Showing papers by "Clinical Trial Service Unit published in 2020"

Physical distancing interventions and incidence of coronavirus disease 2019: natural experiment in 149 countries.

Abstract: Objective To evaluate the association between physical distancing interventions and incidence of coronavirus disease 2019 (covid-19) globally. Design Natural experiment using interrupted time series analysis, with results synthesised using meta-analysis. Setting 149 countries or regions, with data on daily reported cases of covid-19 from the European Centre for Disease Prevention and Control and data on the physical distancing policies from the Oxford covid-19 Government Response Tracker. Participants Individual countries or regions that implemented one of the five physical distancing interventions (closures of schools, workplaces, and public transport, restrictions on mass gatherings and public events, and restrictions on movement (lockdowns)) between 1 January and 30 May 2020. Main outcome measure Incidence rate ratios (IRRs) of covid-19 before and after implementation of physical distancing interventions, estimated using data to 30 May 2020 or 30 days post-intervention, whichever occurred first. IRRs were synthesised across countries using random effects meta-analysis. Results On average, implementation of any physical distancing intervention was associated with an overall reduction in covid-19 incidence of 13% (IRR 0.87, 95% confidence interval 0.85 to 0.89; n=149 countries). Closure of public transport was not associated with any additional reduction in covid-19 incidence when the other four physical distancing interventions were in place (pooled IRR with and without public transport closure was 0.85, 0.82 to 0.88; n=72, and 0.87, 0.84 to 0.91; n=32, respectively). Data from 11 countries also suggested similar overall effectiveness (pooled IRR 0.85, 0.81 to 0.89) when school closures, workplace closures, and restrictions on mass gatherings were in place. In terms of sequence of interventions, earlier implementation of lockdown was associated with a larger reduction in covid-19 incidence (pooled IRR 0.86, 0.84 to 0.89; n=105) compared with a delayed implementation of lockdown after other physical distancing interventions were in place (pooled IRR 0.90, 0.87 to 0.94; n=41). Conclusions Physical distancing interventions were associated with reductions in the incidence of covid-19 globally. No evidence was found of an additional effect of public transport closure when the other four physical distancing measures were in place. Earlier implementation of lockdown was associated with a larger reduction in the incidence of covid-19. These findings might support policy decisions as countries prepare to impose or lift physical distancing measures in current or future epidemic waves.

Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure.

Abstract: Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

GDF15 mediates the effects of metformin on body weight and energy balance

Abstract: Metformin, the world’s most prescribed anti-diabetic drug, is also effective in preventing type 2 diabetes in people at high risk1,2. More than 60% of this effect is attributable to the ability of metformin to lower body weight in a sustained manner3. The molecular mechanisms by which metformin lowers body weight are unknown. Here we show—in two independent randomized controlled clinical trials—that metformin increases circulating levels of the peptide hormone growth/differentiation factor 15 (GDF15), which has been shown to reduce food intake and lower body weight through a brain-stem-restricted receptor. In wild-type mice, oral metformin increased circulating GDF15, with GDF15 expression increasing predominantly in the distal intestine and the kidney. Metformin prevented weight gain in response to a high-fat diet in wild-type mice but not in mice lacking GDF15 or its receptor GDNF family receptor α-like (GFRAL). In obese mice on a high-fat diet, the effects of metformin to reduce body weight were reversed by a GFRAL-antagonist antibody. Metformin had effects on both energy intake and energy expenditure that were dependent on GDF15, but retained its ability to lower circulating glucose levels in the absence of GDF15 activity. In summary, metformin elevates circulating levels of GDF15, which is necessary to obtain its beneficial effects on energy balance and body weight, major contributors to its action as a chemopreventive agent. In mouse studies, metformin treatment results in increased secretion of growth/differentiation factor 15 (GDF15), which prevents weight gain in response to high-fat diet, and GDF15-independent lowering of circulating blood glucose.

The Magic of Randomization versus the Myth of Real-World Evidence

Abstract: The Magic of Randomization Nonrandomized observational analyses have been promoted as alternatives to randomized clinical trials. However, randomization ensures balance between groups, whereas nonr...

Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals

Abstract: Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.

Genome-Wide Association Study of Susceptibility to Idiopathic Pulmonary Fibrosis.

