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Purpose: Concern has been raised over alleged increases in antisocial behaviour by military personnel returning from the deployment in Iraq and Afghanistan. U.S.-based research has shown that post-deployment violence is related not only to combat experience, but also to pre-enlistment antisocial behaviour (ASB). This study aimed to examine the association between pre-enlistment ASB and later behavioural outcomes, including aggression, in a large randomly selected U.K. military cohort.Methods: Baseline data from a cohort study of 10,272 U.K. military personnel in service at the time of the Iraq war in 2003 were analysed. The associations between pre-enlistment ASB and a range of socio-demographic and military variables were examined as potential confounders. Logistic regression analyses were performed to examine the relationship between pre-enlistment ASB and military behavioural outcomes such as severe alcohol use, violence/aggression and risk-taking behaviour, controlling for confounders.Results: 18.1% were defined as having displayed pre-enlistment ASB. Pre-enlistment ASB was significantly associated with factors such as younger age, low educational achievement, male gender, non-officer rank, Army personnel, being a regular, increasing time spent on the deployment and having a combat role. Pre-enlistment ASB was associated with increased risk of negative behavioural outcomes (severe alcohol misuse, outbursts of anger or irritability, fighting or assaultative behaviour and risk-taking behaviour), after controlling for confounders, suggesting that such background information may identify individuals who are more vulnerable to subsequent behavioural disturbance.Conclusion: The results of this study suggest that those already demonstrating ASB prior to joining the military are more likely to continue on this trajectory, thus emphasising the importance of considering pre-enlistment behaviour when exploring the aetiology of aggression in military personnel. [ABSTRACT FROM AUTHOR]

BACKGROUND: There is considerable interest in understanding further the factors that increase the risk of post-traumatic stress disorder (PTSD) for military personnel. This study aimed to investigate the relative contribution of demographic variables; childhood adversity; the nature of exposure to traumatic events during deployment; appraisal of these experiences; and home-coming experiences in relation to the prevalence of PTSD 'caseness' as measured by a score of 50 on the PTSD Checklist (PCL) in UK Armed Forces personnel who have been deployed in Iraq since 2003.MethodData were drawn from the first stage of a retrospective cohort study comparing UK military personnel who were deployed to the 2003 Iraq War with personnel serving in the UK Armed Forces on 31 March 2003 but who were not deployed to the initial phase of war fighting. Participants were randomly selected and invited to participate. The response rate was 61%. We have limited these analyses to 4762 regular service individuals who responded to the survey and who have been deployed in Iraq since 2003. RESULTS: Post-traumatic stress symptoms were associated with lower rank, being unmarried, having low educational attainment and a history of childhood adversity. Exposure to potentially traumatizing events, in particular being deployed to a 'forward' area in close contact with the enemy, was associated with post-traumatic stress symptoms. Appraisals of the experience as involving threat to one's own life and a perception that work in theatre was above an individual's trade and experience were strongly associated with post-traumatic stress symptoms. Low morale and poor social support within the unit and non-receipt of a home-coming brief (psycho-education) were associated with greater risk of post-traumatic stress symptoms. CONCLUSIONS: Personal appraisal of threat to life during the trauma emerged as the most important predictor of post-traumatic stress symptoms. These results also raise the possibility that there are important modifiable occupational factors such as unit morale, leadership, preparing combatants for their role in theatre which may influence an individual's risk of post-traumatic stress symptoms. Therefore interventions focused on systematic preparation of personnel for the extreme stress of combat may help to lessen the psychological impact of deployment. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to identify the factors associated with poor outcomes for personnel leaving the United Kingdom Armed Forces early.Method: We studied a population thought to be at high risk of poor outcomes: those leaving the Services early via the United Kingdom Military Corrective Training Centre. Participants were interviewed 1 week before leaving (predischarge) and followed up 6 months later. One hundred eleven participants completed predischarge interviews. Seventy-four (67%) were successfully followed up and interviewed 6 months later.Results: Thirty-eight of those followed up (56%) were classed as being disadvantaged after leaving. Being disadvantaged at follow-up was associated with: having predischarge mental health problems, receiving an administrative discharge, or having a short sentence length.Conclusion: Factors associated with poor outcomes on leaving were often interrelated, making causal relationships complex. However, this study does provide a basis from which to identify, at the point of discharge, those most at risk of further disadvantage. [ABSTRACT FROM AUTHOR]

