Epigenetic reprogramming of fallopian tube fimbriae in BRCA mutation carriers defines early ovarian cancer evolution

The exact timing and contribution of epigenetic reprogramming to carcinogenesis are unclear. Women harbouring BRCA1/2 mutations demonstrate a 30–40-fold increased risk of high-grade serous extra-uterine Müllerian cancers (HGSEMC), otherwise referred to as ‘ovarian carcinomas’, which frequently develop from fimbrial cells but not from the proximal portion of the fallopian tube. Here we compare the DNA methylome of the fimbrial and proximal ends of the fallopian tube in BRCA1/2 mutation carriers and non-carriers. We show that the number of CpGs displaying significant differences in methylation levels between fimbrial and proximal fallopian tube segments are threefold higher in BRCA mutation carriers than in controls, correlating with overexpression of activation-induced deaminase in their fimbrial epithelium. The differentially methylated CpGs accurately discriminate HGSEMCs from non-serous subtypes. Epigenetic reprogramming is an early pre-malignant event integral to BRCA1/2 mutation-driven carcinogenesis. Our findings may provide a basis for cancer-preventative strategies

Incidence, aetiology and outcomes of obstetric-related acute kidney injury in Malawi: a prospective observational study

BACKGROUND: Obstetric-related acute kidney injury (AKI) is thought to be a key contributor to the overall burden of AKI in low resource settings, causing significant and preventable morbidity and mortality. However, epidemiological data to corroborate these hypotheses is sparse. This prospective observational study aims to determine the incidence, aetiology and maternal-fetal outcomes of obstetric-related AKI in Malawi. METHODS: Women greater than 20 weeks gestation or less than 6 weeks postpartum admitted to obstetric wards at a tertiary hospital in Blantyre, Malawi, and at high-risk of AKI were recruited between 21st September and 11th December 2015. All participants had serum creatinine tested at enrolment; those with creatinine above normal range (> 82 μmol/L) underwent serial measurement, investigations to determine cause of kidney injury, and were managed by obstetric and nephrology teams. AKI was diagnosed and staged by Kidney Disease Improving Global Outcomes (KDIGO) criteria. Primary outcomes were the incidence proportion and aetiology of AKI. Secondary outcomes were in-hospital maternal mortality, need for dialysis, renal recovery and length of stay; in-hospital perinatal mortality, gestational age at delivery, birthweight and Apgar score. RESULTS: 354 patients were identified at risk of AKI from the approximate 2300 deliveries that occurred during the study period. Three hundred twenty-two were enrolled and 26 (8.1%) had AKI (median age 27 years; HIV 3.9%). The most common primary causes of AKI were preeclampsia/eclampsia (n = 19, 73.1%), antepartum haemorrhage (n = 3, 11.5%), and sepsis (n = 3, 11.5%). There was an association between preeclampsia spectrum and AKI (12.2% AKI incidence in preeclampsia spectrum vs. 4.3% in other patients, p = 0.015). No women with AKI died or required dialysis and complete renal recovery occurred in 22 (84.6%) cases. The perinatal mortality rate across all high-risk admissions was 13.8%. AKI did not impact on maternal or fetal outcomes. CONCLUSIONS: The incidence of AKI in high-risk obstetric admissions in Malawi is 8.1% and preeclampsia was the commonest cause. With tertiary nephrology and obstetric care the majority of AKI resolved with no effect on maternal-fetal outcomes. Maternal-fetal outcomes in Sub-Saharan Africa may be improved with earlier detection of hypertensive disease in pregnancy

Evaluating a team-based approach to research capacity building using a matched-pairs study design

Background: There is a continuing need for research capacity building initiatives for primary health care professionals. Historically strategies have focused on interventions aimed at individuals but more recently theoretical frameworks have proposed team-based approaches. Few studies have evaluated these new approaches. This study aims to evaluate a team-based approach to research capacity building (RCB) in primary health using a validated quantitative measure of research capacity in individual, team and organisation domains

A preliminary study of genetic factors that influence susceptibility to bovine tuberculosis in the British cattle herd