Abstract: Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease characterized by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. Geno...

COVID-19 pandemic and admission rates for and management of acute coronary syndromes in England

Abstract: BACKGROUND: Several countries affected by the COVID-19 pandemic have reported a substantial drop in the number of patients attending the emergency department with acute coronary syndromes and a reduced number of cardiac procedures. We aimed to understand the scale, nature, and duration of changes to admissions for different types of acute coronary syndrome in England and to evaluate whether in-hospital management of patients has been affected as a result of the COVID-19 pandemic. METHODS: We analysed data on hospital admissions in England for types of acute coronary syndrome from Jan 1, 2019, to May 24, 2020, that were recorded in the Secondary Uses Service Admitted Patient Care database. Admissions were classified as ST-elevation myocardial infarction (STEMI), non-STEMI (NSTEMI), myocardial infarction of unknown type, or other acute coronary syndromes (including unstable angina). We identified revascularisation procedures undertaken during these admissions (ie, coronary angiography without percutaneous coronary intervention [PCI], PCI, and coronary artery bypass graft surgery). We calculated the numbers of weekly admissions and procedures undertaken; percentage reductions in weekly admissions and across subgroups were also calculated, with 95% CIs. FINDINGS: Hospital admissions for acute coronary syndrome declined from mid-February, 2020, falling from a 2019 baseline rate of 3017 admissions per week to 1813 per week by the end of March, 2020, a reduction of 40% (95% CI 37-43). This decline was partly reversed during April and May, 2020, such that by the last week of May, 2020, there were 2522 admissions, representing a 16% (95% CI 13-20) reduction from baseline. During the period of declining admissions, there were reductions in the numbers of admissions for all types of acute coronary syndrome, including both STEMI and NSTEMI, but relative and absolute reductions were larger for NSTEMI, with 1267 admissions per week in 2019 and 733 per week by the end of March, 2020, a percent reduction of 42% (95% CI 38-46). In parallel, reductions were recorded in the number of PCI procedures for patients with both STEMI (438 PCI procedures per week in 2019 vs 346 by the end of March, 2020; percent reduction 21%, 95% CI 12-29) and NSTEMI (383 PCI procedures per week in 2019 vs 240 by the end of March, 2020; percent reduction 37%, 29-45). The median length of stay among patients with acute coronary syndrome fell from 4 days (IQR 2-9) in 2019 to 3 days (1-5) by the end of March, 2020. INTERPRETATION: Compared with the weekly average in 2019, there was a substantial reduction in the weekly numbers of patients with acute coronary syndrome who were admitted to hospital in England by the end of March, 2020, which had been partly reversed by the end of May, 2020. The reduced number of admissions during this period is likely to have resulted in increases in out-of-hospital deaths and long-term complications of myocardial infarction and missed opportunities to offer secondary prevention treatment for patients with coronary heart disease. The full extent of the effect of COVID-19 on the management of patients with acute coronary syndrome will continue to be assessed by updating these analyses. FUNDING: UK Medical Research Council, British Heart Foundation, Public Health England, Health Data Research UK, and the National Institute for Health Research Oxford Biomedical Research Centre.

Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors.

Abstract: Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits.

White Blood Cells and Blood Pressure: A Mendelian Randomization Study

Abstract: Background: High blood pressure (BP) is a risk factor for cardiovascular morbidity and mortality. While BP is regulated by the function of kidney, vasculature, and sympathetic nervous system, recen...

Cervical cancer survival in sub-Saharan Africa by age, stage at diagnosis and Human Development Index: A population-based registry study.

