Pregnancy glycaemia and cord-blood levels of insulin and leptin in Pakistani and white British mother–offspring pairs: findings from a prospective pregnancy cohort

Aims/hypothesis To determine the extent to which gestational fasting and postload levels of glucose explain differences in infant fat mass between UK-born Pakistani and white British infants. Methods Analyses were undertaken in a prospective pregnancy cohort study of 1,415 women and their singleton live-born infants (629 white British and 786 Pakistani). Infant fat mass was assessed by cord-blood leptin levels and fetal insulin secretion by cord-blood insulin levels. Maternal OGTTs were completed at 26–28 weeks of gestation. Results Pakistani women had higher fasting and postload glucose levels and greater incidence of gestational diabetes than white British women. Higher fasting and postload glucose levels were associated with higher cord-blood levels of insulin and leptin in all participants, irrespective of ethnicity. Cord-blood leptin levels were 16% (95% CI 6, 26) higher in Pakistani than in white British infants. After adjustment for fasting glucose levels, this difference attenuated to 7% (−3, 16), and with additional adjustment for cord-blood insulin levels it attenuated further to 5% (−4, 14). Path analyses supported the hypothesis that fasting glucose levels mediate the relationship of Pakistani ethnicity to greater fat mass at birth, as measured by cord-blood leptin levels; on average, 19% of this mediation involved fetal insulin secretion. Postload glucose levels did not act as an important mediator of ethnic differences in cord-blood leptin levels. Results were very similar when 130 women with gestational diabetes were removed. Conclusions/interpretation These novel findings suggest a role of maternal pregnancy glycaemia in mediating differences in fat mass between Pakistani and white British infants

Adaptive venom evolution and toxicity in octopods is driven by extensive novel gene formation, expansion, and loss

Background: Cephalopods represent a rich system for investigating the genetic basis underlying organismal novelties. This diverse group of specialized predators has evolved many adaptations including proteinaceous venom. Of particular interest is the blue-ringed octopus genus (Hapalochlaena), which are the only octopods known to store large quantities of the potent neurotoxin, tetrodotoxin, within their tissues and venom gland. Findings: To reveal genomic correlates of organismal novelties, we conducted a comparative study of 3 octopod genomes, including the Southern blue-ringed octopus (Hapalochlaena maculosa). We present the genome of this species and reveal highly dynamic evolutionary patterns at both non-coding and coding organizational levels. Gene family expansions previously reported in Octopus bimaculoides (e.g., zinc finger and cadherins, both associated with neural functions), as well as formation of novel gene families, dominate the genomic landscape in all octopods. Examination of tissue-specific genes in the posterior salivary gland revealed that expression was dominated by serine proteases in non–tetrodotoxin-bearing octopods, while this family was a minor component in H. maculosa. Moreover, voltage-gated sodium channels in H. maculosa contain a resistance mutation found in pufferfish and garter snakes, which is exclusive to the genus. Analysis of the posterior salivary gland microbiome revealed a diverse array of bacterial species, including genera that can produce tetrodotoxin, suggestive of a possible production source. Conclusions: We present the first tetrodotoxin-bearing octopod genome H. maculosa, which displays lineage-specific adaptations to tetrodotoxin acquisition. This genome, along with other recently published cephalopod genomes, represents a valuable resource from which future work could advance our understanding of the evolution of genomic novelty in this family

The identification and treatment of women with hyperglycaemia in pregnancy: an analysis of individual participant data, systematic reviews, meta-analyses and an economic evaluation

