Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.</p

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

Cranberry syrup vs trimethoprim in the prophylaxis of recurrent urinary tract infections among children: a controlled trial

Jose Uberos,1 Mercedes Nogueras-Ocana,2 Ver&amp;oacute;nica Fernandez-Puentes,1 Rocio Rodriguez-Belmonte,1 Eduardo Narbona-L&amp;oacute;pez,1 Antonio Molina-Carballo,1 Antonio Munoz-Hoyos11Paediatric Clinical Management Unit, San Cecilio University Clinical Hospital, Avda de Madrid s/n, Granada, Spain; 2Paediatric Urology, San Cecilio University Clinical Hospital, Avda de Madrid s/n, Granada, SpainObjectives: The present study forms part of the ISRCTN16968287 clinical assay. The objective of this study was to determine the effectiveness of cranberry syrup in the prophylaxis of recurrent urinary tract infection (UTI).Design: Phase III randomized clinical trial.Setting: The study was conducted at the San Cecilio Clinical Hospital (Granada, Spain).Participants: A total of 192 patients were recruited. The subjects were aged between 1 month and 13 years. Criteria for inclusion were a background of recurrent UTI (more than two episodes of infection in the last 6 months), associated or otherwise with vesicoureteral reflux of any degree, or renal pelvic dilatation associated with UTI. Criteria for exclusion from recruitment to the study included the co-existence of UTI with other infectious diseases or with metabolic diseases, chronic renal insufficiency, and the presence of allergy or intolerance to any of the components of cranberry syrup or trimethoprim.Primary outcome measures: The primary objective was to determine the risk of UTI associated with each intervention.Results: Of the 198 patients initially eligible, 192 were finally included in the study to receive either cranberry syrup or trimethoprim. UTI was observed in 47 patients, 17 of whom were males and 30 females. We recruited 95 patients diagnosed with recurrent UTI on entry; during follow-up, 26 patients had a UTI (27.4%, 95% CI: 18.4%&amp;ndash;36.3%). Six patients (6.3%) were male and 20 (21.1%) were female. Eighteen patients (18.9% of the total, 95% CI: 11%&amp;ndash;26.3%) receiving trimethoprim had a UTI and eight patients (8.4% of the total, 95% CI: 2.8%&amp;ndash;13.9%) were given cranberry. Sixty-six percent of the episodes of UTI recurrence were caused by Escherichia coli, with no significant differences being found between the two treatment branches. No differences were observed between the two treatment branches in the rate of resistance to antibiotics.Conclusion: Our study confirms that cranberry syrup is a safe treatment for the pediatric population. Cranberry prophylaxis has noninferiority with respect to trimethoprim in recurrent UTI. (European Clinical Trials Registry EuDract 2007-004397-62) (ISRCTN16968287).Keywords: cranberry, urinary tract infections, trimethoprim, vesicoureteral reflux, antibiotic prophylaxis&amp;nbsp

The International Network for Evaluating Outcomes (iNeo) of neonates: evolution, progress and opportunities

Neonates born very preterm (before 32 weeks’ gestational age), are a significant public health concern because of their high-risk of mortality and life-long disability. In addition, caring for very preterm neonates can be expensive, both during their initial hospitalization and their long-term cost of permanent impairments. To address these issues, national and regional neonatal networks around the world collect and analyse data from their constituents to identify trends in outcomes, and conduct benchmarking, audit and research. Improving neonatal outcomes and reducing health care costs is a global problem that can be addressed using collaborative approaches to assess practice variation between countries, conduct research and implement evidence-based practices. The International Network for Evaluating Outcomes (iNeo) of neonates was established in 2013 with the goal of improving outcomes for very preterm neonates through international collaboration and comparisons. To date, 10 national or regional population-based neonatal networks/datasets participate in iNeo collaboration. The initiative now includes data on >200,000 very preterm neonates and has conducted important epidemiological studies evaluating outcomes, variations and trends. The collaboration has also surveyed >320 neonatal units worldwide to learn about variations in practices, healthcare service delivery, and physical, environmental and manpower related factors and support services for parents. The iNeo collaboration serves as a strong international platform for Neonatal-Perinatal health services research that facilitates international data sharing, capacity building, and global efforts to improve very preterm neonate care