Abstract: Breast cancer is the leading cancer diagnosis and second most common cause of cancer deaths in sub-Saharan Africa (SSA). Yet, there are few population-level survival data from Africa and none on the survival differences by stage at diagnosis. Here, we estimate breast cancer survival within SSA by area, stage and country-level human development index (HDI). We obtained data on a random sample of 2,588 breast cancer incident cases, diagnosed in 2008-2015 from 14 population-based cancer registries in 12 countries (Benin, Cote d'Ivoire, Ethiopia, Kenya, Mali, Mauritius, Mozambique, Namibia, Seychelles, South Africa, Uganda and Zimbabwe) through the African Cancer Registry Network. Of these, 2,311 were included for survival analyses. The 1-, 3- and 5-year observed and relative survival (RS) were estimated by registry, stage and country-level HDI. We equally estimated the excess hazards adjusting for potential confounders. Among patients with known stage, 64.9% were diagnosed in late stages, with 18.4% being metastatic at diagnosis. The RS varied by registry, ranging from 21.6%(8.2-39.8) at Year 3 in Bulawayo to 84.5% (70.6-93.5) in Namibia. Patients diagnosed at early stages had a 3-year RS of 78% (71.6-83.3) in contrast to 40.3% (34.9-45.7) at advanced stages (III and IV). The overall RS at Year 1 was 86.1% (84.4-87.6), 65.8% (63.5-68.1) at Year 3 and 59.0% (56.3-61.6) at Year 5. Age at diagnosis was not independently associated with increased mortality risk after adjusting for the effect of stage and country-level HDI. In conclusion, downstaging breast cancer at diagnosis and improving access to quality care could be pivotal in improving breast cancer survival outcomes in Africa.

Mendel’s laws, Mendelian randomization and causal inference in observational data: substantive and nomenclatural issues

Abstract: We respond to criticisms of Mendelian randomization (MR) by Mukamal, Stampfer and Rimm (MSR). MSR consider that MR is receiving too much attention and should be renamed. We explain how MR links to Mendel’s laws, the origin of the name and our lack of concern regarding nomenclature. We address MSR’s substantive points regarding MR of alcohol and cardiovascular disease, an issue on which they dispute the MR findings. We demonstrate that their strictures with respect to population stratification, confounding, weak instrument bias, pleiotropy and confounding have been addressed, and summarise how the field has advanced in relation to the issues they raise. We agree with MSR that “the hard problem of conducting high-quality, reproducible epidemiology” should be addressed by epidemiologists. However we see more evidence of confrontation of this issue within MR, as opposed to conventional observational epidemiology, within which the same methods that have demonstrably failed in the past are simply rolled out into new areas, leaving their previous failures unexamined.

Association of Depression With All-Cause and Cardiovascular Disease Mortality Among Adults in China

Abstract: Importance Depression is associated with increased disease burden worldwide and with higher risk of mortality in Western populations. Objective To investigate whether depression is a risk factor for all-cause and cardiovascular disease (CVD) mortality in adults in China. Design, Setting, and Participants This cohort study prospectively followed adults aged 30 to 79 years in the China Kadoorie Biobank (CKB) study from June 1, 2004, to December 31, 2016, and adults aged 32 to 104 years in the Dongfeng-Tongji (DFTJ) study from September 1, 2008, to December 31, 2016. Data analysis was conducted from June 1, 2018, to March 31, 2019. Main Outcomes and Measures Depression was evaluated using the Chinese version of the World Health Organization Composite International Diagnostic Interview–Short Form in the CKB cohort and a 7-item symptoms questionnaire modified from the Composite International Diagnostic Interview–Short Form in the DFTJ cohort. Multivariable-adjusted Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% CIs for the association of depression with mortality. Covariates in the final models included sociodemographic characteristics, lifestyle factors, and personal and family medical history. Results Among 512 712 individuals (mean [SD] age, 52.0 [10.7] years; 302 509 [59.0%] women) in the CKB cohort, there were 44 065 deaths, including 18 273 CVD deaths. The 12-month prevalence of major depressive episode in the CKB cohort was 0.64%, and the 1-month prevalence of clinically significant depressive symptoms was 17.96% in the DFTJ cohort. Among 26 298 individuals (mean [SD] age, 63.6 [7.8] years; 14 508 [55.2%] women) in the DFTJ cohort, there were 2571 deaths, including 1013 CVD deaths. In the multivariable-adjusted model, depression was associated with increased risk of all-cause mortality (CKB cohort: HR, 1.32 [95% CI, 1.20-1.46];P Conclusions and Relevance These findings suggest that depression is associated with an increased risk of all-cause and CVD mortality in adults in China, particularly in men. These findings highlight the importance and urgency of depression management as a measure for preventing premature deaths in China.

Frailty index and all-cause and cause-specific mortality in Chinese adults: a prospective cohort study.

