The NESHIE and CP Genetics Resource (NCGR): A database of genes and variants reported in neonatal encephalopathy with suspected hypoxic ischemic encephalopathy (NESHIE) and consequential cerebral palsy (CP)

DATA AVAILABILTY : All data generated or analysed during this study are included in this published article, supplementary information files, and the NCGR database repository. Access to the NCGR database is available at http://ncgr.bi.up.ac.za/. Additional data will be made available on request.SUPPLEMENTARY DATA : SUPPLEMENTARY FIG. 1. User input for a complex query generated using NCGR's filter functionality to prioritise genes likely to predispose individuals to NESHIE. Abbreviations: CP: cerebral palsy; NESHIE: neonatal encephalopathy with suspected hypoxic ischemic encephalopathy; HPO: human phenotype ontology; NCGR: NESHIE and CP genetics resource.SUPPLEMENTARY FIG. 2. Protein-protein interaction network constructed using genes that were prioritised based on evidence of potential involvement in a genetic predisposition to neonatal encephalopathy with suspected hypoxic ischaemic encephalopathy (NESHIE). Protein products of the input set of genes are represented by blue nodes. Additional direct and secondary interactors of the input set are represented in grey.SUPPLEMENTARY DATA A. Methods used to perform gene ontology enrichment and protein-protein interaction network analyses.SUPPLEMENTARY DATA B. Gene Ontology enrichment resultsSUPPLEMENTARY TABLE 1. Variant Details table data.SUPPLEMENTARY TABLE 2. Ensembl Variant Effect Prediction table data.SUPPLEMENTARY TABLE 3. Gene Details table data.SUPPLEMENTARY TABLE 4. Gene Human Phenotype Ontology table data.SUPPLEMENTARY TABLE 5. MutationTaster Variant Effect Prediction table data.SUPPLEMENTARY TABLE 6. Study Details table data.SUPPLEMENTARY TABLE 7. Study Findings table data.Neonatal encephalopathy (NE) with suspected hypoxic ischaemic encephalopathy (HIE) (NESHIE) is a complex syndrome occurring in newborns, characterised by altered neurological function. It has been suggested that genetic variants may influence NESHIE susceptibility and outcomes. Unlike NESHIE, for which a limited number of genetic studies have been performed, many studies have identified genetic variants associated with cerebral palsy (CP), which can develop from severe NESHIE. Identifying variants in patients with CP, as a consequence of NESHIE, may provide a starting point for the identification of genetic variants associated with NESHIE outcomes. We have constructed NCGR (NESHIE and CP Genetics Resource), a database of genes and variants reported in patients with NESHIE and CP (where relevant to NESHIE), for the purpose of collating and comparing genetic findings between the two conditions. In this paper we describe the construction and functionality of NCGR. Furthermore, we demonstrate how NCGR can be used to prioritise genes and variants of potential clinical relevance that may underlie a genetic predisposition to NESHIE and contribute to an understanding of its pathogenesis.The Bill & Melinda Gates Foundation, Seattle, USA; the South African Medical Research Council, Cape Town, South Africa; and the University of Pretoria through the Institute for Cellular and Molecular Medicine.https://www.elsevier.com/locate/ygenohj2023BiochemistryGeneticsImmunologyMicrobiology and Plant Patholog

Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers

The risk of germline copy number variants (CNVs) in BRCA1 and BRCA2 pathogenic variant carriers in breast cancer is assessed, with CNVs overlapping SULT1A1 decreasing breast cancer risk in BRCA1 carriers.The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.Peer reviewe

Hypernatraemia in South African hospitalized patients

CITATION: Abohajir, A., Rensburg, M. A. & Davids, M. R. 2019. Hypernatraemia in South African hospitalized patients. African Journal of Nephrology, 22(1):12-16, doi:10.21804/22-1-3285.The original publication is available at http://www.journals.ac.za/index.php/ajn/Background: Hypernatraemia is a common electrolyte problem in hospitalized patients and is associated with a high mortality rate. We determined the incidence, causes, management, and outcomes of hypernatraemia in adult hospitalized patients at a large South African tertiary hospital. Methods: A retrospective study was conducted at Tygerberg Hospital in Cape Town, South Africa. Adult patients with hypernatraemia (at least one serum sodium concentration ≥150 mmol/L) during a 3-month period in 2014 were identified from our laboratory database for inclusion. Results: There were 204 patients with hypernatraemia, a prevalence of 1.5%. Of these patients, 101 (49.5%) were male, and the mean age was 53 years. There were 66 patients (32.4%) who had hypernatraemia on admission, and 138 who developed it during the course of their stay in hospital. The overall in-hospital mortality was 38.7%, with higher rates for older patients and those with more severe degrees of hypernatraemia. Contributory causes which were most commonly present included dehydration/hypovolaemia (45%), followed by sepsis (39%). Net sodium gain, rather than water deficit, was identified as the main mechanism in most of the patients who developed hypernatraemia in the intensive care units. We found little evidence of any diagnostic work-up and also found that the details of fluid therapy and intake–output charting were poorly documented. Conclusions: There is a very high mortality rate in our hospitalized patients with hypernatraemia. The diagnostic work-up and therapy were often inadequate or poorly documented. The management of this important condition needs to be improved with the aid of standardized protocols.http://www.journals.ac.za/index.php/ajn/article/view/3285Publisher's versio

Distribution and association of hs-CRP with cardiovascular risk variables of metabolic syndrome in adolescent learners