Associations between specific host genes and susceptibility to Mycobacterial infections such as tuberculosis have been reported in several species. Bovine tuberculosis (bTB) impacts greatly the UK cattle industry, yet genetic predispositions have yet to be identified. We therefore used a candidate gene approach to study 384 cattle of which 160 had reacted positively to an antigenic skin test (‘reactors’). Our approach was unusual in that it used microsatellite markers, embraced high breed diversity and focused particularly on detecting genes showing heterozygote advantage, a mode of action often overlooked in SNP-based studies. A panel of neutral markers was used to control for population substructure and using a general linear model-based approach we were also able to control for age. We found that substructure was surprisingly weak and identified two genomic regions that were strongly associated with reactor status, identified by markers INRA111 and BMS2753. In general the strength of association detected tended to vary depending on whether age was included in the model. At INRA111 a single genotype appears strongly protective with an overall odds ratio of 2.2, the effect being consistent across nine diverse breeds. Our results suggest that breeding strategies could be devised that would appreciably increase genetic resistance of cattle to bTB (strictly, reduce the frequency of incidence of reactors) with implications for the current debate concerning badger-culling

A comparison of two methods for expert elicitation in health technology assessments.

BACKGROUND: When data needed to inform parameters in decision models are lacking, formal elicitation of expert judgement can be used to characterise parameter uncertainty. Although numerous methods for eliciting expert opinion as probability distributions exist, there is little research to suggest whether one method is more useful than any other method. This study had three objectives: (i) to obtain subjective probability distributions characterising parameter uncertainty in the context of a health technology assessment; (ii) to compare two elicitation methods by eliciting the same parameters in different ways; (iii) to collect subjective preferences of the experts for the different elicitation methods used. METHODS: Twenty-seven clinical experts were invited to participate in an elicitation exercise to inform a published model-based cost-effectiveness analysis of alternative treatments for prostate cancer. Participants were individually asked to express their judgements as probability distributions using two different methods - the histogram and hybrid elicitation methods - presented in a random order. Individual distributions were mathematically aggregated across experts with and without weighting. The resulting combined distributions were used in the probabilistic analysis of the decision model and mean incremental cost-effectiveness ratios and the expected values of perfect information (EVPI) were calculated for each method, and compared with the original cost-effectiveness analysis. Scores on the ease of use of the two methods and the extent to which the probability distributions obtained from each method accurately reflected the expert's opinion were also recorded. RESULTS: Six experts completed the task. Mean ICERs from the probabilistic analysis ranged between £162,600-£175,500 per quality-adjusted life year (QALY) depending on the elicitation and weighting methods used. Compared to having no information, use of expert opinion decreased decision uncertainty: the EVPI value at the £30,000 per QALY threshold decreased by 74-86 % from the original cost-effectiveness analysis. Experts indicated that the histogram method was easier to use, but attributed a perception of more accuracy to the hybrid method. CONCLUSIONS: Inclusion of expert elicitation can decrease decision uncertainty. Here, choice of method did not affect the overall cost-effectiveness conclusions, but researchers intending to use expert elicitation need to be aware of the impact different methods could have.This paper presents independent research funded by the National Institute of Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for the South West Peninsula

The Role of Hydrogeography and Climate in the Landscape Epidemiology of West Nile Virus in New York State from 2000 to 2010

The epidemiology and ecology of West Nile virus (WNV) have not yet been completely described. In particular, the specific roles of climate and water in the landscape in the occurrence of human WNV cases remain unknown. This study used Poisson regression to describe the relationships between WNV cases and temperature, precipitation, and the hydrogeography of the landscape in New York State from 2000 to 2010. Fully adjusted models showed that hydrogeographic area was significantly inversely associated with WNV cases (incidence rate ratio (IRR) = 0.99; 95% C.I. = 0.98–0.997, p = 0.04), such that each one square kilometer increase in hydrogeographic area was associated with a 1% decrease in WNV incidence. This association was independent of both temperature, which was also associated with WNV incidence (IRR = 2.06; 95% C.I. = 1.84–2.31, p<0.001), and precipitation, which was not (IRR = 1.0; 95% C.I. = 0.99–1.01, p = 0.16). While the results are only suggestive due to the county-level aggregated data, these findings do identify a potentially important surveillance signal in the landscape epidemiology of WNV infection

Influence of auxin and its polar transport inhibitor on the development of somatic embryos in Digitalis trojana