Abstract: Summary Background The fraily index is a useful proxy measure of accelerated biological ageing and in estimating all-cause and cause-specific mortality in older individuals in European and US populations. However, the predictive value of the frailty index in other populations outside of Europe and the USA and in adults younger than 50 years is unknown. We aimed to examine the association between the frailty index and mortality in a population of Chinese adults. Methods In this prospective cohort study, we used data from the China Kadoorie Biobank. We included adults aged 30–79 years from ten areas (five urban areas and five rural areas) of China who had no missing values for the items that made up the frailty index. We did not exclude participants on the basis of baseline morbidity status. We calculated the follow-up person-years from the baseline date to either the date of death, loss to follow-up, or Dec 31, 2017, whichever came first, through linkage with the registries of China's Disease Surveillance Points system and local residential records. Active follow-up visits to local communities were done annually for participants who were not linked to any established registries. Causes of death from official death certificates were supplemented, if necessary, by reviewing medical records or doing standard verbal autopsy procedures. The frailty index was calculated using 28 baseline variables, all of which were health status deficits measured by use of questionnaires and physical examination. We defined three categories of frailty status: robust (frailty index ≤0·10), prefrail (frailty index >0·10 to Findings 512 723 participants, recruited between June 25, 2004, and July 15, 2008, were followed up for a median of 10·8 years (IQR 10·2–13·1; total follow-up 5 551 974 person-years). 291 954 (56·9%) people were categorised as robust, 205 075 (40·0%) people were categorised as prefrail, and 15 694 (3·1%) people were categorised as frail. Women aged between 45 years and 79 years had a higher mean frailty index and a higher prevalence of frailty than did men. During follow-up, 49 371 deaths were recorded. After adjustment for established and potential risk factors for death, each 0·1 increment in the frailty index was associated with a higher risk of all-cause mortality (hazard ratio [HR] 1·68, 95% CI 1·66–1·71). Such associations were stronger among younger adults than among older adults (pinteraction Interpretation The frailty index is associated with all-cause and cause-specific mortality independent of chronological age in younger and older Chinese adults. The identification of younger adults with accelerated ageing by use of surrogate measures could be useful for the prevention of premature death and the extension of healthy active life expectancy. Funding The National Natural Science Foundation of China, the National Key R&D Program of China, the Chinese Ministry of Science and Technology, the Kadoorie Charitable Foundation, and the Wellcome Trust.

Genetic risk, incident gastric cancer, and healthy lifestyle: a meta-analysis of genome-wide association studies and prospective cohort study.

Abstract: Summary Background Genetic variants and lifestyle factors have been associated with gastric cancer risk, but the extent to which an increased genetic risk can be offset by a healthy lifestyle remains unknown. We aimed to establish a genetic risk model for gastric cancer and assess the benefits of adhering to a healthy lifestyle in individuals with a high genetic risk. Methods In this meta-analysis and prospective cohort study, we first did a fixed-effects meta-analysis of the association between genetic variants and gastric cancer in six independent genome-wide association studies (GWAS) with a case-control study design. These GWAS comprised 21 168 Han Chinese individuals, of whom 10 254 had gastric cancer and 10 914 geographically matched controls did not. Using summary statistics from the meta-analysis, we constructed five polygenic risk scores in a range of thresholds (p=5 × 10−4 p=5 × 10−5 p=5 × 10−6 p=5 × 10−7, and p=5 × 10−8) for gastric cancer. We then applied these scores to an independent, prospective, nationwide cohort of 100 220 individuals from the China Kadoorie Biobank (CKB), with more than 10 years of follow-up. The relative and absolute risk of incident gastric cancer associated with healthy lifestyle factors (defined as not smoking, never consuming alcohol, the low consumption of preserved foods, and the frequent intake of fresh fruits and vegetables), was assessed and stratified by genetic risk (low [quintile 1 of the polygenic risk score], intermediate [quintile 2–4 of the polygenic risk score], and high [quintile 5 of the polygenic risk score]). Individuals with a favourable lifestyle were considered as those who adopted all four healthy lifestyle factors, those with an intermediate lifestyle adopted two or three factors, and those with an unfavourable lifestyle adopted none or one factor. Findings The polygenic risk score derived from 112 single-nucleotide polymorphisms (p Interpretation Chinese individuals at an increased risk of incident gastric cancer could be identified by use of our newly developed polygenic risk score. Compared with individuals at a high genetic risk who adopt an unhealthy lifestyle, those who adopt a healthy lifestyle could substantially reduce their risk of incident gastric cancer. Funding National Key R&D Program of China, National Natural Science Foundation of China, 333 High-Level Talents Cultivation Project of Jiangsu Province, and China Postdoctoral Science Foundation.