Despite advances in surgical and therapeutic approaches, high-grade serous ovarian carcinoma (HGSOC) prognosis remains poor. Surgery is an indispensable component of therapeutic protocols, as removal of all visible tumor lesions (cytoreduction) profoundly improves the overall survival. Enhanced predictive tools for assessing cytoreduction are essential to optimize therapeutic precision. Patients' immune status broadly reflects the tumor cell biological behavior and the patient responses to disease and treatment. Serum cytokine profiling is a sensitive measure of immune adaption and deviation, yet its integration into treatment paradigms is underexplored. This study is part of the IMPACT trial (NCT03378297) and aimed to characterize immune responses before and during primary treatment for HGSOC to identify biomarkers for treatment selection and prognosis. Longitudinal serum samples from 22 patients were collected from diagnosis until response evaluation. Patients underwent primary cytoreductive surgery or neoadjuvant chemotherapy (NACT) based on laparoscopy scoring. Twenty-seven serum cytokines analyzed by Bio-Plex 200, revealed two immune phenotypes at diagnosis: Immune High with marked higher serum cytokine levels than Immune Low. The immune phenotypes reflected the laparoscopy scoring and allocation to surgical treatment. The five Immune High patients undergoing primary cytoreductive surgery exhibited immune mobilization and extended progression-free survival, compared to the Immune Low patients undergoing the same treatment. Both laparoscopy and cytoreductive surgery induced substantial and transient changes in serum cytokines, with upregulation of the inflammatory cytokine IL-6 and downregulation of the multifunctional cytokines IP-10, Eotaxin, IL-4, and IL-7. Over the study period, cytokine levels uniformly decreased in all patients, leading to the elimination of the initial immune phenotypes regardless of treatment choice. This study reveals distinct pre-treatment immune phenotypes in HGSOC patients that might be informative for treatment stratification and prognosis. This potential novel biomarker holds promise as a foundation for improved assessment of treatment responses in patients with HGSOC. ClinicalTrials.gov Identifier: NCT03378297., Competing Interests: CT reports personal fees from AstraZeneca, Pfizer, and GlaxoSmithKline. LT reports personal fees from Bayer, Eisai Co. and AstraZeneca. LT and LB report financial support from AstraZeneca for this researcher-initiated trial. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Torkildsen, Austdal, Jarmund, Kleinmanns, Lamark, Nilsen, Stefansson, Sande, Iversen, Thomsen and Bjørge.)

Breast milk from people with overweight/obesity may differ in composition compared with that from normal-weight people. Exercise training can modify breast milk composition in rodent models, with a beneficial impact demonstrated on the offspring's metabolism, but whether these findings translate to humans is unclear. This trial aims to determine the effect of an exercise intervention on breast milk composition and whether an exercise-induced modification of breast milk impacts the infants' growth and body composition. Effect of Exercise Training on Breastmilk Composition is a randomised, controlled trial with two parallel groups, one exercise group and one control group, with a 1:1 allocation. We will include a minimum of 62 exclusively breastfeeding participants, 6 weeks postpartum. The exercise intervention lasts 8 weeks and comprises 25 supervised endurance exercise sessions with moderate or high intensity. The primary outcome measure is the change in the relative concentration of the human milk oligosaccharide 3'sialyllactose in breast milk from baseline at 6 weeks postpartum to the end of the intervention period. Secondary outcomes include breast milk concentrations of other metabolites, cytokines, hormones and microRNA, maternal health outcomes, infant growth, infant gut microbiome and infant circulating microRNA. Maternal and infant outcomes will be measured before, during and after the intervention period, with a follow-up of the infants until they are 24 months old. Trial registration number NCT05488964., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Gestational diabetes mellitus (GDM) is associated with increased risk for type 2 diabetes in the mother and cardiometabolic diseases in the child. The preconception period is an optimal window to adapt the lifestyle for improved outcomes for both mother and child. Our aim is to determine the effect of a lifestyle intervention, initiated before and continued throughout pregnancy, on maternal glucose tolerance and other maternal and infant cardiometabolic outcomes., Methods and Analysis: This ongoing randomised controlled trial has included 167 females aged 18-39 years old at increased risk for GDM who are contemplating pregnancy. The participants were randomly allocated 1:1 to an intervention or control group. The intervention consists of exercise (volume is set by a heart rate-based app and corresponds to ≥ 1 hour of weekly exercise at ≥ 80% of individual heart rate maximum), and time-restricted eating (≤ 10 hours/day window of energy intake). The primary outcome measure is glucose tolerance in gestational week 28. Maternal and offspring outcomes are measured before and during pregnancy, at delivery, and at 6-8 weeks post partum. Primary and secondary continuous outcome measures will be compared between groups based on the 'intention to treat' principle using linear mixed models., Ethics and Dissemination: The Regional Committees for Medical and Health Research Ethics in Norway has approved the study (REK 143756). The anonymised results will be submitted for publication and posted in a publicly accessible database of clinical study results., Trial Registration Number: Clinical trial gov NCT04585581., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Context: Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with low-grade systemic inflammation and increased risk of pregnancy complications. Metformin treatment reduces the risk of late miscarriage and preterm birth in pregnant women with PCOS. Whether the protective effect of metformin involves immunological changes has not been determined., Objective: To investigate the effect of metformin on the maternal immunological status in women with PCOS., Methods: A post-hoc analysis was performed of two randomized controlled trials, PregMet and PregMet2, including longitudinal maternal serum samples from 615 women with PCOS. Women were randomized to metformin or placebo from first trimester to delivery. Twenty-two cytokines and C-reactive protein were measured in serum sampled at gestational weeks 5 to 12, 19, 32, and 36., Results: Metformin treatment was associated with higher serum levels of several multifunctional cytokines throughout pregnancy, with the strongest effect on eotaxin (P < .001), interleukin-17 (P = .03), and basic fibroblast growth factor (P = .04). Assessment of the combined cytokine development confirmed the impact of metformin on half of the 22 cytokines. The immunomodulating effect of metformin was more potent in normal weight and overweight women than in obese women. Moreover, normoandrogenic women had the strongest effect of metformin in early pregnancy, whereas hyperandrogenic women presented increasing effect throughout pregnancy., Conclusion: It appears that metformin has immunomodulating rather than anti-inflammatory properties in pregnancy. Its effect on the serum levels of many multifunctional cytokines demonstrates robust, persisting, and body mass-dependent immune mobilization in pregnant women with PCOS., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