Background Gestational diabetes mellitus (GDM) is associated with a higher risk of important adverse outcomes. Practice varies and the best strategy for identifying and treating GDM is unclear. Aim To estimate the clinical effectiveness and cost-effectiveness of strategies for identifying and treating women with GDM. Methods We analysed individual participant data (IPD) from birth cohorts and conducted systematic reviews to estimate the association of maternal glucose levels with adverse perinatal outcomes; GDM prevalence; maternal characteristics/risk factors for GDM; and the effectiveness and costs of treatments. The cost-effectiveness of various strategies was estimated using a decision tree model, along with a value of information analysis to assess where future research might be worthwhile. Detailed systematic searches of MEDLINE® and MEDLINE In-Process & Other Non-Indexed Citations®, EMBASE, Cumulative Index to Nursing and Allied Health Literature Plus, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Health Technology Assessment database, NHS Economic Evaluation Database, Maternity and Infant Care database and the Cochrane Methodology Register were undertaken from inception up to October 2014. Results We identified 58 studies examining maternal glucose levels and outcome associations. Analyses using IPD alone and the systematic review demonstrated continuous linear associations of fasting and post-load glucose levels with adverse perinatal outcomes, with no clear threshold below which there is no increased risk. Using IPD, we estimated glucose thresholds to identify infants at high risk of being born large for gestational age or with high adiposity; for South Asian (SA) women these thresholds were fasting and post-load glucose levels of 5.2 mmol/l and 7.2 mmol/l, respectively and for white British (WB) women they were 5.4 and 7.5 mmol/l, respectively. Prevalence using IPD and published data varied from 1.2% to 24.2% (depending on criteria and population) and was consistently two to three times higher in SA women than in WB women. Lowering thresholds to identify GDM, particularly in women of SA origin, identifies more women at risk, but increases costs. Maternal characteristics did not accurately identify women with GDM; there was limited evidence that in some populations risk factors may be useful for identifying low-risk women. Dietary modification additional to routine care reduced the risk of most adverse perinatal outcomes. Metformin (Glucophage,® Teva UK Ltd, Eastbourne, UK) and insulin were more effective than glibenclamide (Aurobindo Pharma – Milpharm Ltd, South Ruislip, Middlesex, UK). For all strategies to identify and treat GDM, the costs exceeded the health benefits. A policy of no screening/testing or treatment offered the maximum expected net monetary benefit (NMB) of £1184 at a cost-effectiveness threshold of £20,000 per quality-adjusted life-year (QALY). The NMB for the three best-performing strategies in each category (screen only, then treat; screen, test, then treat; and test all, then treat) ranged between –£1197 and –£1210. Further research to reduce uncertainty around potential longer-term benefits for the mothers and offspring, find ways of improving the accuracy of identifying women with GDM, and reduce costs of identification and treatment would be worthwhile. Limitations We did not have access to IPD from populations in the UK outside of England. Few observational studies reported longer-term associations, and treatment trials have generally reported only perinatal outcomes. Conclusions Using the national standard cost-effectiveness threshold of £20,000 per QALY it is not cost-effective to routinely identify pregnant women for treatment of hyperglycaemia. Further research to provide evidence on longer-term outcomes, and more cost-effective ways to detect and treat GDM, would be valuable

On the Importance of Countergradients for the Development of Retinotopy: Insights from a Generalised Gierer Model

During the development of the topographic map from vertebrate retina to superior colliculus (SC), EphA receptors are expressed in a gradient along the nasotemporal retinal axis. Their ligands, ephrin-As, are expressed in a gradient along the rostrocaudal axis of the SC. Countergradients of ephrin-As in the retina and EphAs in the SC are also expressed. Disruption of any of these gradients leads to mapping errors. Gierer's (1981) model, which uses well-matched pairs of gradients and countergradients to establish the mapping, can account for the formation of wild type maps, but not the double maps found in EphA knock-in experiments. I show that these maps can be explained by models, such as Gierer's (1983), which have gradients and no countergradients, together with a powerful compensatory mechanism that helps to distribute connections evenly over the target region. However, this type of model cannot explain mapping errors found when the countergradients are knocked out partially. I examine the relative importance of countergradients as against compensatory mechanisms by generalising Gierer's (1983) model so that the strength of compensation is adjustable. Either matching gradients and countergradients alone or poorly matching gradients and countergradients together with a strong compensatory mechanism are sufficient to establish an ordered mapping. With a weaker compensatory mechanism, gradients without countergradients lead to a poorer map, but the addition of countergradients improves the mapping. This model produces the double maps in simulated EphA knock-in experiments and a map consistent with the Math5 knock-out phenotype. Simulations of a set of phenotypes from the literature substantiate the finding that countergradients and compensation can be traded off against each other to give similar maps. I conclude that a successful model of retinotopy should contain countergradients and some form of compensation mechanism, but not in the strong form put forward by Gierer

Reduced levels of two modifiers of epigenetic gene silencing, Dnmt3a and Trim28, cause increased phenotypic noise

Background: Inbred individuals reared in controlled environments display considerable variance in many complex traits but the underlying cause of this intangible variation has been an enigma. Here we show that two modifiers of epigenetic gene silencing play a critical role in the process.Results: Inbred mice heterozygous for a null mutation in DNA methyltransferase 3a (Dnmt3a) or tripartite motif protein 28 (Trim28) show greater coefficients of variance in body weight than their wild-type littermates. Trim28 mutants additionally develop metabolic syndrome and abnormal behavior with incomplete penetrance. Genome-wide gene expression analyses identified 284 significantly dysregulated genes in Trim28 heterozygote mutants compared to wild-type mice, with Mas1, which encodes a G-protein coupled receptor implicated in lipid metabolism, showing the greatest average change in expression (7.8-fold higher in mutants). This gene also showed highly variable expression between mutant individuals.Conclusions: These studies provide a molecular explanation of developmental noise in whole organisms and suggest that faithful epigenetic control of transcription is central to suppressing deleterious levels of phenotypic variation. These findings have broad implications for understanding the mechanisms underlying sporadic and complex disease in humans

Evaluation of the impact of universal testing for gestational diabetes mellitus on maternal and neonatal health outcomes: a retrospective analysis