Metabolically healthy obesity, transition to unhealthy metabolic status, and vascular disease in Chinese adults: A cohort study.

Abstract: Background Metabolically healthy obesity (MHO) and its transition to unhealthy metabolic status have been associated with risk of cardiovascular disease (CVD) in Western populations. However, it is unclear to what extent metabolic health changes over time and whether such transition affects risks of subtypes of CVD in Chinese adults. We aimed to examine the association of metabolic health status and its transition with risks of subtypes of vascular disease across body mass index (BMI) categories. Methods and findings The China Kadoorie Biobank was conducted during 25 June 2004 to 15 July 2008 in 5 urban (Harbin, Qingdao, Suzhou, Liuzhou, and Haikou) and 5 rural (Henan, Gansu, Sichuan, Zhejiang, and Hunan) regions across China. BMI and metabolic health information were collected. We classified participants into BMI categories: normal weight (BMI 18.5–23.9 kg/m²), overweight (BMI 24.0–27.9 kg/m²), and obese (BMI ≥ 28 kg/m²). Metabolic health was defined as meeting less than 2 of the following 4 criteria (elevated waist circumference, hypertension, elevated plasma glucose level, and dyslipidemia). The changes in obesity and metabolic health status were defined from baseline to the second resurvey with combination of overweight and obesity. Among the 458,246 participants with complete information and no history of CVD and cancer, the mean age at baseline was 50.9 (SD 10.4) years, and 40.8% were men, and 29.0% were current smokers. During a median 10.0 years of follow-up, 52,251 major vascular events (MVEs), including 7,326 major coronary events (MCEs), 37,992 ischemic heart disease (IHD), and 42,951 strokes were recorded. Compared with metabolically healthy normal weight (MHN), baseline MHO was associated with higher hazard ratios (HRs) for all types of CVD; however, almost 40% of those participants transitioned to metabolically unhealthy status. Stable metabolically unhealthy overweight or obesity (MUOO) (HR 2.22, 95% confidence interval [CI] 2.00–2.47, p < 0.001) and transition from metabolically healthy to unhealthy status (HR 1.53, 1.34–1.75, p < 0.001) were associated with higher risk for MVE, compared with stable healthy normal weight. Similar patterns were observed for MCE, IHD, and stroke. Limitations of the analysis included lack of measurement of lipid components, fasting plasma glucose, and visceral fat, and there might be possible misclassification. Conclusions Among Chinese adults, MHO individuals have increased risks of MVE. Obesity remains a risk factor for CVD independent of major metabolic factors. Our data further suggest that metabolic health is a transient state for a large proportion of Chinese adults, with the highest vascular risk among those remained MUOO.

Evaluating the cardiovascular safety of sclerostin inhibition using evidence from meta-analysis of clinical trials and human genetics.

Abstract: Inhibition of sclerostin is a therapeutic approach to lowering fracture risk in patients with osteoporosis. However, data from phase 3 randomized controlled trials (RCTs) of romosozumab, a first-in-class monoclonal antibody that inhibits sclerostin, suggest an imbalance of serious cardiovascular events, and regulatory agencies have issued marketing authorizations with warnings of cardiovascular disease. Here, we meta-analyze published and unpublished cardiovascular outcome trial data of romosozumab and investigate whether genetic variants that mimic therapeutic inhibition of sclerostin are associated with higher risk of cardiovascular disease. Meta-analysis of up to three RCTs indicated a probable higher risk of cardiovascular events with romosozumab. Scaled to the equivalent dose of romosozumab (210 milligrams per month; 0.09 grams per square centimeter of higher bone mineral density), the SOST genetic variants were associated with lower risk of fracture and osteoporosis (commensurate with the therapeutic effect of romosozumab) and with a higher risk of myocardial infarction and/or coronary revascularization and major adverse cardiovascular events. The same variants were also associated with increased risk of type 2 diabetes mellitus and higher systolic blood pressure and central adiposity. Together, our findings indicate that inhibition of sclerostin may elevate cardiovascular risk, warranting a rigorous evaluation of the cardiovascular safety of romosozumab and other sclerostin inhibitors.

