Genetic variants in Apolipoprotein AV alter triglyceride concentrations in pregnancy

BACKGROUND: Triglyceride concentrations are raised in pregnancy and are considered a key fetal fuel. Several gene variants are known to alter triglyceride concentrations, including those in the Apolipoprotein E (ApoE), Lipoprotein Lipase (LPL), and most recently, the Apolipoprotein AV (ApoAV) gene. However, less is known about how variants in these genes alter triglyceride concentrations in pregnancy or affect fetal growth. We aimed to determine the effect of the recently identified ApoAV gene on triglycerides in pregnancy and fetal growth. We assessed the role of two ApoAV haplotypes, defined by the C and W alleles of the -1131T>C and S19W polymorphisms, in 483 pregnant women and their offspring from the Exeter Family Study of Childhood Health. RESULTS: The -1131T>C and S19W variants have rare allele frequencies of 6.7% and 4.9% and are present in 13.4% and 9.7% of subjects respectively. In carriers of the -1131C and 19W alleles triglyceride concentrations were raised by 11.0% (1.98 mmol/ l(1.92 – 2.04) to 2.20 mmol/l (2.01 – 2.42), p = 0.035; and 16.2% (1.97 mmol/l (1.91 – 2.03) to 2.29 mmol/l (2.12 – 2.48), p < 0.001 respectively. There is nominally significant evidence that the -1131T>C variant is having an effect on maternal height (164.9 cm (164.3 – 165.5) to 167.0 cm (165.2 – 168.8), p = 0.029). There was no evidence that ApoAV genotype alters any other anthropometric measurements or biochemistries such as High Density Lipoprotein Cholesterol (HDL-C) or Low Density Lipoprotein Cholesterol (LDL-C). There is nominally significant evidence that the presence of a maternal -1131C variant alters fetal birth length (50.2 cm (50.0 – 50.4) to 50.9 cm (50.3 – 51.4), p = 0.022), and fetal birth crown-rump length (34.0 cm (33.8 – 34.1) to 34.5 cm (34.1 – 35.0), p = 0.023). There is no evidence that ApoAV genotype alters fetal birth weight or other fetal growth measurements. CONCLUSION: In conclusion variation in the ApoAV gene raises triglyceride concentrations in pregnancy, as well as normolipaemic states and there is preliminary evidence that it alters fetal growth parameters

Parental experiences of a diagnosis of neonatal diabetes and perceptions of newborn screening for glucose: a qualitative study

Neonatal diabetes presents <6 months of life but delays in recognition result in presentation with life-threatening hyperglycaemia/diabetic ketoacidosis. Early identification and rapid genetic diagnosis is crucial and ensures correct treatment/management. Adding 'glucose' to newborn bloodspot screening (NBS) could aid prompt detection but requires evidence of parental acceptance. Objectives: Increase understanding of parental experience of presentation/recognition of neonatal diabetes and perceptions of glucose testing within NBS. Setting: UK families confirmed with a genetic diagnosis of neonatal diabetes, November 2014-2018, were invited to participate. Participants: In-depth qualitative interviews were conducted with 10 parents of 14 children. 8 had transient neonatal diabetes: KCNJ11 (n=5), ABCC8 (n=1), 6q24 (n=2), 6 had permanent neonatal diabetes: KCNJ11 (n=4), INS (n=1), homozygous GCK (n=1). Primary and secondary outcome measures: Interviews audio recorded, transcribed and subjected to thematic content analysis. Results: 3 key themes emerged:Babies were extremely ill at hospital admission, with extended stays in intensive care required.Identification of diabetes was not 'standardised' and perceived a 'chance' finding.Adding glucose to NBS was universally considered extremely positive. Conclusions: Diagnosis of neonatal diabetes is frequently delayed, resulting in critically ill presentation with prolonged intensive care support, additional healthcare costs and familial distress. Potential to detect hyperglycaemia earlier was universally endorsed by parents with no negative consequences identified. Although further study including a larger number of individuals is needed to confirm our findings this study provides the first evidence of acceptability of glucose testing fulfilling Wilson-Jungner criteria for implementation within the NBS programme.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.MS is a National Institute for Health Research (NIHR) 70@70 Senior Nurse and Midwife Research Leaderpublished version, accepted version, submitted versio

GABA-modulating bacteria of the human gut microbiota.