CITATION: Rensburg, M. A., et al. 2012. Distribution and association of hs-CRP with cardiovascular risk variables of metabolic syndrome in adolescent learners. African Journal of Laboratory Medicine, 1(1): 1-6, doi: 10.4102/ajlm.v1i1.10.The original publication is available at http://www.ajlmonline.orgObjective: Metabolic syndrome (MetS) and its associated cardiovascular risk are on the increase in children. High-sensitivity C-reactive protein (hs-CRP) has emerged as a useful marker for inflammation associated with atherosclerosis and cardiovascular disease. Our aim was to determine the distribution of hs-CRP in an effort to identify the MetS variable that is critical in modulating plasma CRP levels in a population of South African adolescents. Design: A cross-sectional analytical study design was used for this investigation, where the dependent and independent variables were measured simultaneously. Methods: Anthropometric variables, blood pressure, fasting blood glucose and lipids were performed on 324 consenting learners aged 15–18 years from three different ethnic groups (Black, White and Coloured). The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) for ages 15–18 year olds was used to define MetS. Results: The prevalence of MetS and obesity was 3.7% and 7.1%, respectively. The hs-CRP levels were significantly higher in subjects with a waist-circumference greater than the 90th percentile (p < 0.01) and in obese learners with MetS, but was lower in adolescents with normal weight and MetS. Median hs-CRP levels increased with an increasing number of metabolic abnormalities and exceeded 3 mg/L in 19% of adolescents. Gender and ethnic differences were observed. Conclusion: Our findings suggest that obesity and waist circumference appear to be major mediators of hs-CRP levels in South African adolescents.http://www.ajlmonline.org/index.php/ajlm/article/view/10Publisher's versio

Bolus administration of intravenous glucose in the treatment of hyperkalemia : a randomized controlled trial

Please cite as follows:Chothia, M-Y. et al. 2014. Bolus Administration of Intravenous Glucose in the Treatment of Hyperkalemia: A Randomized Controlled Trial. Nephron Physiology, 1(26):1-8, doi:10.1159/000358836.The original publication is available at http://www.karger.com/Journal/Issue/261595Background: Hyperkalemia is a common medical emergency that may result in serious cardiac arrhythmias. Standard therapy with insulin plus glucose reliably lowers the serum potassium concentration ([K + ]) but carries the risk of hypoglycemia. This study examined whether an intravenous glucose- only bolus lowers serum [K + ] in stable, nondiabetic, hyperkalemic patients and compared this intervention with insulin-plus-glucose therapy. Methods: A randomized, crossover study was conducted in 10 chronic hemodialysis patients who were prone to hyperkalemia. Administration of 10 units of insulin with 100 ml of 50% glucose (50 g) was compared with the administration of 100 ml of 50% glucose only. Serum [K + ] was measured up to 60 min. Patients were monitored for hypoglycemia and EKG changes. Results: Baseline serum [K + ] was 6.01 ± 0.87 and 6.23 ± 1.20 mmol/l in the insulin and glucose-only groups, respectively (p = 0.45). At 60 min, the glucose-only group had a fall in [K + ] of 0.50 ± 0.31 mmol/l (p < 0.001). In the insulin group, there was a fall of 0.83 ± 0.53 mmol/l at 60 min (p < 0.001) and a lower serum [K + ] at that time compared to the glucose-only group (5.18 ± 0.76 vs. 5.73 ± 1.12 mmol/l, respectively; p = 0.01). In the glucose-only group, the glucose area under the curve (AUC) was greater and the insulin AUC was smaller. Two patients in the insulin group developed hypoglycemia. Conclusion: Infusion of a glucose-only bolus caused a clinically significant decrease in serum [K + ] without any episodes of hypoglycemia.Post-prin

Chronic kidney diseases in mixed ancestry South African populations : prevalence, determinants and concordance between kidney function estimators

The original publication is available at http://www.biomedcentral.com/1471-2369/14/75Bibliography.ABSTRACT: Population-based data on the burden of chronic kidney disease (CKD) in sub-Saharan Africa is still very limited. We assessed the prevalence and determinants of CKD, and evaluated the concordance of commonly advocated estimators of glomerular filtration rate (eGFR) in a mixed ancestry population from South Africa. Methods Participants were a population-based sample of adults selected from the Bellville-South community in the metropolitan city of Cape Town. eGFR was based on the Cockroft-Gault (CG), Modification of Diet in Kidney Disease (MDRD) and CKD Epidemiology Collaboration (CKD-EPI) equations (with and without adjustment for ethnicity). Kidney function staging used the Kidney Disease Outcome Quality Initiative (KDOQI) classification. Logistic regressions and kappa statistic were used to investigate determinants of CKD and assess the agreement between different estimators. Results The crude prevalence of CKD stage 3–5 was 14.8% for Cockcroft-Gault, 7.6% and 23.9% respectively for the MDRD with and without ethnicity correction, and 7.4% and 17.3% for the CKD-EPI equations with and without ethnicity correction. The highest agreement between GFR estimators was between MDRD and CKD-EPI equations, both with ethnicity correction, Kappa 0.91 (95% CI: 0.86-0.95), correlation coefficient 0.95 (95% CI: 0.94-0.96). In multivariable logistic regression models, sex, age and known hypertension were consistently associated with CKD stage 3–5 across the 5 estimators. Conclusions The prevalence of CKD stages greater than 3 is the highest reported in Africa. This study provides evidence for support of the CKD-EPI equation for eGFR reporting and CKD classification.Publishers' Versio