Tobacco smoking and the risk of Parkinson disease: A 65-year follow-up of 30,000 male British doctors.

Abstract: Objective To investigate the causal relevance of current tobacco smoking for the risk of Parkinson disease (PD). Methods We compared the risks of death from PD with smoking habits in 30,000 male doctors in the British Doctors cohort study in 1951 and in survivors who had been resurveyed periodically for 5 decades. Cause-specific mortality was monitored for 65 years and included 283 deaths from PD. The relative risks (RRs) of PD (and 95% confidence intervals [CIs]) were estimated using Cox models for smoking habits (smoking status, amount smoked, and years since quitting) at baseline or updated habits at resurvey. Results The prevalence of current smoking declined progressively during follow-up from 67% to 8% between 1951 and 1998. The crude rates of PD death were lower in current smokers than in never smokers at baseline (30 vs 46/100,000 persons-years). After adjustment for age at risk, current smokers at baseline had a 30% lower risk of PD (RR 0.71; 95% CI 0.60–0.84), and continuing smokers classified using updated smoking habits at resurvey had a 40% lower risk (RR 0.60; 95% CI 0.46–0.77) of PD compared with never smokers. The risks of PD were inversely associated with the amount of tobacco smoked. The protective effect of current smoking vs never smoking for PD was attenuated by increasing duration since quitting smoking. Conclusions In contrast to previous suggestions, the present report demonstrates a causally protective effect of current smoking on the risk of PD, which may provide insights into the etiology of PD.

Fluid Intake and Dietary Factors and the Risk of Incident Kidney Stones in UK Biobank: A Population-based Prospective Cohort Study.

Abstract: Background Fluid intake and diet are thought to influence kidney stone risk. However, prospective studies have been limited to small samples sizes and/or restricted measures. Objective To investigate whether fluid intake and dietary factors are associated with the risk of developing a first kidney stone. Design, setting, and participants Participants were selected from UK Biobank, a population-based prospective cohort study. Outcome measurements and statistical analysis Cox proportional hazards models were used to investigate the association between fluid intake and dietary factors and the risk of a first incident kidney stone, ascertained from hospital inpatient records. Results and limitations After exclusion, 439 072 participants were available for the analysis, of whom 2057 had hospital admission with an incident kidney stone over a mean of 6.1 yr of follow-up. For every additional drink (200 ml) consumed per day of total fluid, the risk of kidney stones declined by 13% (hazard ratio [HR] = 0.87, 95% confidence interval [CI] 0.85–0.89). Similar patterns of associations were observed for tea, coffee, and alcohol, although no association was observed for water intake. Fruit and fibre intake was also associated with a lower risk (HR per 100 g increase of fruits per day = 0.88, 95% CI 0.83–0.93, and HR per 10 g fibre per day = 0.82, 95% CI 0.77–0.87), whereas meat and salt intake was associated with a higher risk (HR per 50 g increase in meat per week = 1.17, 95% CI 1.05–1.29, and HR for always vs never/rarely added salt to food = 1.33, 95% CI 1.12–1.58). Vegetable, fish, and cheese intake was not associated with kidney stone risk. Conclusions The finding that high intake of total fluid, fruit, and fibre was associated with a lower risk of hospitalisation for a first kidney stone suggests that modifiable dietary factors could be targeted to prevent kidney stone development. Patient summary We found that higher intake of total fluid, specifically tea, coffee, and alcohol (but not water), and consumption of fruit and foods high in fibre are linked with a reduced likelihood of developing kidney stones.

Cancer in Africa 2018: The role of infections.

