Early-Life Adversity Due to Bereavement and Inflammatory Diseases in the Next Generation: A Population Study in Transgenerational Stress Exposure

Emerging evidence suggests that trauma experienced in childhood has negative transgenerational implications for offspring mental and physical health. We aimed to investigate whether early-life adversity experienced as bereavement is associated with chronic inflammatory health in offspring. The study population included 3 generations of Swedish families with a base population of 453,516 children (generation 3) born in 2001-2012. Exposure was defined as the middle generation's (generation 2) experiencing bereavement in childhood due to the death of a parent (generation 1). Outcomes in generation 3 included 2 diagnoses of inflammatory diseases, including asthma, allergic diseases, eczema, and autoimmune diseases. Survival analysis was used to identify causal pathways, including investigation of mediation by generation 2 mood disorders and socioeconomic status (SES). We found that early-life bereavement experienced by women was associated with early-onset offspring asthma (hazard ratio = 1.15, 95% confidence interval: 1.08, 1.23); mediation analysis revealed that 28%-33% of the association may be mediated by SES and 9%-20% by mood disorders. Early-life bereavement experienced by men was associated with autoimmune diseases in offspring (hazard ratio = 1.31, 95% confidence interval: 1.06, 1.62), with no evidence of mediation. In conclusion, adversity experienced early in life may contribute to an increased risk of inflammatory diseases which is partly mediated by mood disorders and SES

Exogenously added GPI-anchored tissue inhibitor of matrix metal loproteinase-1 (TIMP-1) displays enhanced and novel biological activities

The family of tissue inhibitors of metalloproteinases (TIMPs) exhibits diverse physiological/biological functions including the inhibition of active matrix metalloproteinases, regulation of proMMP activation, cell growth, and the modulation of angiogenesis. TIMP-1 is a secreted protein that can be detected on the cell surface through its interaction with surface proteins. The diverse biological functions of TIMP-1 are thought to lie, in part, in the kinetics of TIMP-1/MMP/surface protein interactions. Proteins anchored by glycoinositol phospholipids (GPIs), when purified and added to cells in vitro, are incorporated into their surface membranes. A GPI anchor was fused to TIMP-1 to generate a reagent that could be added directly to cell membranes and thus focus defined concentrations of TIMP-1 protein on any cell surface independent of protein-protein interaction. Unlike native TIMP-1, exogenously added GPI-anchored TIMP-1 protein effectively blocked release of MMP-2 and MMP-9 from osteosarcoma cells. TIMP-1-GP1 was a more effective modulator of migration and proliferation than TIMP-1. While control hTIMP-1 protein did not significantly affect migration of primary microvascular endothelial cells at the concentrations tested, the GPI-anchored TIMP-1 protein showed a pronounced suppression of endothelial cell migration in response to bFGF. In addition, TIMP-1-GPI was more effective at inducing microvascular endothelial proliferation. In contrast, fibroblast proliferation was suppressed by the agent. Reagents based on this method should assist in the dissection of the protease cascades and activities involved in TIMP biology. Membrane-fixed TIMP-1 may represent a more effective version of the protein for use in therapeutic expression

The representation of scientific research in the national curriculum and secondary school pupils’ perceptions of research, its function, usefulness and value to their lives

Young people’s views on what research is, how it is conducted and whether it is important, influences the decisions they make about their further studies and career choices. In this paper we report the analysis of questionnaire data with a particular focus on pupil perceptions of research in the sciences and of the scientific method. The questionnaire was a 25-item Likert Scale (1-5) distributed to seven collaborating schools. We received 2634 returns from pupils across key stages 3, 4 and 5. We also asked teachers to complete the questionnaire in order to explore how they thought their pupils would respond. We received 54 teacher responses. Statistically significant differences in the responses were identified through a chi-square test on SPSS. As what is being taught influences secondary pupil views on research we also consider how the term ‘research’ appears in the national curriculum for England and Wales and the three main English exam boards. The main theoretical construct that informs our analysis of the questionnaire data and the national curriculum is Angela Brew’s 4-tier descriptor of perceptions of research (domino, trading, layer, journey). We use this framework in order to map what, when and how research is presented to school pupils in England and Wales. We also use this framework in order to highlight and discuss certain pupil views that emerged from the questionnaire data and which indicate areas where curriculum and pedagogy intervention may be necessary: pupils seem less confident in their understanding of research as involving the identification of a research question; and, they often see research as a means to confirm one’s own opinion. They do however understand research as involving the generation of new knowledge and the collection of new data, such as interviews and questionnaires as well as laboratory work, field trips and library searches and they appear relatively confident in their statements about their ability to do research, their school experiences of research and the importance of research in their future career choice

Combination of indoor residual spraying with long-lasting insecticide-treated nets for malaria control in Zambezia, Mozambique: a cluster randomised trial and cost-effectiveness study protocol.