The gut microbiota affects many important host functions, including the immune response and the nervous system1. However, while substantial progress has been made in growing diverse microorganisms of the microbiota2, 23-65% of species residing in the human gut remain uncultured3,4, which is an obstacle for understanding their biological roles. A likely reason for this unculturability is the absence in artificial media of key growth factors that are provided by neighbouring bacteria in situ5,6. In the present study, we used co-culture to isolate KLE1738, which required the presence of Bacteroides fragilis to grow. Bioassay-driven purification of B. fragilis supernatant led to the isolation of the growth factor, which, surprisingly, is the major inhibitory neurotransmitter GABA (γ-aminobutyric acid). GABA was the only tested nutrient that supported the growth of KLE1738, and a genome analysis supported a GABA-dependent metabolism mechanism. Using growth of KLE1738 as an indicator, we isolated a variety of GABA-producing bacteria, and found that Bacteroides ssp. produced large quantities of GABA. Genome-based metabolic modelling of the human gut microbiota revealed multiple genera with the predicted capability to produce or consume GABA. A transcriptome analysis of human stool samples from healthy individuals showed that GABA-producing pathways are actively expressed by Bacteroides, Parabacteroides and Escherichia species. By coupling 16S ribosmal RNA sequencing with functional magentic resonance imaging in patients with major depressive disorder, a disease associated with an altered GABA-mediated response, we found that the relative abundance levels of faecal Bacteroides are negatively correlated with brain signatures associated with depression

Will all scientists working on snails and the diseases they transmit please stand up?

Copyright © 2012 Adema et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.No abstract available

Moisture transport by Atlantic tropical cyclones onto the North American continent

Tropical Cyclones (TCs) are an important source of freshwater for the North American continent. Many studies have tried to estimate this contribution by identifying TC-induced precipitation events, but few have explicitly diagnosed the moisture fluxes across continental boundaries. We design a set of attribution schemes to isolate the column-integrated moisture fluxes that are directly associated with TCs and to quantify the flux onto the North American Continent due to TCs. Averaged over the 2004–2012 hurricane seasons and integrated over the western, southern and eastern coasts of North America, the seven schemes attribute 7 to 18 % (mean 14 %) of total net onshore flux to Atlantic TCs. A reduced contribution of 10 % (range 9 to 11 %) was found for the 1980–2003 period, though only two schemes could be applied to this earlier period. Over the whole 1980–2012 period, a further 8 % (range 6 to 9 % from two schemes) was attributed to East Pacific TCs, resulting in a total TC contribution of 19 % (range 17 to 22 %) to the ocean-to-land moisture transport onto the North American continent between May and November. Analysis of the attribution uncertainties suggests that incorporating details of individual TC size and shape adds limited value to a fixed radius approach and TC positional errors in the ERA-Interim reanalysis do not affect the results significantly, but biases in peak wind speeds and TC sizes may lead to underestimates of moisture transport. The interannual variability does not appear to be strongly related to the El Nino-Southern Oscillation phenomenon

Outcomes at five to eight years of age for children with Hirschsprung's disease.

OBJECTIVE: This study describes core outcomes of Hirschsprung's disease (HD) in a UK-wide cohort of primary school-aged children. DESIGN: A prospective cohort study conducted from 1 October 2010 to 30 September 2012. Outcomes data were collected from parents and clinicians when children were 5-8 years of age, and combined with data collected at birth, and 28 days and 1 year post diagnosis. SETTING: All 28 UK and Irish paediatric surgical centres. PARTICIPANTS: Children with histologically proven HD diagnosed at <6 months of age. MAIN OUTCOME MEASURES: NETS1HD core outcomes. RESULTS: Data were returned for 239 (78%) of 305 children. Twelve children (5%) died prior to 5 years of age.Of the 227 surviving children, 30 (13%) had a stoma and 21 (9%) were incontinent of urine. Of the 197 children without a stoma, 155 (79%) maintained bowel movements without enemas/washouts, while 124 (63%) reported faecal incontinence. Of the 214 surviving children who had undergone a pull-through operation, 95 (44%) underwent ≥1 unplanned reoperation. 89 unplanned reoperations (27%) were major/complex.Of the 83 children with returned PedsQL scores, 37 (49%) had quality of life scores, and 31 (42%) had psychological well-being scores, that were ≥1 SD lower than the reference population mean for children without HD. CONCLUSION: This study gives a realistic picture of population outcomes of HD in primary school-aged children in the UK/Ireland. The high rates of faecal incontinence, unplanned procedures and low quality of life scores are sobering. Ensuring clinicians address the bladder, bowel and psychological problems experienced by children should be a priority

Energy transitions and uncertainty: creating low carbon investment opportunities in the UK electricity sector

This paper examines how actors in the UK electricity sector are attempting to deliver investment in low carbon generation. Low carbon technologies, because of their relative immaturity, capital intensity and low operational costs, do not readily fit with existing electricity markets and investment templates which were designed for fossil fuel based energy. We analyse key electricity market and infrastructure policies in the UK and highlight how these are aimed at making low carbon technologies ‘investable’ by reducing uncertainty, managing investment risks and repositioning actors within the electricity socio-technical ‘regime’. We argue that our study can inform contemporary debates on the politics and governance of sustainability transitions by empirically investigating the agency of incumbent regime actors in the face of uncertainty and by offering critical insights on the role of markets and finance in shaping socio-technical change

Toward a predictive understanding of Earth’s microbiomes to address 21st century challenges