Abstract: We estimate the fractions of cancer attributed to infections in Africa in 2018. The number of new cancer cases occurring was taken from Globocan2018 with some additional estimations based on data from African population-based registries. Population attributable fractions were calculated using prevalence of infection and relative risk in exposed vs. nonexposed. The greatest share of infection-associated cancers is due to the human papillomaviruses (12.1% of all cancers in Africa and 15.4% in sub-Saharan Africa [SSA]); of these, cervical cancer is by far the most common. Kaposi sarcoma-associated herpesvirus is responsible for 3.1% of all cancers in Africa, the hepatitis viruses (B and C) for 2.9% and Helicobacter pylori for 2.7% (non-Cardia Gastric cancer and primary gastric lymphomas). Two percent of cancers are attributable to the Epstein-Barr virus, Schistosoma haematobium increases the risk of bladder cancer resulting in 1.0% of all cancers. HIV-related NHL and squamous cell carcinoma of the conjunctiva account for 0.6% of cancers. Altogether 24.5% of cancers in Africa and 28.7% in SSA are due to infectious agents. Infections are by far the most common cancer risk factor for cancer in Africa-the traditional risk factors (smoking, alcohol and unhealthy diet) probably cause only one in eight cancers in Africa. Prevention should focus on those infectious diseases preventable through vaccination (HPV and hepatitis B) which could reduce two-thirds of the burden. Helicobacter pylori and schistosomiasis are treatable with antibiotics and praziquantel, with a potential reduction of one in eight infection-associated cancers.

Genetic determinants of blood lipids and cerebral small vessel disease: role of high-density lipoprotein cholesterol.

Abstract: Blood lipids are causally involved in the pathogenesis of atherosclerosis, but their role in cerebral small vessel disease remains largely elusive. Here, we explored associations of genetic determinants of blood lipid levels, lipoprotein particle components, and targets for lipid-modifying drugs with small vessel disease phenotypes. We selected genetic instruments for blood levels of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides, for cholesterol and triglycerides components of size-defined lipoprotein particles, and for lipid-modifying drug targets based on published genome-wide association studies (up to 617 303 individuals). Applying two-sample Mendelian randomization approaches we investigated associations with ischaemic and haemorrhagic manifestations of small vessel disease [small vessel stroke: 11 710 cases, 287 067 controls; white matter hyperintensities (WMH): 10 597 individuals; intracerebral haemorrhage: 1545 cases, 1481 controls]. We applied the inverse-variance weighted method and multivariable Mendelian randomization as our main analytical approaches. Genetic predisposition to higher HDL-C levels was associated with lower risk of small vessel stroke [odds ratio (OR) per standard deviation = 0.85, 95% confidence interval (CI) = 0.78-0.92] and lower WMH volume (β = -0.07, 95% CI = -0.12 to -0.02), which in multivariable Mendelian randomization remained stable after adjustments for LDL-C and triglycerides. In analyses of lipoprotein particle components by size, we found these effects to be specific for cholesterol concentration in medium-sized high-density lipoprotein, and not large or extra-large high-density lipoprotein particles. Association estimates for intracerebral haemorrhage were negatively correlated with those for small vessel stroke and WMH volume across all lipid traits and lipoprotein particle components. HDL-C raising genetic variants in the gene locus of the target of CETP inhibitors were associated with lower risk of small vessel stroke (OR: 0.82, 95% CI = 0.75-0.89) and lower WMH volume (β = -0.08, 95% CI = -0.13 to -0.02), but a higher risk of intracerebral haemorrhage (OR: 1.64, 95% CI = 1.26-2.13). Genetic predisposition to higher HDL-C, specifically to cholesterol in medium-sized high-density lipoprotein particles, is associated with both a lower risk of small vessel stroke and lower WMH volume. These analyses indicate that HDL-C raising strategies could be considered for the prevention of ischaemic small vessel disease but the net benefit of such an approach would need to be tested in a randomized controlled trial.

COVID-19 mortality: a complex interplay of sex, gender and ethnicity.