Background: Most of the reduction in malaria prevalence seen in Africa since 2000 has been attributed to vector control interventions. Yet increases in the distribution and intensity of insecticide resistance and higher costs of newer insecticides pose a challenge to sustaining these gains. Thus, endemic countries face challenging decisions regarding the choice of vector control interventions. Methods: A cluster randomised trial is being carried out in Mopeia District in the Zambezia Province of Mozambique, where malaria prevalence in children under 5 is high (68% in 2015), despite continuous and campaign distribution of long-lasting insecticide-treated nets (LLINs). Study arm 1 will continue to use the standard, LLIN-based National Malaria Control Programme vector control strategy (LLINs only), while study arm 2 will receive indoor residual spraying (IRS) once a year for 2 years with a microencapsulated formulation of pirimiphos-methyl (Actellic 300 CS), in addition to the standard LLIN strategy (LLINs+IRS). Prior to the 2016 IRS implementation (the first of two IRS campaigns in this study), 146 clusters were defined and stratified per number of households. Clusters were then randomised 1:1 into the two study arms. The public health impact and cost-effectiveness of IRS intervention will be evaluated over 2 years using multiple methods: (1) monthly active malaria case detection in a cohort of 1548 total children aged 6-59 months; (2) enhanced passive surveillance at health facilities and with community health workers; (3) annual cross-sectional surveys; and (4) entomological surveillance. Prospective microcosting of the intervention and provider and societal costs will be conducted. Insecticide resistance status pattern and changes in local Anopheline populations will be included as important supportive outcomes. Discussion: By evaluating the public health impact and cost-effectiveness of IRS with a non-pyrethroid insecticide in a high-transmission setting with high LLIN ownership, it is expected that this study will provide programmatic and policy-relevant data to guide national and global vector control strategies. Trial registration number: NCT02910934

Pulmonary Metastasectomy in Colorectal Cancer burden of care study: analysis of local treatments for lung metastases and systemic chemotherapy in 220 patients in the PulMiCC cohort

AIM: To examine the burden of further treatments in patients with colorectal cancer (CRC) following a decision about lung metastasectomy. METHODS: Five teams participating in the study of Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC) provided details on subsequent local treatments for lung metastases including the use of chemotherapy. For patients in three groups (no metastasectomy, one metastasectomy or multiple local interventions), baseline factors and selection criteria for additional treatments were examined. RESULTS: The five teams recruited 220 patients between October 2010 and January 2017. No lung metastasectomy was performed in 51 patients, 114 had one, and 55 patients had multiple local interventions. Selection for initial metastasectomy was associated with non-elevated CEA, fewer metastases, and no prior liver metastasectomy. These patients also had better ECOG scores and lung function at baseline. Four sites provided information on chemotherapy in 139 patients: 79 (57%) had 1-5 courses of chemotherapy, to a total of 179 courses. The patterns of survival after one or multiple metastasectomy interventions showed evidence of guarantee-time bias contributing to an impression of benefit over no metastasectomy. After repeated metastasectomy, a significantly higher risk of death was observed with no apparent reduction in chemotherapy usage. CONCLUSION: Repeated metastasectomy is associated with higher risk of death without reducing use of chemotherapy. Continued monitoring without surgery might reassure patients with indolent disease or allow response assessment during systemic treatment. Overall, the carefully collected information from the PulMICC study provides no indication of an important survival benefit from metastasectomy

NeuroSAFE frozen section during robot-assisted radical prostatectomy (RARP): Peri-operative and Histopathological Outcomes from the NeuroSAFE PROOF Feasibility Randomised Controlled Trial

Objectives: To report on the methods, peri‐operative outcomes and histopathological concordance between frozen and final section from the NeuroSAFE PROOF Feasibility study (NCT03317990). Patients and Methods: Between May 2018 and March 2019 49 men at 2 UK centres underwent robot‐assisted robotic prostatectomy (RARP). 25 men were randomised to NeuroSAFE RARP (intervention arm) vs. 24 men to standard RARP (control arm). Frozen section was compared to final paraffin section margin assessment in the 25 men in the NeuroSAFE arm. Operation timings and complications were collected prospectively in both arms. Results: 50 NVB from 25 patients in the NeuroSAFE arm were analysed. When analysed by each pathological section (n=250, average 5 per side) we note sensitivity 100%, specificity 99.2%, AUC was 0.994 (95% CI 0.985 to 1, P= <.001). On an NVB basis (n=50) we note sensitivity of 100%, specificity 92.7%, and AUC of 0.963 (95% CI 0.914 to 1, p = <0.001. NeuroSAFE RARP lasted a mean 3 hours 16 minutes (knife to skin to off table, 95% CI 3 hrs 2 mins ‐ 3 hrs 30 mins) compared to 2 hours 14 minutes (2 hrs 2 mins ‐ 2 hours 25 mins, P=<0.001) for standard RARP. There was no morbidity associated with the additional length of operation in the NeuroSAFE arm. Conclusion: This feasibility study demonstrates the safety, the reproducibility and the excellent histopathological concordance of the NeuroSAFE technique in the NeuroSAFE PROOF trial. Though the technique increases the duration of RARP, this does not cause short‐term harm. Confirmation of feasibility has led to the opening of the fully powered NeuroSAFE PROOF RCT, which is currently underway at 4 sites in the UK

Initiating undergraduate medical students into communities of research practise: what do supervisors recommend?

