Differential pathways to adult metabolic dysfunction following poor nutrition at two critical developmental periods in sheep

Epidemiological and experimental studies suggest early nutrition has long-term effects on susceptibility to obesity, cardiovascular and metabolic diseases. Small and large animal models confirm the influence of different windows of sensitivity, from fetal to early postnatal life, on offspring phenotype. We showed previously that undernutrition in sheep either during the first month of gestation or immediately after weaning induces differential, sex-specific changes in adult metabolic and cardiovascular systems. The current study aims to determine metabolic and molecular changes that underlie differences in lipid and glucose metabolism induced by undernutrition during specific developmental periods in male and female sheep. Ewes received 100% (C) or 50% nutritional requirements (U) from 1–31 days gestation, and 100% thereafter. From weaning (12 weeks) to 25 weeks, offspring were then fed either ad libitum (CC, UC) or were undernourished (CU, UU) to reduce body weight to 85% of their individual target. From 25 weeks, all offspring were fed ad libitum. A cohort of late gestation fetuses were studied after receiving either 40% nutritional requirements (1–31 days gestation) or 50% nutritional requirements (104–127 days gestation). Post-weaning undernutrition increased in vivo insulin sensitivity, insulin receptor and glucose transporter 4 expression in muscle, and lowered hepatic methylation at the delta-like homolog 1/maternally expressed gene 3 imprinted cluster in adult females, but not males. Early gestational undernutrition induced lower hepatic expression of gluconeogenic factors in fetuses and reduced in vivo adipose tissue insulin sensitivity in adulthood. In males, undernutrition in early gestation increased adipose tissue lipid handling mechanisms (lipoprotein lipase, glucocorticoid receptor expression) and hepatic methylation within the imprinted control region of insulin-like growth factor 2 receptor in adulthood. Therefore, undernutrition during development induces changes in mechanisms of lipid and glucose metabolism which differ between tissues and sexes dependent on the period of nutritional restriction. Such changes may increase later life obesity and dyslipidaemia risk

Neuropsychological and psychiatric functioning in sheep farmers exposed to low levels of organophosphate pesticides

The study aim was to determine whether low level exposure to organophosphate pesticides (OPs) causes neuropsychological or psychiatric impairment. Methodological weaknesses of earlier studies were addressed by: recruiting participants who had retired on ill health grounds; excluding participants with a history of acute poisoning, medical or psychiatric conditions that might account for ill health; and exploring factors which may render some individuals more vulnerable to the effects of OPs than others. Performance on tests of cognition and mood of 127 exposed sheep farmers (67 working, 60 retired) was compared with 78 unexposed controls (38 working, 40 retired) and published test norms derived from a cross section of several thousand adults in the general population. Over 40% of the exposed cohort reported clinically significant levels of anxiety and depression compared to less than 23% of controls. Exposed subjects performed significantly worse than controls and standardisation samples on tests of memory, response speed, fine motor control, mental flexibility and strategy making, even after controlling for the effects of mood. The pattern was similar for both working and retired groups. The cognitive deficits identified cannot be attributed to mood disorder, malingering, a history of acute exposure or genetic vulnerability in terms of PON1(192) polymorphisms. Results suggest a relationship may exist between low level exposure to organophosphates and impaired neurobehavioural functioning and these findings have implications for working practice and for other occupational groups exposed to OPs such as aviation workers and Gulf War veterans

Nitroglycerin for treatment of retained placenta: a randomized, placebo-controlled, multicentre double blind trial in the UK

Funding: The GOT-IT trial was funded by the UK National Institute for Health Research (NIHR; https://www.nihr.ac.uk) Health Technology Assessment (HTA) Program in response to a specific commissioned grant call (Project number 12/29/01). The following co-authors were grant holders: FCD, GM, MP, JB, GS, JL, JN and JEN. The funders played no role in the study design, data collection, analysis, decision to publish or preparation of the manuscript. This work was undertaken in the MRC Centre for Reproductive Health which is funded by MRC Centre grant (MRC G1002033). Data Availability: The GOT-IT Trial contains a centrally-managed cross centre dataset which is available, upon request, from the Digital Curation Centre within the University of Edinburgh. Data requests can be made at [email protected] reviewedPublisher PD

Feasibility and design of a trial regarding the optimal mode of delivery for preterm birth:the CASSAVA multiple methods study

