OBJECTIVE Folic acid fortification has reduced neural tube defect prevalence by 50% to 70%. It is unlikely that fortification levels will be increased to reduce neural tube defect prevalence further. Therefore, it is important to identify other modifiable risk factors. Vitamin B12 is metabolically related to folate; moreover, previous studies have found low B12 status in mothers of children affected by neural tube defect. Our objective was to quantify the effect of low B12 status on neural tube defect risk in a high-prevalence, unfortified population. METHODS We assessed pregnancy vitamin B12 status concentrations in blood samples taken at an average of 15 weeks’ gestation from 3 independent nested case-control groups of Irish women within population-based cohorts, at a time when vitamin supplementation or food fortification was rare. Group 1 blood samples were from 95 women during a neural tube defect–affected pregnancy and 265 control subjects. Group 2 included blood samples from 107 women who had a previous neural tube defect birth but whose current pregnancy was not affected and 414 control subjects. Group 3 samples were from 76 women during an affected pregnancy and 222 control subjects. RESULTS Mothers of children affected by neural tube defect had significantly lower B12 status. In all 3 groups those in the lowest B12 quartiles, compared with the highest, had between two and threefold higher adjusted odds ratios for being the mother of a child affected by neural tube defect. Pregnancy blood B12 concentrations of <250 ng/L were associated with the highest risks. CONCLUSIONS Deficient or inadequate maternal vitamin B12 status is associated with a significantly increased risk for neural tube defects. We suggest that women have vitamin B12 levels of >300 ng/L (221 pmol/L) before becoming pregnant. Improving B12 status beyond this level may afford a further reduction in risk, but this is uncertain.

Recent reports have implicated the "thermolabile" (T) variant of methylenetetrahydrofolate reductase (MTHFR) in the causation of folate-dependent neural tube defects (NTDs). We report herein the largest genetic study of NTD cases (n=271) and families (n=218) to date, establishing that, in Ireland, the "TT" genotype is found in 18.8% of cases versus 8.3% of controls (odds ratio 2.57; confidence interval [CI] 1.48-4.45; P=.0005). The maternal and paternal TT genotypes have intermediate frequencies of 13.8% and 11.9%, respectively, indicating that the predominant MTHFR-related genetic effect acts via the TT genotype of the developing embryo. Analysis of the 218 family triads of mother, father, and affected child with log-linear models supports this interpretation, providing significant evidence that the case TT genotype is associated with NTDs (P=.02) but no evidence of a maternal TT genotypic effect (P=. 83). The log-linear model predicted that the risk of NTDs conferred by the case TT genotype is 1.61 (CI 1.06-2.46), consistent with the paramount importance of the case TT genotype in determining risk. There is no compelling evidence for more than a modest additional risk conferred by a maternal TT genotype. These results favor a biological model of MTHFR-related NTD pathogenesis in which suboptimal maternal folate status imposes biochemical stress on the developing embryo, a stress it is ill-equipped to tolerate if it has a TT genotype.

S-to-N acyl transfer is a high-yielding chemoselective process for amide bond formation. It is widely utilized by chemists for synthetic applications, including peptide and protein synthesis, chemical modification of proteins, protein-protein ligation and the development of probes and molecular machines. Recent advances in our understanding of S-to-N acyl transfer processes in biology and innovations in methodology for thioester formation and desulfurization, together with an extension of the size of cyclic transition states, have expanded the boundaries of this process well beyond peptide ligation. As the field develops, this chemistry will play a central role in our molecular understanding of Biology.

Background Hospital doctors face significant challenges in the current health care environment, working with staff shortages and cutbacks to health care expenditure, alongside increased demand for health care and increased public expectations. Objective This article analyses challenges faced by junior hospital doctors, providing insight into the experiences of these frontline staff in delivering health services in recessionary times. Design A qualitative methodology was chosen. Methods Semi‐structured in‐depth interviews were conducted with 20 doctors from urban Irish hospitals. Interviews were recorded via note taking. Full transcripts were analysed thematically using NVivo software. Results Dominant themes included the following: (1) unrealistic workloads: characterized by staff shortages, extended working hours, irregular and frequently interrupted breaks; (2) fatigue and its impact: the quality of care provided to patients while doctors were sleep‐deprived was questioned; however, little reflection was given to any impact this may have had on junior doctors own health; (3) undervalued and disillusioned: insufficient training, intensive workloads and a perceived lack of power to influence change resulted in a sense of detachment among junior doctors. They appeared immune to their surroundings. Conclusion Respondents ascribed little importance to the impact of current working conditions on their own health. They felt their roles were underappreciated and undervalued by policy makers and hospital management. Respondents were concerned with the lack of time and opportunity for training. This study highlighted several ‘red flags’, which need to be addressed in order to increase retention and sustain a motivated junior medical workforce. Statement of contribution What is already known on this subject? Loss of public funding in Ireland has led to large numbers of Irish trained doctors emigrating. Research indicates the likelihood of medical graduates returning depends on improvements to working conditions. Good working conditions are likely to encourage doctor retention yet little research has been conducted in this area. What does this study add? Intense workplace demands reduce confidence and productivity among doctors. Junior doctors were reluctant to reflect on the impact current working conditions had on their own health. Early warning signs of burnout appear to resonate with many of the issues raised by junior doctors in this study.