Randomized Polypill Crossover Trial in People Aged 50 and Over

PMCID: PMC3399742This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Trends in Down’s syndrome live births and antenatal diagnoses in England and Wales from 1989 to 2008: analysis of data from the National Down Syndrome Cytogenetic Register

Objectives To describe trends in the numbers of Down’s syndrome live births and antenatal diagnoses in England and Wales from 1989 to 2008

Reconciling the Evidence on Serum Homocysteine and Ischaemic Heart Disease: A Meta-Analysis

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

EUROlinkCAT: A linked European cohort of children with congenital anomalies

Objective To establish a linked European cohort of children with congenital anomalies (CAs) to evaluate mortality and morbidity outcomes of these children up to the age of 10 years. Method EUROlinkCAT supported 22 EUROCAT population-based congenital anomaly registries in 14 countries to link their data on children with CAs to mortality, vital statistics, hospital discharge and prescription databases. All live births with a CA born 1995-2014 recorded in the registries were followed up to age 10 years or to 31st December 2015. Each registry transformed their local mortality and morbidity data to a Common Data Model (CDM) and ran centrally created syntax scripts and produced tables/outputs in a standard form for meta-analysis. Analyses were performed on 100 different congenital anomaly subgroups for children <1 year,1-4 years, and 5-9 years. Results Sixteen registries linked their data on children with CAs to mortality databases, eleven to regional/national hospital databases, and six to prescription databases. Data on children without a CA born during the same time-period and from the same population area (reference population) were available for seven registries linking to hospital databases and for all six registries linking to prescription databases. For the mortality studies, linked information on survival was available for 96% of children recorded in the anomaly registries (180,00 live births). For the morbidity studies, 89% of children with a CA (n=99,000) and 95% of reference children (n=2 million) were linked. For the prescription studies, 95% of children with a CA (n=60,000) and 95% of reference children (n= 1,700,000) were linked. Conclusion The EUROlinkCAT project was successful in creating a linked cohort of children with and without CAs in Western Europe. More efforts are needed to support data linkage in Eastern European countries. We have developed a set of recommendations for data linkage studies based on our experiences in establishing this cohort

Blood pressure intervention levels in preterm infants : pilot randomised trial

OBJECTIVE: To examine the feasibility of a trial allocating different blood pressure (BP) intervention levels for treatment in extremely preterm infants. DESIGN: Three-arm open randomised controlled trial performed between February 2013 and April 2015. SETTING: Single tertiary level neonatal intensive care unit. PATIENTS: Infants born <29 weeks' gestation were eligible to participate, if parents consented and they did not have a major congenital malformation. INTERVENTIONS: Infants were randomised to different levels of mean arterial BP at which they received cardiovascular support: active (<30 mm Hg), moderate (<gestational age mm Hg) or permissive (signs of poor perfusion or <19 mm Hg). Once this threshold was breached, all were managed using the same treatment guideline. BP profiles were downloaded continuously; cardiac output and carotid blood flow were measured at 1 day and 3 days, and amplitude integrated EEG was recorded during the first week. Cranial ultrasound scans were reviewed blind to study allocation. MAIN OUTCOME MEASURE: Inotrope usage and achieved BP. RESULTS: Of 134 cases screened, 60 were enrolled, with mean gestation 25.8 weeks (SD 1.5) and birth weight 817 g (SD 190). Invasively measured BP on the first day and inotrope usage were highest in the active and lowest in the permissive arms. There were no differences in haemodynamic or EEG variables or in clinical complications. Predefined cranial ultrasound findings did not differ significantly; no infants in the active arm had parenchymal brain lesions. CONCLUSION: The BP threshold used to trigger treatment affects the achieved BP and inotrope usage, and it was possible to explore these effects using this study design. TRIAL REGISTRATION NUMBER: ISRCTN83507686

Occupational Exposure to Hydrazine and Subsequent Risk of Lung Cancer: 50-Year Follow-Up

