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BackgroundThe UK-wide National Review of Asthma Deaths sought to identify avoidable factors from the high numbers of deaths, but did not examine variation by socioeconomic status (SES) or region.MethodsWe used asthma deaths in England over the period 2002–2015 obtained from national deaths registers, summarised by quintiles of Index of Multiple Deprivation (IMD) and Government Office Region. Emergency asthma admissions were obtained from Hospital Episode Statistics for England 2001–2011. The prevalence of asthma was derived from the Health Survey for England 2010. Associations of mortality, admissions and prevalence with IMD quintile and region were estimated cross-sectionally using incidence rate ratios (IRRs) adjusted for age and sex and, where possible, smoking.ResultsAsthma mortality decreased among more deprived groups at younger ages. Among 5–44 year olds, those in the most deprived quintile, mortality was 19% lower than those in the least deprived quintile (IRR 0.81 (95% CI 0.69 to 0.96). In older adults, this pattern was reversed (45–74 years: IRR 1.37 (1.24–1.52), ≥75 years: IRR 1.30 (1.22–1.39)). In 5–44 year olds the inverse trend with asthma mortality contrasted with large positive associations for admissions (IRR 3.34 (3.30–3.38)) and prevalence of severe symptoms (IRR 2.38 (1.70–3.33)). Prevalence trends remained after adjustment for smoking. IRRs for asthma mortality, admissions and prevalence showed significant heterogeneity between English regions.ConclusionsDespite asthma mortality, emergency admissions and prevalence decreasing over recent decades, England still experiences significant SES and regional variations. The previously undocumented inverse relation between deprivation and mortality in the young requires further investigation.

ObjectiveTo investigate whether the incidence of dementia is related to residential levels of air and noise pollution in London.DesignRetrospective cohort study using primary care data.Setting75 Greater London practices.Participants130 978 adults aged 50–79 years registered with their general practices on 1 January 2005, with no recorded history of dementia or care home residence.Primary and secondary outcome measuresA first recorded diagnosis of dementia and, where specified, subgroups of Alzheimer’s disease and vascular dementia during 2005–2013. The average annual concentrations during 2004 of nitrogen dioxide (NO2), particulate matter with a median aerodynamic diameter ≤2.5 µm (PM2.5) and ozone (O3) were estimated at 20×20 m resolution from dispersion models. Traffic intensity, distance from major road and night-time noise levels (Lnight) were estimated at the postcode level. All exposure measures were linked anonymously to clinical data via residential postcode. HRs from Cox models were adjusted for age, sex, ethnicity, smoking and body mass index, with further adjustments explored for area deprivation and comorbidity.Results2181 subjects (1.7%) received an incident diagnosis of dementia (39% mentioning Alzheimer’s disease, 29% vascular dementia). There was a positive exposure response relationship between dementia and all measures of air pollution except O3, which was not readily explained by further adjustment. Adults living in areas with the highest fifth of NO2 concentration (>41.5 µg/m3) versus the lowest fifth (<31.9 µg/m3) were at a higher risk of dementia (HR=1.40, 95% CI 1.12 to 1.74). Increases in dementia risk were also observed with PM2.5, PM2.5 specifically from primary traffic sources only and Lnight, but only NO2 and PM2.5 remained statistically significant in multipollutant models. Associations were more consistent for Alzheimer’s disease than vascular dementia.ConclusionsWe have found evidence of a positive association between residential levels of air pollution across London and being diagnosed with dementia, which is unexplained by known confounding factors.

