Royal Devon and Exeter Hospital

About: Royal Devon and Exeter Hospital is a healthcare organization based out in Exeter, United Kingdom. It is known for research contribution in the topics: Population & Randomized controlled trial. The organization has 2282 authors who have published 2526 publications receiving 78866 citations. The organization is also known as: RD&E.

Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease.

Abstract: Importance: Use of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM). Objective: To identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD). Design, Setting, and Participants: Case-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients. Exposures: Genetic variants associated with TIM. Main Outcomes and Measures: Thiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 × 109/L or less or a decline in absolute neutrophil cell count to 1.0 × 109/L or less leading to a dose reduction or drug withdrawal. Results: Among 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 × 10-9). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 × 10-8), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P = .03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 × 10-7) of TIM, independent of TPMT genotype and thiopurine dose. Conclusions and Relevance: Among patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required.

Varicose veins and their management

Abstract: Varicose veins are tortuous, widened veins in the subcutaneous tissues of the legs and are often easily visible. Their valves are usually incompetent so that reflux of blood occurs, and the resulting venous hypertension can cause symptoms. Varicose veins are widely seen as medically unimportant and deserving low priority for treatment. They are common, affecting nearly a third of adults in Western societies, and few people with varicose veins are ever harmed by them. However, they cause concern and distress on a large scale, most of which can be dealt with by good explanation and reassurance, or by a variety of treatments which are evolving rapidly at present. Patients can now be referred for more precise assessment and a greater range of therapeutic options than ever before. A large UK population study has shown age adjusted prevalences of 40% in men and 32% in women, although women more often present for treatment.1 The age of onset varies; some people develop varicose veins in their teens, but prevalence rises with age. Varicose veins often appear first in pregnancy, and further pregnancies can make them worse. A family history is common,1 but people should be reassured that having close relatives with severe symptoms from varicose veins or ulcers does not confer any great likelihood that they will have similar problems. #### Data sources and selection criteria This review is based on three main sources: #### Summary points Most people with varicose veins are never harmed by them—good explanation and reassurance are fundamental Ultrasound techniques (hand held …

Human longevity is influenced by many genetic variants: evidence from 75,000 UK Biobank participants

Abstract: Variation in human lifespan is 20 to 30% heritable in twins but few genetic variants have been identified. We undertook a Genome Wide Association Study (GWAS) using age at death of parents of middle-aged UK Biobank participants of European decent (n=75,244 with father's and/or mother's data, excluding early deaths). Genetic risk scores for 19 phenotypes (n=777 proven variants) were also tested. In GWAS, a nicotine receptor locus(CHRNA3, previously associated with increased smoking and lung cancer) was associated with fathers' survival. Less common variants requiring further confirmation were also identified. Offspring of longer lived parents had more protective alleles for coronary artery disease, systolic blood pressure, body mass index, cholesterol and triglyceride levels, type-1 diabetes, inflammatory bowel disease and Alzheimer's disease. In candidate analyses, variants in the TOMM40/APOE locus were associated with longevity, but FOXO variants were not. Associations between extreme longevity (mother >=98 years, fathers >=95 years, n=1,339) and disease alleles were similar, with an additional association with HDL cholesterol (p=5.7x10-3). These results support a multiple protective factors model influencing lifespan and longevity (top 1% survival) in humans, with prominent roles for cardiovascular-related pathways. Several of these genetically influenced risks, including blood pressure and tobacco exposure, are potentially modifiable.

A dose‐ranging study of the efficacy and safety of tamsulosin, the first prostate‐selective a1A‐adrenoceptor antagonist*, in patients with benign prostatic obstruction

Abstract: Objective To evaluate the efficacy and safety in a dose-ranging study of tamsulosin (once-daily) as a modified-release formulation compared with placebo in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic obstruction (BPO), and to establish the optimum dosage for phase III clinical studies. Patients and methods Of 169 patients with LUTS associated with BPO enrolled in a 3 week placebo run-in period, 126 were subsequently randomized to receive placebo (28), or 0.2 mg (35), 0.4 mg (30), or 0.6 mg (33) of tamsulosin once daily for 4 weeks. Free-flow and pressure-flow measurements, and modified Boyarsky symptom scores were used to determine efficacy. Safety was evaluated by monitoring adverse events and vital signs (including 8 h after the first dose), and by laboratory determinations. Results Tamsulosin 0.4 mg and 0.6 mg produced significantly greater improvements in maximum urinary flow rate (Qmax ) (2.2 mL/s, 22.6%, and 1.8 mL/s, 20.2%, respectively) than did placebo (−0.1 mL/s, −0.9%). The results from the pressure-flow studies confirmed the results for Qmax in the free flow studies, with optimum and significant effects for tamsulosin 0.4 mg. This also applied for detrusor pressure at maximum flow, which decreased by 26.6 cmH2O (−28.2%) on 0.4 mg tamsulosin whereas it increased by 4.9 cm H2O (5.7%) on placebo. The greatest reductions in total symptom score were obtained with tamsulosin 0.4 mg and 0.6 mg (4.1, −28.7%, and 4.4 points, −28.2%, respectively) compared with reductions of 3.4 (−20.1%) in the tamsulosin (0.2 mg) and 2.9 points (−17.7%) in the placebo groups. The difference in effects on total symptom score between treatment groups was not statistically significant, which can be attributed to the small sample size. Tamsulosin was well tolerated; at least one adverse event was reported by 29%, 23%, 27% and 36% of patients in the placebo and tamsulosin 0.2 mg, 0.4 mg and 0.6 mg groups, respectively. There were no apparent tamsulosin dose-dependent changes in vital signs from baseline to the end of 4 weeks of randomized treatment. Tamsulosin caused no statistically significantly greater changes in blood pressure than placebo during the initial 8 h after the first dose. There were no clinically significant changes in laboratory variables. Conclusion Tamsulosin is well tolerated and effective in improving urinary flow and relieving LUTS associated with BPO. Optimal effects are achieved with tamsulosin 0.4 mg administered once daily.