Hydrazine is carcinogenic in animals, but there is inadequate evidence to determine if it is carcinogenic in humans. This study aimed to evaluate the association between hydrazine exposure and the risk of lung cancer.The cause specific mortality rates of a cohort of 427 men who were employed at an English factory that produced hydrazine between 1945 and 1971 were compared with national mortality rates.By the end of December 2012 205 deaths had occurred. For men in the highest exposure category with greater than two years exposure and after more than ten years since first exposure the relative risks compared with national rates were: 0.85 (95% CI: 0.18-2.48) for lung cancer, 0.61 (95% CI: 0.07-2.21) for cancers of the digestive system, and 0.44 (95% CI: 0.05-1.57) for other cancers.After 50 years of follow up, the results provide no evidence of an increased risk of death from lung cancer or death from any other cause

Size at birth, growth trajectory in early life, and cardiovascular and metabolic risks in early adulthood: EPICure study.

OBJECTIVE: To investigate whether size at birth and growth trajectories in infancy and childhood are associated with determinants of cardiovascular and metabolic risks in young adults born extremely preterm (EP, <26 weeks of gestation). METHODS: We used longitudinal data from the EPICure study of 129 EP survivors up to 19 years in the UK and Ireland in 1995. Determinants of cardiovascular and metabolic risks at 19 years included the presence of metabolic syndrome, body mass index (BMI) and systolic blood pressure (SBP). Predictors were birth weight for gestation and gain in weight z-scores in the following periods: birth-postmenstrual age of 40 weeks (term), infancy (term-2.5 years), early childhood (2.5-6.0 years) and late childhood (6-11 years). RESULTS: Metabolic syndrome was present in 8.7% of EP participants at 19 years. Compared with subjects without metabolic syndrome, those with metabolic syndrome tended to have a smaller size at birth (difference in means: -0.55 SD, 95% CI -1.10 to 0.01, p=0.053) and a greater increase in weight z-scores from term to 2.5 years (difference in means: 1.00 SD, 95% CI -0.17 to 2.17, p=0.094). BMI at 19 years was positively related to growth from 2.5 to 6.0 years (β: 1.03, 95% CI 0.31 to 1.75, p=0.006); an inverse association with birthweight z-scores was found in the lower socioeconomic status group (β: -1.79, 95% CI -3.41 to -0.17, p=0.031). Central SBP was positively related to growth from 2.5 to 6.0 years (β: 1.75, 95% CI 0.48 to 3.02, p=0.007). CONCLUSION: Size at EP birth and increased catch-up in weight from 2.5 to 6.0 years were associated with BMI and central SBP in early adulthood

Chromosomal disorders:estimating baseline birth prevalence and pregnancy outcomes worldwide

Chromosomal disorders, of which Down syndrome is the most common, can cause multi-domain disability. In addition, compared to the general population, there is a higher frequency of death before the age of five. In many settings, large gaps in data availability have hampered policy-making, programme priorities and resource allocation for these important conditions. We have developed methods, which overcome this lack of data and allow estimation of the burden of affected pregnancies and their outcomes in different settings worldwide. For example, the methods include a simple equation relating the percentage of mothers 35 and over to Down syndrome birth prevalence. The results obtained provide a starting point for consideration of services that can be implemented for the care and prevention of these disorders

Intrauterine exposure to carbamazepine and specific congenital malformations: systematic review and case-control study.