Background: Around 60,000 babies are born preterm (prior to 37 weeks’ gestation) each year in the UK. There is little evidence on the optimal birth mode (vaginal or caesarean section). Objective: The overall aim of the CASSAVA project was to determine if a trial to define the optimal mode of preterm birth could be carried out and, if so, determine what sort of trial could be conducted and how it could best be performed. We aimed to determine the specific groups of preterm women and babies for whom there are uncertainties about the best planned mode of birth, and if there would be willingness to recruit to, and participate in, a randomised trial to address some, but not all, of these uncertainties. This project was conducted in response to a Heath Technology Assessment programme commissioning call (17/22 ‘Mode of delivery for preterm infants’). Methods: We conducted clinician and patient surveys (n = 224 and n = 379, respectively) to identify current practice and opinion, and a consensus survey and Delphi workshop (n = 76 and n = 22 participants, respectively) to inform the design of a hypothetical clinical trial. The protocol for this clinical trial/vignette was used in telephone interviews with clinicians (n = 24) and in focus groups with potential participants (n = 13). Results: Planned sample size and data saturation was achieved for all groups except for focus groups with participants, as this had to be curtailed because of the COVID-19 pandemic and data saturation was not achieved. There was broad agreement from parents and health-care professionals that a trial is needed. The clinician survey demonstrated a variety of practice and opinion. The parent survey suggested that women and their families generally preferred vaginal birth at later gestations and caesarean section for preterm infants. The interactive workshop and Delphi consensus process confirmed the need for more evidence (hence the case for a trial) and provided rich information on what a future trial should entail. It was agreed that any trial should address the areas with most uncertainty, including the management of women at 26–32 weeks’ gestation, with either spontaneous preterm labour (cephalic presentation) or where preterm birth was medically indicated. Clear themes around the challenges inherent in conducting any trial emerged, including the concept of equipoise itself. Specific issues were as follows: different clinicians and participants would be in equipoise for each clinical scenario, effective conduct of the trial would require appropriate resources and expertise within the hospital conducting the trial, potential participants would welcome information on the trial well before the onset of labour and minority ethnic groups would require tailored approaches. Conclusion: Given the lack of evidence and the variation of practice and opinion in this area, and having listened to clinicians and potential participants, we conclude that a trial should be conducted and the outlined challenges resolved. Future work: The CASSAVA project could be used to inform the design of a randomised trial and indicates how such a trial could be carried out. Any future trial would benefit from a pilot with qualitative input and a study within a trial to inform optimal recruitment. Limitations: Certainty that a trial could be conducted can be determined only when it is attempted. Trial registration: Current Controlled Trials ISRCTN12295730. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 61. See the NIHR Journals Library website for further project information

Glyceryl trinitrate to reduce the need for manual removal of retained placenta following vaginal delivery:the GOT-IT RCT

Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 70. See the NIHR Journals Library website for further project information.Peer reviewedPublisher PD

A pragmatic group sequential placebo controlled randomised trial to determine the effectiveness of Glyceryl trinitrate for retained placenta (GOT-IT): a study protocol

A retained placenta is diagnosed when the placenta is not delivered following delivery of the baby. It is a major cause of postpartum haemorrhage and treated by the operative procedure of manual removal of placenta (MROP).The aim of this pragmatic, randomised, placebo-controlled, double-blind UK-wide trial, with an internal pilot and nested qualitative research to adjust strategies to refine delivery of the main trial, is to determine whether sublingual glyceryl trinitrate (GTN) is (or is not) clinically and cost-effective for (medical) management of retained placenta. The primary clinical outcome is need for MROP, defined as the placenta remaining undelivered 15 min poststudy treatment and/or being required within 15 min of treatment due to safety concerns. The primary safety outcome is measured blood loss between administration of treatment and transfer to the postnatal ward or other clinical area. The primary patient-sided outcome is satisfaction with treatment and a side effect profile. The primary economic outcome is net incremental costs (or cost savings) to the National Health Service of using GTN versus standard practice. Secondary outcomes are being measured over a range of clinical and economic domains. The primary outcomes will be analysed using linear models appropriate to the distribution of each outcome. Health service costs will be compared with multiple trial outcomes in a cost-consequence analysis of GTN versus standard practice.Ethical approval has been obtained from the North-East Newcastle and North Tyneside 2 Research Ethics Committee (13/NE/0339). Dissemination plans for the trial include the Health Technology Assessment Monograph, presentation at international scientific meetings and publication in high-impact, peer-reviewed journals.ISCRTN88609453; Pre-results

Psycho-educational interventions for adults with severe or difficult asthma: a systematic review.

types: Journal Article; Research Support, Non-U.S. Gov't; ReviewThis is the author's version of the work that was accepted for publication in the Journal of Asthma. The final version can be accessed via the DOI in this record.Research highlights psychosocial factors associated with adverse asthma events. This systematic review therefore examined whether psycho-educational interventions improve health and self-management outcomes in adults with severe or difficult asthma. Seventeen controlled studies were included. Characteristics and content of interventions varied even within broad types. Study quality was generally poor and several studies were small. Any positive effects observed from qualitative and quantitative syntheses were mainly short term and, in planned subgroup analyses (involving < 5 trials), effects on hospitalizations, quality of life, and psychological morbidity in patients with severe asthma did not extend to those in whom multiple factors complicate management.UK NHS Health Technology Assessment Programm