The COVID-19 pandemic's first wave in England during spring 2020 resulted in an approximate 50% increase in all-cause mortality. Previously, risk factors such as age and ethnicity, were identified by studying COVID-related deaths only, but these were under-recorded during this period. To use a large electronic primary care database to estimate the impact of risk factors (RFs) on excess mortality in England during the first wave, compared with the impact on total mortality during 2015-19. Medical history, ethnicity, area-based deprivation and vital status data were extracted for an average of 4.8 million patients aged 30-104 years, for each year between 18-March and 19-May over a 6-year period (2015-2020). We used Poisson regression to model total mortality adjusting for age and sex, with interactions between each RF and period (pandemic vs. 2015-19). Total mortality during the pandemic was partitioned into \"usual\" and \"excess\" components, assuming 2015-19 rates represented \"usual\" mortality. The association of each RF with the 2020 \"excess\" component was derived as the excess mortality ratio (EMR), and compared with the usual mortality ratio (UMR). RFs where excess mortality was greatest and notably higher than usual were age >80, non-white ethnicity (e.g., black vs. white EMR = 2.50, 95%CI 1.97-3.18; compared to UMR = 0.92, 95%CI 0.85-1.00), BMI>40, dementia, learning disability, severe mental illness, place of residence (London, care-home, most deprived). By contrast, EMRs were comparable to UMRs for sex. Although some co-morbidities such as cancer produced EMRs significantly below their UMRs, the EMRs were still >1. In contrast current smoking has an EMR below 1 (EMR = 0.80, 95%CI 0.65-0.98) compared to its UMR = 1.64. Studying risk factors for excess mortality during the pandemic highlighted differences from studying cause-specific mortality. Our approach illustrates a novel methodology for evaluating a pandemic's impact by individual risk factor without requiring cause-specific mortality data.

Low circulating vitamin D levels have been associated with risk of asthma, atopic dermatitis, and elevated total immunoglobulin E (IgE). These epidemiological associations, if true, would have public health importance, since vitamin D insufficiency is common and correctable. We aimed to test whether genetically lowered vitamin D levels were associated with risk of asthma, atopic dermatitis, or elevated serum IgE levels, using Mendelian randomization (MR) methodology to control bias owing to confounding and reverse causation. The study employed data from the UK Biobank resource and from the SUNLIGHT, GABRIEL and EAGLE eczema consortia. Using four single-nucleotide polymorphisms (SNPs) strongly associated with 25-hydroxyvitamin D (25OHD) levels in 33,996 individuals, we conducted MR studies to estimate the effect of lowered 25OHD on the risk of asthma (n = 146,761), childhood onset asthma (n = 15,008), atopic dermatitis (n = 40,835), and elevated IgE level (n = 12,853) and tested MR assumptions in sensitivity analyses. None of the four 25OHD-lowering alleles were associated with asthma, atopic dermatitis, or elevated IgE levels (p ≥ 0.2). The MR odds ratio per standard deviation decrease in log-transformed 25OHD was 1.03 (95% confidence interval [CI] 0.90-1.19, p = 0.63) for asthma, 0.95 (95% CI 0.69-1.31, p = 0.76) for childhood-onset asthma, and 1.12 (95% CI 0.92-1.37, p = 0.27) for atopic dermatitis, and the effect size on log-transformed IgE levels was -0.40 (95% CI -1.65 to 0.85, p = 0.54). These results persisted in sensitivity analyses assessing population stratification and pleiotropy and vitamin D synthesis and metabolism pathways. The main limitations of this study are that the findings do not exclude an association between the studied outcomes and 1,25-dihydoxyvitamin D, the active form of vitamin D, the study was underpowered to detect effects smaller than an OR of 1.33 for childhood asthma, and the analyses were restricted to white populations of European ancestry. This research has been conducted using the UK Biobank Resource and data from the SUNLIGHT, GABRIEL and EAGLE Eczema consortia. In this study, we found no evidence that genetically determined reduction in 25OHD levels conferred an increased risk of asthma, atopic dermatitis, or elevated total serum IgE, suggesting that efforts to increase vitamin D are unlikely to reduce risks of atopic disease.