OBJECTIVE: To identify specific major congenital malformations associated with use of carbamazepine in the first trimester of pregnancy. DESIGN: A review of all published cohort studies to identify key indications and a population based case-control study to test these indications. SETTING: Review of PubMed, Web of Science, and Embase for papers about carbamazepine exposure in the first trimester of pregnancy and specific malformations, and the EUROCAT Antiepileptic Study Database, including data from 19 European population based congenital anomaly registries, 1995-2005. PARTICIPANTS: The literature review covered eight cohort studies of 2680 pregnancies with carbamazepine monotherapy exposure, and the EUROCAT dataset included 98 075 registrations of malformations covering over 3.8 million births. MAIN OUTCOME MEASURES: Overall prevalence for a major congenital malformation after exposure to carbamazepine monotherapy in the first trimester. Odds ratios for malformations with exposure to carbamazepine among cases (five types of malformation identified in the literature review) compared with two groups of controls: other non-chromosomal registrations of malformations and chromosomal syndromes. RESULTS: The literature review yielded an overall prevalence for a major congenital malformation of 3.3% (95% confidence interval 2.7 to 4.2) after exposure to carbamazepine monotherapy in the first trimester. In 131 registrations of malformations, the fetus had been exposed to carbamazepine monotherapy. Spina bifida was the only specific major congenital malformation significantly associated with exposure to carbamazepine monotherapy (odds ratio 2.6 (95% confidence interval 1.2 to 5.3) compared with no antiepileptic drug), but the risk was smaller for carbamazepine than for valproic acid (0.2, 0.1 to 0.6). There was no evidence for an association with total anomalous pulmonary venous return (no cases with carbamazepine exposure), cleft lip (with or without palate) (0.2, 0.0 to 1.3), diaphragmatic hernia (0.9, 0.1 to 6.6), or hypospadias (0.7, 0.3 to 1.6) compared with no exposure to antiepileptic drugs. Further exploratory analysis suggested a higher risk of single ventricle and atrioventricular septal defect. CONCLUSION: Carbamazepine teratogenicity is relatively specific to spina bifida, though the risk is less than with valproic acid. Despite the large dataset, there was not enough power to detect moderate risks for some rare major congenital malformations

Modelling a two-stage adult population screen for autosomal dominant familial hypercholesterolaemia: cross-sectional analysis within the UK Biobank

Background: Most people with autosomal dominant familial hypercholesterolaemia (FH) remain undetected, which represents a missed opportunity for coronary heart disease prevention. Objective: To evaluate the performance of two-stage adult population screening for FH. Design: Using data from UK Biobank, we estimated the screening performance of different low-density lipoprotein cholesterol (LDL-C) cut-offs (stage 1) to select adults for DNA sequencing (stage 2) to identify individuals with FH-causing variants inLDLR, APOB, PCSK9andAPOE. We estimated the number of additional FH cases detected by cascade testing of first-degree relatives of index cases and compared the overall approach with screening in childhood. Setting: UK Biobank. Participants: 140 439 unrelated participants of European ancestry from UK Biobank with information on circulating LDL-C concentration and exome sequence. Main outcome measures: For different LDL-C cut-offs, we estimated the detection and false-positive rate, the proportion of individuals who would be referred for DNA sequencing (stage 1 screen positive rate), and the number of FH cases identified by population screening followed by cascade testing. Results: We identified 488 individuals with an FH-causing variant and 139 951 without (prevalence 1 in 288). An LDL-C cut-off of &gt;4.8 mmol/L had a stage 1 detection rate (sensitivity) of 40% (95% CI 36 to 44%) for a false-positive rate of 10% (95% CI 10 to 11%). Detection rate increased at lower LDL-C cut-offs but at the expense of higher false-positive and screen positive rates, and vice versa. Two-stage screening of 100 000 adults using an LDL-C cut-off of 4.8 mmol/L would generate 10 398 stage 1 screen positives for sequencing, detect 138 FH cases and miss 209. Up to 207 additional cases could be detected throughtwo-generationcascade testing of first-degree relatives. By comparison, based on previously published data, childhood screening followed by cascade testing was estimated to detect nearly three times as many affected individuals for around half the sequencing burden. Conclusions: Two-stage adult population screening for FH could help achieve the 25% FH case detection target set in the National Health Service Long Term Plan, but less efficiently than childhood screening and with a greater sequencing requirement