Abstract Background Much has been written in the educational literature on the value of communities of practise in enhancing student learning. Here, we take the experience of senior undergraduate medical students involved in short-term research as a member of a team as a paradigm for learning in a community of practise. Based on feedback from experienced supervisors, we offer recommendations for initiating students into the research culture of their team. In so doing, we endeavour to create a bridge between theory and practise through disseminating advice on good supervisory practise, where the supervisor is perceived as an educator responsible for designing the research process to optimize student learning. Methods Using the questionnaire design tool SurveyMonkey and comprehensive lists of contact details of staff who had supervised research projects at the University of Edinburgh during 1995 - 2008, current and previous supervisors were invited to recommend procedures which they had found successful in initiating students into the research culture of a team. Text responses were then coded in the form of derivative recommendations and categorized under general themes and sub-themes. Results Using the chi-square tests of linear trend and association, evidence was found for a positive trend towards more experienced supervisors offering responses (χ2 = 16.833, p 2 = 0.482, p = 0.487, n = 203), respectively. A total of 126 codes were extracted from the text responses of 65 respondents. These codes were simplified to form a complete list of 52 recommendations, which were in turn categorized under seven derivative overarching themes, the most highly represented themes being Connecting the student with others and Cultivating self-efficacy in research competence. Conclusions Through the design of a coding frame for supervisor responses, a wealth of ideas has been captured to make communities of research practise effective mediums for undergraduate student learning. The majority of these recommendations are underpinned by educational theory and have the potential to take the learner beyond the stage of initiation to that of integration within their community of research practise.</p

Research lives of physical education teacher educators

peer-reviewed.This paper aims to provide insights into the research worlds of an international group of mid- and late-career physical education teacher educators. Specifically, it explores participants’ motives for research engagement and choices, and investigates what challenges and facilitates their research efforts. Two rounds of individual in-depth semi-structured interviews were conducted with 14 physical education teacher educators across 7 countries. Findings point to a distinction between research motives. Embarking on formal theses or specific funded projects was often motivated by practical and contextual drivers, such as job requirements or a wish for promotion, and was associated with feelings of frustration and stress. Motives for engaging in research in general, on the other hand, tended to be more personal or altruistic and elicited feelings such as enjoyment and passion. Time constraints, skill gaps and language barriers were all seen as challenges to research endeavours, while learning through doing, seeing and reading, and collaboration with others were seen as the main facilitators.ACCEPTEDpeer-reviewe

Development and validation of a high density SNP genotyping array for Atlantic salmon (Salmo salar)

BackgroundDense single nucleotide polymorphism (SNP) genotyping arrays provide extensive information on polymorphic variation across the genome of species of interest. Such information can be used in studies of the genetic architecture of quantitative traits and to improve the accuracy of selection in breeding programs. In Atlantic salmon (Salmo salar), these goals are currently hampered by the lack of a high-density SNP genotyping platform. Therefore, the aim of the study was to develop and test a dense Atlantic salmon SNP array. ResultsSNP discovery was performed using extensive deep sequencing of Reduced Representation (RR-Seq), Restriction site-Associated DNA (RAD-Seq) and mRNA (RNA-Seq) libraries derived from farmed and wild Atlantic salmon samples (n = 283) resulting in the discovery of &gt; 400 K putative SNPs. An Affymetrix Axiom&reg; myDesign Custom Array was created and tested on samples of animals of wild and farmed origin (n = 96) revealing a total of 132,033 polymorphic SNPs with high call rate, good cluster separation on the array and stable Mendelian inheritance in our sample. At least 38% of these SNPs are from transcribed genomic regions and therefore more likely to include functional variants. Linkage analysis utilising the lack of male recombination in salmonids allowed the mapping of 40,214 SNPs distributed across all 29 pairs of chromosomes, highlighting the extensive genome-wide coverage of the SNPs. An identity-by-state clustering analysis revealed that the array can clearly distinguish between fish of different origins, within and between farmed and wild populations. Finally, Y-chromosome-specific probes included on the array provide an accurate molecular genetic test for sex. ConclusionsThis manuscript describes the first high-density SNP genotyping array for Atlantic salmon. This array will be publicly available and is likely to be used as a platform for high-resolution genetics research into traits of evolutionary and economic importance in salmonids and in aquaculture breeding programs via genomic selection