Asthma is the most common chronic disease in children globally. The Global Asthma Network (GAN) Phase I study aimed to determine if the worldwide burden of asthma symptoms is changing. This updated cross-sectional study used the same methods as the International study of Asthma and Allergies in Childhood (ISAAC) Phase III. Asthma symptoms were assessed from centres that completed GAN Phase I and ISAAC Phase I (1993–95), ISAAC Phase III (2001–03), or both. We included individuals from two age groups (children aged 6–7 years and adolescents aged 13–14 years) who self-completed written questionnaires at school. We estimated the 10-year rate of change in prevalence of current wheeze, severe asthma symptoms, ever having asthma, exercise wheeze, and night cough (defined by core questions in the questionnaire) for each centre, and we estimated trends across world regions and income levels using mixed-effects linear regression models with region and country income level as confounders. Overall, 119 795 participants from 27 centres in 14 countries were included: 74 361 adolescents (response rate 90%) and 45 434 children (response rate 79%). About one in ten individuals of both age groups had wheeze in the preceding year, of whom almost half had severe symptoms. Most centres showed a change in prevalence of 2 SE or more between ISAAC Phase III to GAN Phase I. Over the 27-year period (1993–2020), adolescents showed a significant decrease in percentage point prevalence per decade in severe asthma symptoms (–0·37, 95% CI –0·69 to –0·04) and an increase in ever having asthma (1·25, 0·67 to 1·83) and night cough (4·25, 3·06 to 5·44), which was also found in children (3·21, 1·80 to 4·62). The prevalence of current wheeze decreased in low-income countries (–1·37, –2·47 to –0·27], in children and –1·67, –2·70 to –0·64, in adolescents) and increased in lower-middle-income countries (1·99, 0·33 to 3·66, in children and 1·69, 0·13 to 3·25, in adolescents), but it was stable in upper-middle-income and high-income countries. Trends in prevalence and severity of asthma symptoms over the past three decades varied by age group, country income, region, and centre. The high worldwide burden of severe asthma symptoms would be mitigated by enabling access to effective therapies for asthma. International Union Against Tuberculosis and Lung Disease, Boehringer Ingelheim New Zealand, AstraZeneca Educational Grant, National Institute for Health Research, UK Medical Research Council, European Research Council, and Instituto de Salud Carlos III.

Data for trends in prevalence of asthma, allergic rhinoconjunctivitis, and eczema over time are scarce. We repeated the International Study of Asthma and Allergies in Childhood (ISAAC) at least 5 years after Phase One, to examine changes in the prevalence of symptoms of these disorders. For the ISAAC Phase Three study, between 2002 and 2003, we did a cross-sectional questionnaire survey of 193 404 children aged 6–7 years from 66 centres in 37 countries, and 304 679 children aged 13–14 years from 106 centres in 56 countries, chosen from a random sample of schools in a defined geographical area. Phase Three was completed a mean of 7 years after Phase One. Most centres showed a change in prevalence of 1 or more SE for at least one disorder, with increases being twice as common as decreases, and increases being more common in the 6–7 year age-group than in the 13–14 year age-group, and at most levels of mean prevalence. An exception was asthma symptoms in the older age-group, in which decreases were more common at high prevalence. For both age-groups, more centres showed increases in all three disorders more often than showing decreases, but most centres had mixed changes. The rise in prevalence of symptoms in many centres is concerning, but the absence of increases in prevalence of asthma symptoms for centres with existing high prevalence in the older age-group is reassuring. The divergent trends in prevalence of symptoms of allergic diseases form the basis for further research into the causes of such disorders.