The present study reports the role of auxin and its transport inhibitor during the establishment of an efficient and optimized protocol for the somatic embryogenesis in Digitalis trojana Ivan. Hypocotyl segments (5 mm long) were placed vertically in the Murashige and Skoog medium supplemented with three sets [indole-3-acetic acid (IAA) alone or 2,3,5-triiodobenzoic acid (TIBA) alone or IAA-TIBA combination] of formulations of plant growth regulators, to assess their differential influence on induction and proliferation of somatic embryos (SEs). IAA alone was found to be the most effective, at a concentration of 0.5 mg/l, inducing similar to 10 SEs per explant with 52% induction frequency. On the other hand, the combination of 0.5 mg/l of IAA and 1 mg/l of TIBA produced significantly fewer (similar to 3.6 SEs) and abnormal (enlarged, oblong, jar and cup-shaped) SEs per explant with 24% induction frequency in comparison to that in the IAA alone. The explants treated with IAA-TIBA exhibited a delayed response along with the formation of abnormal SEs. Our study revealed that IAA induces high-frequency SE formation when used singly, but the frequency gradually declines when IAA was coupled with increasing levels of TIBA. Eventually, our findings bring new insights into the roles of auxin and its polar transport in somatic embryogenesis of D. trojana

Does child weight influence how mothers report their feeding practices?

Objectives. The present study aimed to ascertain whether parental reports of their feeding practices are associated with independent observations of these behaviours, and whether the reliability of maternal report depends upon the child's weight. Methods. A total of 56 mothers and their children ate a lunch to satiety which was videotaped and coded for maternal use of control during feeding. Mothers also completed questionnaires about their feeding practices and children were weighed and measured. Results. Maternal reports of controlling feeding practices were poorly related to independent observations of these behaviours in the laboratory. However, there was a significant interaction between child BMI z score and observed pressure to eat in predicting maternally reported pressure to eat. There was also a significant interaction between child BMI z score and observed maternal restriction with food in predicting maternally reported restriction. When decomposed, these interactions suggested that only mothers of relatively underweight children were accurate at reporting their use of pressure to eat when compared to independent observations. For mothers of relatively overweight children there was a significant negative relationship between observed and reported restriction over food. Conclusions. Overall there was poor correspondence between maternal reports and independent observations of the use of controlling feeding practices. Further research is needed to replicate these findings and to ascertain whether parents who are inaccurate at reporting their use of these feeding practices are unaware that they are using controlling feeding practices or whether they are responding in socially desirable ways to questionnaires assessing their feeding behaviour. © 2011 Informa Healthcare

Growth arrest-specific gene 6 expression in human breast cancer

Growth arrest-specific gene 6 (Gas6), identified in 1995, acts as the ligand to the Axl/Tyro3 family of tyrosine kinase receptors and exerts mitogenic activity when bound to these receptors. Overexpression of the Axl/Tyro3 receptor family has been found in breast, ovarian and lung tumours. Gas6 is upregulated 23-fold by progesterone acting through the progesterone receptor B (PRB). Recently, Gas6 has been shown to be a target for overexpression and amplification in breast cancer. Quantitative real-time PCR analysis was used to determine the levels of Gas6 mRNA expression in 49 primary breast carcinomas. Expression of PRB protein was evaluated immunohistochemically with a commercially available PRB antibody. The results showed a positive association between PRB protein and Gas6 mRNA levels (P=0.04). Gas6 correlated positively with a number of favourable prognostic variables including lymph node negativity (P=0.0002), younger age at diagnosis (P=0.04), smaller size of tumours (P=0.02), low Nottingham prognostic index scores (P=0.03) and low nuclear morphology (P=0.03). This study verifies for the first time the association between PRB and Gas6 in breast cancer tissue

A Measurement of Rb using a Double Tagging Method

The fraction of Z to bbbar events in hadronic Z decays has been measured by the OPAL experiment using the data collected at LEP between 1992 and 1995. The Z to bbbar decays were tagged using displaced secondary vertices, and high momentum electrons and muons. Systematic uncertainties were reduced by measuring the b-tagging efficiency using a double tagging technique. Efficiency correlations between opposite hemispheres of an event are small, and are well understood through comparisons between real and simulated data samples. A value of Rb = 0.2178 +- 0.0011 +- 0.0013 was obtained, where the first error is statistical and the second systematic. The uncertainty on Rc, the fraction of Z to ccbar events in hadronic Z decays, is not included in the errors. The dependence on Rc is Delta(Rb)/Rb = -0.056*Delta(Rc)/Rc where Delta(Rc) is the deviation of Rc from the value 0.172 predicted by the Standard Model. The result for Rb agrees with the value of 0.2155 +- 0.0003 predicted by the Standard Model.Comment: 42 pages, LaTeX, 14 eps figures included, submitted to European Physical Journal