Abstract: Several studies have reported a higher rate of COVID-19 mortality in men. A higher rate of COVID-19 mortality has also been reported in Black, Asian and minority ethnic (BAME) groups, especially among healthcare providers. The exact reasons for these disparities are not known but may be due to differential susceptibility based on biological sex, as well as gender differences in health behaviours (e.g. smoking) giving rise to differences in comorbidities (e.g. cardiovascular disease) that increase the risk of COVID-19 mortality in men. However, there are social influences that could influence gender differences in exposure and infection; e.g., women are more likely to be involved in service sector work/healthcare; men are more involved in other high-risk jobs such as drivers. In regards to ethnic differences, people from BAME background may be more likely to be in the frontline, exposed, jobs; they may be more likely to live in crowded multi-generation households making it challenging to maintain physical distancing from elderly family members. In the context of gender and ethnic differences in COVID-19 mortality, additional important policy-related issues include our understanding of (i) whether there are ethnic variations in COVID-19 mortality in men and women, (ii) whether there is heterogeneity in gender differences within individual ethnic groups and (iii) whether we could identify some factors that may help explain these disparities, if any. Most studies of COVID-19 mortality have statistically ‘adjusted’ for factors (e.g. socioeconomic deprivation) that may potentially help to explain gender and ethnic disparities. While often necessary, these adjustments are seldom sufficient in explaining the full spectrum of the disparities. Frequently, we do not have complete information on the causal pathways. Many known or hypothesized factors that could account for gender/ethnic disparities in health are not readily available in routine health records. Methodological and analytic approaches may also affect these conclusions. For example, in the context of gender, ethnicity, and COVID-19 mortality, if gender is ‘adjusted’ in a statistical model, it assumes that the ethnicity-specific risk estimates are fixed in men and women, i.e., it renders invisible any heterogeneity in gender differences within individual ethnic groups. Similarly, if ethnicity is adjusted, the model assumes that the gender-specific risk estimates are fixed in different ethnic groups, i.e., it masks any ethnic variation in men and women. Therefore, just because an association is reported as ‘adjusted’, it is no panacea. We elaborate these issues further drawing on results from three recent reports published using the UK data. The OpenSAFELY study

The genetic architecture of sporadic and multiple consecutive miscarriage.

Abstract: Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10-8, odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10-8, OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10-9, OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10-8, OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.

Development of a polygenic risk score to improve screening for fracture risk: A genetic risk prediction study

Abstract: BACKGROUND: Since screening programs identify only a small proportion of the population as eligible for an intervention, genomic prediction of heritable risk factors could decrease the number needing to be screened by removing individuals at low genetic risk. We therefore tested whether a polygenic risk score for heel quantitative ultrasound speed of sound (SOS)-a heritable risk factor for osteoporotic fracture-can identify low-risk individuals who can safely be excluded from a fracture risk screening program. METHODS AND FINDINGS: A polygenic risk score for SOS was trained and selected in 2 separate subsets of UK Biobank (comprising 341,449 and 5,335 individuals). The top-performing prediction model was termed "gSOS", and its utility in fracture risk screening was tested in 5 validation cohorts using the National Osteoporosis Guideline Group clinical guidelines (N = 10,522 eligible participants). All individuals were genome-wide genotyped and had measured fracture risk factors. Across the 5 cohorts, the average age ranged from 57 to 75 years, and 54% of studied individuals were women. The main outcomes were the sensitivity and specificity to correctly identify individuals requiring treatment with and without genetic prescreening. The reference standard was a bone mineral density (BMD)-based Fracture Risk Assessment Tool (FRAX) score. The secondary outcomes were the proportions of the screened population requiring clinical-risk-factor-based FRAX (CRF-FRAX) screening and BMD-based FRAX (BMD-FRAX) screening. gSOS was strongly correlated with measured SOS (r2 = 23.2%, 95% CI 22.7% to 23.7%). Without genetic prescreening, guideline recommendations achieved a sensitivity and specificity for correct treatment assignment of 99.6% and 97.1%, respectively, in the validation cohorts. However, 81% of the population required CRF-FRAX tests, and 37% required BMD-FRAX tests to achieve this accuracy. Using gSOS in prescreening and limiting further assessment to those with a low gSOS resulted in small changes to the sensitivity and specificity (93.4% and 98.5%, respectively), but the proportions of individuals requiring CRF-FRAX tests and BMD-FRAX tests were reduced by 37% and 41%, respectively. Study limitations include a reliance on cohorts of predominantly European ethnicity and use of a proxy of fracture risk. CONCLUSIONS: Our results suggest that the use of a polygenic risk score in fracture risk screening could decrease the number of individuals requiring screening tests, including BMD measurement, while maintaining a high sensitivity and specificity to identify individuals who should be recommended an intervention.

Monitoring respiratory infections in covid-19 epidemics.

Abstract: Ka Hung Chan and colleagues argue that monitoring influenza-like illness could be a complementary approach to assessing the effectiveness of general infection control measures against covid-19