Guy's and St Thomas' NHS Foundation Trust

About: Guy's and St Thomas' NHS Foundation Trust is a healthcare organization based out in London, United Kingdom. It is known for research contribution in the topics: Population & Randomized controlled trial. The organization has 7686 authors who have published 9631 publications receiving 399353 citations. The organization is also known as: Guy's and St Thomas' National Health Service Foundation Trust & Guy's and St Thomas' National Health Service Trust.

Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer

Abstract: The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (, 40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (lambda) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values, 10 25 and 39 SNPs had p-values<10(-4). These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, p = 3: 8 x 10(-5)) and for rs311499 was 0.72 (95% CI 0.61-0.85, p = 6: 6 x 10(-5)). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, p = 1: 2 x 10(-8)). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer.

Obesity Hypoventilation Syndrome

Abstract: Obesity hypoventilation syndrome (OHS) is defined as hypercapnia ­during wakefulness in an obese patient, without any other known cause, accompanied with some form of sleep-disordered breathing as reported by Mokhlesi et al. (Proc Am Thorac Soc 5:218–25, 2008). Although the effects of OHS are inadequately studied, available data show that morbidity and mortality are high. Among those with obstructive sleep apnea (OSA), risk factors for having OHS include a higher body mass index (BMI), an increased severity of sleep-disordered breathing, and a restrictive defect on pulmonary function testing. While the pathophysiology of the disorder remains unclear, it likely involves the presence of several defects, most notably a blunted central respiratory drive. The most effective treatment option consists of ventilatory support during sleep, in the form of positive airway pressure therapy, with or without supplemental oxygen.

The global burden of atopic dermatitis: lessons from the Global Burden of Disease Study 1990-2017.

Abstract: Background The Global Burden of Disease (GBD) Study provides an annually updated resource to study disease-related morbidity and mortality worldwide. Objectives Here we present the burden estimates for atopic dermatitis (AD), including data from inception of the GBD project in 1990 until 2017. Methods Data on the burden of AD were obtained from the GBD Study. Results Atopic dermatitis (AD) ranks 15th among all nonfatal diseases and has the highest disease burden among skin diseases as measured by disability-adjusted life-years (DALYs). Overall, the global DALY rate for AD in 1990 was 121 [95% uncertainty interval (UI) 65·4-201] and remained similar in 2017 at 123 (95% UI 66·8-205). The three countries with the highest DALY rates of AD were Sweden (327, 95% UI 178-547), the UK (284, 95% UI 155-478) and Iceland (277, 95% UI 149-465), whereas Uzbekistan (85·1, 95% UI 45·2-144), Armenia (85·1, 95% UI 45·8-143) and Tajikistan (85·1, 95% UI 46·1-143) ranked lowest. Conclusions The global prevalence rate of AD has remained stable from 1990 to 2017. However, the distribution of AD by age groups shows a bimodal curve with the highest peak in early childhood, decreasing in prevalence among young adults, and a second peak in middle-aged and older populations. We also found a moderate positive correlation between a country's gross domestic product and disease burden. GBD data confirm the substantial worldwide burden of AD, which has remained stable since 1990 but shows significant geographical variation. Lifestyle factors, partially linked to affluence, are likely important disease drivers. However, the GBD methodology needs to be developed further to incorporate environmental risk factors, such as ultraviolet exposure, to understand better the geographical and age-related variations in disease burden.

Observational study of the effect of obesity on lung volumes

Abstract: Background Severe obesity causes respiratory morbidity and mortality. The impact of obesity on the mechanics of breathing is not fully understood. Patients and methods We undertook a comprehensive observational study of lung volumes and elasticity in nine obese and nine normal weight subjects, seated and supine, during spontaneous breathing. Seated and supine total lung capacity (TLC) and subdivisions were measured by multibreath helium dilution method. Using balloon catheters, oesophageal (Poes) and gastric (Pgas) pressures were recorded. Transpulmonary pressure (P L ) was calculated as mouth pressure (Pmouth)-Poes, and complete expiratory P L volume curves were measured. Results The obese group had a body mass index (BMI) of 46.8 (17.2) kg/m 2 , and the normal group had a BMI of 23.2 (1.6) kg/m 2 (p=0.001). Obese and normals were matched for age (p=0.233), gender (p=0.637) and height (p=0.094). The obese were more restricted than the normals (TLC 88.6 (16.9) vs 104.4 (12.3) %predicted, p=0.033; FEV 1 /FVC 79.6 (7.3) vs 82.5 (4.2) %, p=0.325), had dramatically reduced expiratory reserve volume (ERV 0.4 (0.4) vs 1.7 (0.6) L, p 2 O, p=0.015; supine 14.3 (5.7) vs 7.1 (2.6) cm H 2 O, p=0.003), as were end-expiratory oesophageal pressures at FRC (seated 5.2 (6.9) vs −2.0 (3.5) cm H 2 O, p=0.013; supine 14.0 (8.0) vs 5.4 (3.1) cm H 2 O, p=0.008). BMI correlated with end-expiratory gastric (seated R 2 =0.43, supine R 2 =0.66, p 2 =0.51, supine R 2 =0.62, p Conclusions Obese subjects have markedly increased gastric and oesophageal pressures, both when upright and supine, causing dramatically reduced FRC and ERV, which increases work of breathing.