Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis

Background Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. Methods We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses. Findings A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55–2·08], p=5·13×10– ¹⁵) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42–1·71], p=7·65×10– ²⁰) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25–1·48], p=1·69×10– ¹²; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02–8·05]), despite similar baseline disease severity. Interpretation This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials. Funding UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR

Drug therapy of epileptic seizures among adult epileptic outpatients of University of Gondar Referral and Teaching Hospital, Gondar, North West Ethiopia

Eshetie Melese Birru,1 Miftah Shafi,2 Mestayet Geta11Department of Pharmacology, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia; 2Department of Pharmacy, Health Science College, Mizan-Tepi University, Mizan Aman, Ethiopia Objective: The aim of this study was to assess the practice of pharmacotherapy of epilepsy and its treatment outcomes in adult epileptic outpatients at the University of Gondar Referral and Teaching Hospital, Gondar, North West Ethiopia.Methods: An institution based, retrospective cross-sectional study was conducted from the medical charts of 336 adult epileptic patients at the outpatient epileptic clinic of Neurology Department of University of Gondar Teaching Hospital from May 2014 to April 2015. Reviewing follow-up information from the medical charts was used to evaluate antiepileptic drug (AED) prescribing patterns and treatment outcome. Data were collected by using data collection format and analyzed using SPSS software version 16.Results: The most common type of seizure diagnosed was generalized tonic–clonic seizure (n=245, 72.91%). Monotherapy with an AED accounted for 80.35% of the cases, whereas dual therapy and polytherapy with three AED combinations accounted for 16.37% and 3.28%, respectively. The most frequently prescribed AED was phenobarbitone (62.47%) followed by carbamazepine (17.91%). From the total epileptic cases, 277 (82.4%) had well-controlled seizure status in the last three consecutive months.Conclusion: Most of the patients were maintained by monotherapy, and largely this was by the older antiepileptic drug, phenobarbitone. Considering the development of pharmacotherapy of epilepsy and other patient related factors, the standard treatment guideline for Ethiopia needs to be revised periodically.Keywords: antiepileptics, epilepsy, treatment outcomes, prescription pattern

Addressing online information needs in palliative care : an action research-inspired approach

Whereas user participation has been embraced worldwide as a means to provide better patient outcomes, the implementation of formative, action research approaches in online health information has remained under-explored. The purpose of this study is to present an action research-based methodology that allows the scoping of health information and design needs in complex, multi-user online environments. The project\u27s four main stages were informed by an iterative, formative approach involving continuous expert and user evaluation. The study suggests that an action research-inspired formative approach can be successfully employed to generate user-participation. Moreover, sustained user-participation effectively addresses most quality issues regarding content, language, and accessibility raised in the recent literature. The paper concludes that an action research approach geared to develop online health resources deserves more attention. <br /

Obesity, metabolic syndrome, diabetes and smoking

It is becoming increasingly clear that arterial stiffness may be determined not only by age(ing) and blood pressure, but also by exposure to other cardiovascular risk factors. This chapter reviews the evidence provided by studies adopting an aetiological model of analyses of determinants of arterial stiffness, mainly derived, if available, from prospective designs. Specifically, the following risk factors are examined: the critical axis (central) obesity – metabolic syndrome – (type 2) diabetes, and also smoking. There is convincing evidence, reinforced by recent aetiological prospective studies, that these risk factors, all of which may be preventable, increase arterial stiffness. This may explain, at least in part, the increased cardiovascular disease risk observed in these conditions. However, the molecular basis of greater arterial stiffness associated with these risk factors remains to be fully elucidated. In addition, the prognostic significance of arterial stiffness indices in individuals with these risk factors, and the extent to which intervention on these risk factors improves cardiovascular outcome through beneficial impact on arterial stiffness, is still unclear. Given the high and/or increasing prevalence of these risk factors, these issues constitute an important research agenda