A Randomized Trial of Progesterone in Women with Bleeding in Early Pregnancy

BACKGROUND Bleeding in early pregnancy is strongly associated with pregnancy loss. Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone therapy may improve pregnancy outcomes in women who have bleeding in early pregnancy. METHODS We conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate progesterone, as compared with placebo, in women with vaginal bleeding in early pregnancy. Women were randomly assigned to receive vaginal suppositories containing either 400 mg of progesterone or matching placebo twice daily, from the time at which they presented with bleeding through 16 weeks of gestation. The primary outcome was the birth of a live-born baby after at least 34 weeks of gestation. The primary analysis was performed in all participants for whom data on the primary outcome were available. A sensitivity analysis of the primary outcome that included all the participants was performed with the use of multiple imputation to account for missing data. RESULTS A total of 4153 women, recruited at 48 hospitals in the United Kingdom, were randomly assigned to receive progesterone (2079 women) or placebo (2074 women). The percentage of women with available data for the primary outcome was 97% (4038 of 4153 women). The incidence of live births after at least 34 weeks of gestation was 75% (1513 of 2025 women) in the progesterone group and 72% (1459 of 2013 women) in the placebo group (relative rate, 1.03; 95% confidence interval [CI], 1.00 to 1.07; P=0.08). The sensitivity analysis, in which missing primary outcome data were imputed, resulted in a similar finding (relative rate, 1.03; 95% CI, 1.00 to 1.07; P=0.08). The incidence of adverse events did not differ significantly between the groups. CONCLUSIONS Among women with bleeding in early pregnancy, progesterone therapy administered during the first trimester did not result in a significantly higher incidence of live births than placebo. (Funded by the United Kingdom National Institute for Health Research Health Technology Assessment program; PRISM Current Controlled Trials number, ISRCTN14163439. opens in new tab.

Incidence of Schizophrenia and Other Psychoses in England, 1950–2009: A Systematic Review and Meta-Analyses

Background We conducted a systematic review of incidence rates in England over a sixty-year period to determine the extent to which rates varied along accepted (age, sex) and less-accepted epidemiological gradients (ethnicity, migration and place of birth and upbringing, time). Objectives To determine variation in incidence of several psychotic disorders as above. Data Sources Published and grey literature searches (MEDLINE, PSycINFO, EMBASE, CINAHL, ASSIA, HMIC), and identification of unpublished data through bibliographic searches and author communication. Study Eligibility Criteria Published 1950–2009; conducted wholly or partially in England; original data on incidence of non-organic adult-onset psychosis or one or more factor(s) pertaining to incidence. Participants People, 16–64 years, with first -onset psychosis, including non-affective psychoses, schizophrenia, bipolar disorder, psychotic depression and substance-induced psychosis. Study Appraisal and Synthesis Methods Title, abstract and full-text review by two independent raters to identify suitable citations. Data were extracted to a standardized extraction form. Descriptive appraisals of variation in rates, including tables and forest plots, and where suitable, random-effects meta-analyses and meta-regressions to test specific hypotheses; rate heterogeneity was assessed by the I2-statistic. Results 83 citations met inclusion. Pooled incidence of all psychoses (N = 9) was 31.7 per 100,000 person-years (95%CI: 24.6–40.9), 23.2 (95%CI: 18.3–29.5) for non-affective psychoses (N = 8), 15.2 (95%CI: 11.9–19.5) for schizophrenia (N = 15) and 12.4 (95%CI: 9.0–17.1) for affective psychoses (N = 7). This masked rate heterogeneity (I2: 0.54–0.97), possibly explained by socio-environmental factors; our review confirmed (via meta-regression) the typical age-sex interaction in psychosis risk, including secondary peak onset in women after 45 years. Rates of most disorders were elevated in several ethnic minority groups compared with the white (British) population. For example, for schizophrenia: black Caribbean (pooled RR: 5.6; 95%CI: 3.4–9.2; N = 5), black African (pooled RR: 4.7; 95%CI: 3.3–6.8; N = 5) and South Asian groups in England (pooled RR: 2.4; 95%CI: 1.3–4.5; N = 3). We found no evidence to support an overall change in the incidence of psychotic disorder over time, though diagnostic shifts (away from schizophrenia) were reported. Limitations Incidence studies were predominantly cross-sectional, limiting causal inference. Heterogeneity, while evidencing important variation, suggested pooled estimates require interpretation alongside our descriptive systematic results. Conclusions and Implications of Key Findings Incidence of psychotic disorders varied markedly by age, sex, place and migration status/ethnicity. Stable incidence over time, together with a robust socio-environmental epidemiology, provides a platform for developing prediction models for health service planning