Background: Gestational diabetes (GDM) affects a substantial proportion of women in pregnancy and is associated with increased risk of adverse perinatal and long term outcomes. Treatment seems to improve perinatal outcomes, the relative effectiveness of different strategies for identifying women with GDM however is less clear. This paper describes an evaluation of the impact of a change in policy from selective risk factor based offering, to universal offering of an oral glucose tolerance test (OGTT) to identify women with GDM on maternal and neonatal outcomes. Methods: Retrospective six year analysis of 35,674 births at the Women’s and Newborn unit, Bradford Royal Infirmary, United Kingdom. Results: The proportion of the whole obstetric population diagnosed with GDM increased almost fourfold following universal offering of an OGTT compared to selective offering of an OGTT; Rate Ratio (RR) 3.75 (95% CI 3.28 to 4.29), the proportion identified with severe hyperglycaemia doubled following the policy change; 1.96 (1.50 to 2.58). The case detection rate however, for GDM in the whole population and severe hyperglycaemia in those with GDM reduced by 50-60%; 0.40 (0.35 to 0.46) and 0.51 (0.39 to 0.67) respectively. Universally offering an OGTT was associated with an increased induction of labour rate in the whole obstetric population and in women with GDM; 1.43 (1.35 to 1.50) and 1.21 (1.00 to1.49) respectively. Caesarean section, macrosomia and perinatal mortality rates in the whole population were similar. For women with GDM, rate of caesarean section; 0.70 (0.57 to 0.87), macrosomia; 0.22 (0.15 to 0.34) and perinatal mortality 0.12 (0.03 to 0.46) decreased following the policy change. Conclusions: Universally offering an OGTT was associated with increased identification of women with GDM and severe hyperglycaemia and with neonatal benefits for those with GDM. There was no evidence of benefit or adverse effects in neonatal outcomes in the whole obstetric population

Earliest evidence for the ivory trade in southern Africa : isotopic and ZooMS analysis of seventh-tenth century AD ivory from KwaZulu-Natal

KwaGandaganda, Ndondondwane and Wosi were major Early Farming Community settlements in what is today the KwaZulu-Natal province of South Africa. These sites have yielded, among other remains, abundant evidence of ivory and ivory working dating to the seventh–tenth centuries ad, pre-dating by approximately 200 years the better-known ivory artefacts from sites in the Limpopo River Valley and surrounding regions. We report the results of carbon, nitrogen and strontium isotope analysis to explore the origins and procurement of this ivory, in combination with Zooarchaeology by Mass Spectrometry (ZooMS) to identify the species of animals from which it was derived. All of the ivory studied using ZooMS was elephant, despite the presence of hippopotamus remains on all three sites. Some ivory was probably obtained from elephant herds that lived close to the sites, in the densely wooded river valleys favoured by both elephants and early farmers. Other material came from savannah environments further afield. Ivory found at these three sites was drawn from different catchments, implying a degree of landscape/resource partitioning even at this early stage. These communities clearly invested substantial effort in obtaining ivory from across the region, which speaks to the importance of this commodity in the economy of the time. We suggest that some ivory items were for local use, but that some may have been intended for more distant markets via Indian Ocean trade

Towards understanding global patterns of antimicrobial use and resistance in neonatal sepsis: insights from the NeoAMR network.

OBJECTIVE: To gain an understanding of the variation in available resources and clinical practices between neonatal units (NNUs) in the low-income and middle-income country (LMIC) setting to inform the design of an observational study on the burden of unit-level antimicrobial resistance (AMR). DESIGN: A web-based survey using a REDCap database was circulated to NNUs participating in the Neonatal AMR research network. The survey included questions about NNU funding structure, size, admission rates, access to supportive therapies, empirical antimicrobial guidelines and period prevalence of neonatal blood culture isolates and their resistance patterns. SETTING: 39 NNUs from 12 countries. PATIENTS: Any neonate admitted to one of the participating NNUs. INTERVENTIONS: This was an observational cohort study. RESULTS: The number of live births per unit ranged from 513 to 27 700 over the 12-month study period, with the number of neonatal cots ranging from 12 to 110. The proportion of preterm admissions <32 weeks ranged from 0% to 19%, and the majority of units (26/39, 66%) use Essential Medicines List 'Access' antimicrobials as their first-line treatment in neonatal sepsis. Cephalosporin resistance rates in Gram-negative isolates ranged from 26% to 84%, and carbapenem resistance rates ranged from 0% to 81%. Glycopeptide resistance rates among Gram-positive isolates ranged from 0% to 45%. CONCLUSION: AMR is already a significant issue in NNUs worldwide. The apparent burden of AMR in a given NNU in the LMIC setting can be influenced by a range of factors which will vary substantially between NNUs. These variations must be considered when designing interventions to improve neonatal mortality globally