AimsWe examine whether inclusion of artificial intelligence (AI)-enabled retinal vasculometry (RV) improves existing risk algorithms for incident stroke, myocardial infarction (MI) and circulatory mortality.MethodsAI-enabled retinal vessel image analysis processed images from 88 052 UK Biobank (UKB) participants (aged 40–69 years at image capture) and 7411 European Prospective Investigation into Cancer (EPIC)-Norfolk participants (aged 48–92). Retinal arteriolar and venular width, tortuosity and area were extracted. Prediction models were developed in UKB using multivariable Cox proportional hazards regression for circulatory mortality, incident stroke and MI, and externally validated in EPIC-Norfolk. Model performance was assessed using optimism adjusted calibration, C-statistics and R2 statistics. Performance of Framingham risk scores (FRS) for incident stroke and incident MI, with addition of RV to FRS, were compared with a simpler model based on RV, age, smoking status and medical history (antihypertensive/cholesterol lowering medication, diabetes, prevalent stroke/MI).ResultsUKB prognostic models were developed on 65 144 participants (mean age 56.8; median follow-up 7.7 years) and validated in 5862 EPIC-Norfolk participants (67.6, 9.1 years, respectively). Prediction models for circulatory mortality in men and women had optimism adjusted C-statistics and R2 statistics between 0.75–0.77 and 0.33–0.44, respectively. For incident stroke and MI, addition of RV to FRS did not improve model performance in either cohort. However, the simpler RV model performed equally or better than FRS.ConclusionRV offers an alternative predictive biomarker to traditional risk-scores for vascular health, without the need for blood sampling or blood pressure measurement. Further work is needed to examine RV in population screening to triage individuals at high-risk.

Eczema often precedes the development of asthma in a disease course called the ‘atopic march’. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P= 2.1 × 10 −8 ) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P= 5.3 × 10 −9 ). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema. The development of asthma following eczema is known as the atopic march. Here the authors conduct a GWAS on affected children and identify two novel loci associated with the disease phenotype.

Peroxisome Proliferator-Activated Receptor Gamma (PPARG) is one of the three members of the PPAR family of transcription factors. Besides its roles in adipocyte differentiation and lipid metabolism, we recently demonstrated an association between PPARG and metastasis in prostate cancer. In this study a functional effect of PPARG on AKT serine/threonine kinase 3 (AKT3), which ultimately results in a more aggressive disease phenotype was identified. AKT3 has previously been shown to regulate PPARG co-activator 1 alpha (PGC1α) localisation and function through its action on chromosome maintenance region 1 (CRM1). AKT3 promotes PGC1α localisation to the nucleus through its inhibitory effects on CRM1, a known nuclear export protein. Collectively our results demonstrate how PPARG over-expression drives an increase in AKT3 levels, which in turn has the downstream effect of increasing PGC1α localisation within the nucleus, driving mitochondrial biogenesis. Furthermore, this increase in mitochondrial mass provides higher energetic output in the form of elevated ATP levels which may fuel the progression of the tumour cell through epithelial to mesenchymal transition (EMT) and ultimately metastasis.

Childhood obesity and asthma are increasing worldwide. A possible link between the two conditions has been postulated. Cross-sectional studies of stratified random samples of 8-12-year-old children (n = 10 652) (16 centres in affluent and 8 centres in non-affluent countries) used the standardized methodology of ISAAC Phase Two. Respiratory and allergic symptoms were ascertained by parental questionnaires. Tests for allergic disease were performed. Height and weight were measured, and overweight and obesity were defined according to international definitions. Prevalence rates and prevalence odds ratios were calculated. Overweight (odds ratio = 1.14, 95%-confidence interval: 0.98; 1.33) and obesity (odds ratio = 1.67, 95%-confidence interval: 1.25; 2.21) were related to wheeze. The relationship was stronger in affluent than in non-affluent centres. Similar results were found for cough and phlegm, rhinitis and eczema but the associations were mostly driven by children with wheeze. There was a clear association of overweight and obesity with airways obstruction (change in FEV1/FVC, -0.90, 95%-confidence interval: -1.33%; -0.47%, for overweight and -2.46%, 95%-confidence interval: -3.84%; -1.07%, for obesity) whereas the results for the other objective markers, including atopy, were null. Our data from a large international child population confirm that there is a strong relation of body mass index with wheeze especially in affluent countries. Moreover, body mass index is associated with an objective marker of airways obstruction (FEV1/FVC) but no other objective markers of respiratory and allergic disorders.