A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

dentification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 x 10(-8)) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.Peer reviewe

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

Pragmatic Recommendations for the Prevention and Treatment of Acute Kidney Injury in Patients with COVID-19 in Low- and Middle-Income Countries

Current recommendations for the management of patients with COVID-19 and acute kidney injury (AKI) are largely based on evidence from resource-rich settings, mostly located in high-income countries. It is often unpractical to apply these recommendations to resource-restricted settings. We report on a set of pragmatic recommendations for the prevention, diagnosis, and management of patients with COVID-19 and AKI in low- and middle-income countries (LMICs). For the prevention of AKI among patients with COVID-19 in LMICs, we recommend using isotonic crystalloid solutions for expansion of intravascular volume, avoiding nephrotoxic medications, and using a conservative fluid management strategy in patients with respiratory failure. For the diagnosis of AKI, we suggest that any patient with COVID-19 presenting with an elevated serum creatinine level without available historical values be considered as having AKI. If serum creatinine testing is not available, we suggest that patients with proteinuria should be considered to have possible AKI. We suggest expansion of the use of point-of-care serum creatinine and salivary urea nitrogen testing in community health settings, as funding and availability allow. For the management of patients with AKI and COVID-19 in LMICS, we recommend judicious use of intravenous fluid resuscitation. For patients requiring dialysis who do not have acute respiratory distress syndrome (ARDS), we suggest using peritoneal dialysis (PD) as first choice, where available and feasible. For patients requiring dialysis who do have ARDS, we suggest using hemodialysis, where available and feasible, to optimize fluid removal. We suggest using locally produced PD solutions when commercially produced solutions are unavailable or unaffordable

Pragmatic recommendations for identification and triage of patients with COVID-19 in low- And middle-income countries

Effective identification and prognostication of severe COVID-19 patients presenting to healthcare facilities are essential to reducing morbidity and mortality. Low- and middle-income country (LMIC) facilities often suffer from restrictions in availability of human resources, laboratory testing, medications, and imaging during routine functioning, and such shortages may worsen during times of surge. Low- and middle-income country healthcare providers will need contextually appropriate tools to identify and triage potential COVID-19 patients. We report on a series of LMIC-appropriate recommendations and suggestions for screening and triage of COVID-19 patients in LMICs, based on a pragmatic, experience-based appraisal of existing literature. We recommend that all patients be screened upon first contact with the healthcare system using a locally approved questionnaire to identify individuals who have suspected or confirmed COVID-19. We suggest that primary screening tools used to identify individuals who have suspected or confirmed COVID-19 include a broad range of signs and symptoms based on standard case definitions of COVID-19 disease. We recommend that screening include endemic febrile illness per routine protocols upon presentation to a healthcare facility. We recommend that, following screening and implementation of appropriate universal source control measures, suspected COVID-19 patients be triaged with a triage tool appropriate for the setting. We recommend a standardized severity score based on the WHO COVID-19 disease definitions be assigned to all suspected and confirmed COVID-19 patients before their disposition from the emergency unit. We suggest against using diagnostic imaging to improve triage of reverse transcriptase (RT)-PCR-confirmed COVID-19 patients, unless a patient has worsening respiratory status. We suggest against the use of point-of-care lung ultrasound to improve triage of RT-PCR-confirmed COVID-19 patients. We suggest the use of diagnostic imaging to improve sensitivity of appropriate triage in suspected COVID-19 patients who are RT-PCR negative but have moderate to severe symptoms and are suspected of a false-negative RT-PCR with high risk of disease progression. We suggest the use of diagnostic imaging to improve sensitivity of appropriate triage in suspected COVID-19 patients with moderate or severe clinical features who are without access to RT-PCR testing for SARS-CoV-2

Highlights from an Expert Meeting on Opportunities for Cancer Prevention among Older Adults

© 2019 Published by Oxford University Press on behalf of The Gerontological Society of America 2019. This paper provides highlights from an expert meeting to explore opportunities to reduce cancer risk and promote health at older ages. Factors that increase cancer risk among older adults include exposure to carcinogens from multiple sources, chronic conditions such as obesity and diabetes, and unhealthy behaviors. Emerging research points to chronic social stressors - social isolation, loneliness, and financial hardship - as being linked to accelerated biological aging and increased cancer risk later in life. Older adults may disproportionately encounter these stressors as well as barriers to preventive health care services, accurate health information, and environments that promote health. Researchers can use existing cohort studies of older adults to deepen our understanding of the relative benefit of modifying specific behaviors and circumstances. The evidence points to the value of comprehensive, transdisciplinary approaches to promote health and reduce cancer risk across the entire lifespan, extending through older adulthood. Clinical encounters with older adults provide opportunities for psychosocial and behavioral screening and counseling. In the presence of multiple morbidities, preventive health services may offer greater health benefits than cancer-screening tests. Strategies that involve families and caregivers, promote positive attitudes about aging, and engage many different community sectors have the potential to prevent or delay the development of cancer at older ages