© The Author(s), 2016. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in mBio 7 (2016): e00714-16, doi:10.1128/mBio.00714-16.Microorganisms have shaped our planet and its inhabitants for over 3.5 billion years. Humankind has had a profound influence on the biosphere, manifested as global climate and land use changes, and extensive urbanization in response to a growing population. The challenges we face to supply food, energy, and clean water while maintaining and improving the health of our population and ecosystems are significant. Given the extensive influence of microorganisms across our biosphere, we propose that a coordinated, cross-disciplinary effort is required to understand, predict, and harness microbiome function. From the parallelization of gene function testing to precision manipulation of genes, communities, and model ecosystems and development of novel analytical and simulation approaches, we outline strategies to move microbiome research into an era of causality. These efforts will improve prediction of ecosystem response and enable the development of new, responsible, microbiome-based solutions to significant challenges of our time.E.L.B. is supported by the Genomes-to-Watersheds Subsurface Biogeochemical Research Scientific Focus Area, and T.R.N. is supported by ENIGMA-Ecosystems and Networks Integrated with Genes and Molecular Assemblies (http://enigma.lbl.gov) Scientific Focus Area, funded by the U.S. Department of Energy (US DOE), Office of Science, Office of Biological and Environmental Research under contract no. DE-AC02- 05CH11231 to Lawrence Berkeley National Laboratory (LBNL). M.E.M. is also supported by the US DOE, Office of Science, Office of Biological and Environmental Research under contract no. DE-AC02-05CH11231. Z.G.C. is supported by National Science Foundation Integrative Organismal Systems grant #1355085, and by US DOE, Office of Biological and Environmental Research grant # DE-SC0008182 ER65389 from the Terrestrial Ecosystem Science Program. M.J.B. is supported by R01 DK 090989 from the NIH. T.J.D. is supported by the US DOE Office of Science’s Great Lakes Bioenergy Research Center, grant DE-FC02- 07ER64494. J.L.G. is supported by Alfred P. Sloan Foundation G 2-15-14023. R.K. is supported by grants from the NSF (DBI-1565057) and NIH (U01AI24316, U19AI113048, P01DK078669, 1U54DE023789, U01HG006537). K.S.P. is supported by grants from the NSF DMS- 1069303 and the Gordon & Betty Moore Foundation (#3300)

Population-Based Assessment of a Biomarker-Based Screening Pathway to Aid Diagnosis of Monogenic Diabetes in Young-Onset Patients

This is the author accepted manuscript. The final version is available from the American Diabetes Association via the DOI in this record.Objective: Monogenic diabetes, a young-onset form of diabetes, is often misdiagnosed as Type 1 diabetes, resulting in unnecessary treatment with insulin. A screening approach for monogenic diabetes is needed to accurately select suitable patients for expensive diagnostic genetic testing. We used C-peptide and islet autoantibodies, highly sensitive and specific biomarkers for discriminating Type 1 from non-Type 1 diabetes, in a biomarker screening pathway for monogenic diabetes. Research Design and Methods: We studied patients diagnosed ≤30y, currently <50y, in two UK regions with existing high detection of monogenic diabetes. The biomarker screening pathway comprised 3 stages: 1) Assessment of endogenous insulin secretion using urinary C-peptide/creatinine ratio (UCPCR); 2) If UCPCR≥0.2nmol/mmol, measurement of GAD and IA2 islet autoantibodies; 3) If negative for both autoantibodies, molecular genetic diagnostic testing for 35 monogenic diabetes subtypes. Results: 1407 patients participated (1365 no known genetic cause, 34 monogenic diabetes, 8 cystic-fibrosis-related diabetes). 386/1365(28%) had UCPCR≥0.2nmol/mmol. 216/386(56%) of these patients were negative for GAD and IA2 and underwent molecular genetic testing. 17 new cases of monogenic diabetes were diagnosed (8 common MODY (Sanger sequencing), 9 rarer causes (next generation sequencing)) in addition to the 34 known cases (estimated prevalence of 3.6% (51/1407) (95%CI: 2.7-4.7%)). The positive predictive value was 20%, suggesting a 1-in-5 detection rate for the pathway. The negative predictive value was 99.9%. Conclusions: The biomarker screening pathway for monogenic diabetes is an effective, cheap, and easily implemented approach to systematically screening all young-onset patients. The minimum prevalence of monogenic diabetes is 3.6% of patients diagnosed ≤30y.This study was funded by the Department of Health and Wellcome Trust Health Innovation Challenge Award (HICF-1009-041; WT-091985). ATH and SE are Wellcome Trust Senior Investigators. ATH is an NIHR Senior Investigator. BS, ATH, MH, SE, and BK are core members of the NIHR Exeter Clinical Research Facility. EP is a Wellcome Trust New Investigator. TM is supported by NIHR CSO Fellowship. JP is partly funded by the NIHR Collaboration for Leadership in Applied Health Research and Care for the South West (PenCLAHRC)