.

The effect of unexpected bereavement on mortality in older couples.

OBJECTIVES: We sought to determine whether unexpected bereavement has a greater impact on mortality in the surviving partner than death of a partner with preexisting chronic disease or disability. METHODS: In a UK primary care database (The Health Improvement Network), we identified 171,720 couples aged 60 years and older. We compared the rise in mortality in the first year after bereavement in those whose partner died without recorded chronic disease (unexpected bereavement) to those whose deceased partner had a diagnosis of chronic disease (known morbidity). RESULTS: For unexpected bereavement (13.4% of all bereavements), the adjusted hazard ratio for death in the first year after bereavement was 1.61 (95% confidence interval [CI] = 1.39, 1.86) compared with 1.21 (95% CI = 1.14, 1.30) where the partner had known morbidity. Differences between bereaved groups were significant (P = .001) and present for both men and women. CONCLUSIONS: Unexpected bereavement has a greater relative mortality impact than bereavement preceded by chronic disease. Our findings highlight the potential value of preparing individuals for the death of a spouse with known morbidity and providing extra support after bereavement for those experiencing sudden unexpected bereavement.

Mortality in older care home residents in England and Wales.

BACKGROUND: mortality in UK care homes is not well described. OBJECTIVE: to describe 1-year mortality and predictors in older care home residents compared with community residents. METHOD: cohort study using the THIN primary care database with 9,772 care home and 354,306 community residents aged 65-104 years in 293 English and Welsh general practices in 2009. RESULTS: a total of 2,558 (26.2%) care home and 11,602 (3.3%) community residents died within 1 year. The age and sex standardised mortality ratio for nursing homes was 419 (95% CI: 396-442) and for residential homes was 284 (266-302). Age-related increases in mortality were less marked in care homes than community. Comorbidities and identification as inappropriate for chronic disease management targets predicted mortality in both settings, but associations were weaker in care homes. The number of drug classes prescribed and primary care contact were the strongest clinical predictors of mortality in care homes. CONCLUSIONS: older care home residents experience high mortality. Age and diagnostic characteristics are weaker predictors of risk of death within care homes than the community. Measures of primary care utilisation may be useful proxies for frailty and improve difficult end of life care decisions in care homes.

Prevalence of co-morbidity and history of recent infection in patients with neuromuscular disease: A cross-sectional analysis of United Kingdom primary care data.

BACKGROUND: People with neuromuscular disease (NMD) experience a broader range of chronic diseases and health symptoms compared to the general population. However, no comprehensive analysis has directly quantified this to our knowledge. METHODS: We used a large UK primary care database (Clinical Practice Research Datalink) to compare the prevalence of chronic diseases and other health conditions, including recent infections between 23,876 patients with NMD ever recorded by 2019 compared to 95,295 age-sex-practice matched patients without NMD. Modified Poisson regression estimated Prevalence Ratios (PR) to summarise the presence of the disease/condition ever (or for infections in 2018) in NMD patients versus non-NMD patients. RESULTS: Patients with NMD had significantly higher rates for 16 of the 18 conditions routinely recorded in the primary care Quality and Outcomes Framework (QOF). Approximately 1-in-10 adults with NMD had ≥4 conditions recorded (PR = 1.39, 95%CI 1.33-1.45). Disparities were more pronounced at younger ages (18-49). For other (non-QOF) health conditions, significantly higher recorded levels were observed for rarer events (pulmonary embolism PR = 1.96 95%CI 1.76-2.18, hip fractures PR = 1.65 95%CI 1.47-1.85) as well as for more common primary care conditions (constipation PR = 1.52 95%CI 1.46-1.57, incontinence PR = 1.52 95%CI 1.44-1.60). The greatest co-morbidity burden was in patients with a myotonic disorder. Approximately 1-in-6 (17.1%) NMD patients had an infection recorded in the preceding year, with the risk of being hospitalised with an infection nearly double (PR = 1.92, 95%CI 1.79-2.07) compared to non-NMD patients. CONCLUSION: The burden of chronic co-morbidity among patients with NMD is extremely high compared to the general population, and they are also more likely to present in primary and secondary care for acute events such as infections.

Evaluating Ethnic Variations in the Risk of Infections in People With Prediabetes and Type 2 Diabetes: A Matched Cohort Study.

OBJECTIVE: People living with type 2 diabetes (T2D) are at higher infection risk, but it is unknown how this risk varies by ethnicity or whether the risk is similarly observed in people with nondiabetic hyperglycemia ("prediabetes"). RESEARCH DESIGN AND METHODS: We included 527,151 patients in England with T2D and 273,216 with prediabetes, aged 18-90, and alive on 1 January 2015 on the Clinical Practice Research Datalink. Each was matched to two patients without diabetes or prediabetes on age, sex, and ethnic group. Infections during 2015-2019 were collated from primary care and linked hospitalization records. Infection incidence rate ratios (IRRs) for those with prediabetes or T2D were estimated, unadjusted and adjusted for confounders. RESULTS: People with T2D had increased risk for infections presenting in primary care (IRR 1.51, 95% CI 1.51-1.52) and hospitalizations (IRR 1.91, 1.90-1.93). This was broadly consistent overall within each ethnic group, although younger White T2D patients (age <50) experienced a greater relative risk. Adjustment for socioeconomic deprivation, smoking, and comorbidity attenuated associations, but IRRs remained similar by ethnicity. For prediabetes, a significant but smaller risk was observed (primary care IRR 1.35, 95% CI 1.34-1.36; hospitalization IRR 1.33, 1.31-1.35). These were similar within each ethnicity for primary care infections, but less consistent for infection-related hospitalizations. CONCLUSIONS: The elevated infection risk for people with T2D appears similar for different ethnic groups and is also seen in people with prediabetes. Infections are a substantial cause of ill-health and health service use for people with prediabetes and T2D. This has public health implications with rising prediabetes and diabetes prevalence.