High-grade serous ovarian carcinoma (HGSOC) is the most common and deadliest ovarian cancer subtype. Despite advances in treatment, the overall prognosis remains poor. Regardless of efforts to develop biomarkers to predict surgical outcome and recurrence risk and resistance, reproducible indicators are scarce. Exploring the complex tumor heterogeneity, serum profiling of metabolites and lipoprotein subfractions that reflect both systemic and local biological processes were utilized. Furthermore, the overall impact on the patient from the tumor and the treatment was investigated. The aim was to characterize the systemic metabolic effects of primary treatment in patients with advanced HGSOC. In total 28 metabolites and 112 lipoproteins were analyzed by nuclear magnetic resonance (NMR) spectroscopy in longitudinal serum samples (n = 112) from patients with advanced HGSOC (n = 24) from the IMPACT trial with linear mixed effect models and repeated measures ANOVA simultaneous component analysis. The serum profiling revealed treatment-induced changes in both lipoprotein subfractions and circulating metabolites. The development of a more atherogenic lipid profile throughout the treatment, which was more evident in patients with short time to recurrence, indicates an enhanced systemic inflammation and increased risk of cardiovascular disease after treatment. The findings suggest that treatment-induced changes in the metabolome reflect mechanisms behind the diversity in disease-related outcomes.

Background: Matching treatment based on tumour molecular characteristics has revolutionized the treatment of some cancers and has given hope to many patients. Although personalized cancer care is an old concept, renewed attention has arisen due to recent advancements in cancer diagnostics including access to high-throughput sequencing of tumour tissue. Targeted therapies interfering with cancer specific pathways have been developed and approved for subgroups of patients. These drugs might just as well be efficient in other diagnostic subgroups, not investigated in pharma-led clinical studies, but their potential use on new indications is never explored due to limited number of patients., Methods: In this national, investigator-initiated, prospective, open-label, non-randomized combined basket- and umbrella-trial, patients are enrolled in multiple parallel cohorts. Each cohort is defined by the patient's tumour type, molecular profile of the tumour, and study drug. Treatment outcome in each cohort is monitored by using a Simon two-stage-like 'admissible' monitoring plan to identify evidence of clinical activity. All drugs available in IMPRESS-Norway have regulatory approval and are funded by pharmaceutical companies. Molecular diagnostics are funded by the public health care system., Discussion: Precision oncology means to stratify treatment based on specific patient characteristics and the molecular profile of the tumor. Use of targeted drugs is currently restricted to specific biomarker-defined subgroups of patients according to their market authorization. However, other cancer patients might also benefit of treatment with these drugs if the same biomarker is present. The emerging technologies in molecular diagnostics are now being implemented in Norway and it is publicly reimbursed, thus more cancer patients will have a more comprehensive genomic profiling of their tumour. Patients with actionable genomic alterations in their tumour may have the possibility to try precision cancer drugs through IMPRESS-Norway, if standard treatment is no longer an option, and the drugs are available in the study. This might benefit some patients. In addition, it is a good example of a public-private collaboration to establish a national infrastructure for precision oncology. Trial registrations EudraCT: 2020-004414-35, registered 02/19/2021; ClinicalTrial.gov: NCT04817956, registered 03/26/2021., (© 2022. The Author(s).)

Preeclampsia (PE) generally manifests in the second half of pregnancy with hypertension and proteinuria. The understanding of the origin and mechanism behind PE is incomplete, although there is clearly an immune component to this disorder. The placenta constitutes a complicated immune interface between fetal and maternal cells, where regulation and tolerance are key. Stress factors from placental dysfunction in PE are released to the maternal circulation evoking the maternal response. Several complement factors play a role within this intricate landscape, including C1q in vascular remodeling and Factor H (FH) as the key regulator of alternative pathway complement activation. We hypothesize that decreased levels of C1q or FH, or disturbance of their function by autoantibodies, may be associated with PE. Autoantibodies against C1q and FH and the concentrations of C1q and FH were measured by ELISA in maternal sera from women with preeclamptic and normal pregnancies. Samples originated from cohorts collected in the Netherlands (n=63 PE; n=174 control pregnancies, n=51 nonpregnant), Finland (n=181 PE; n=63 control pregnancies) and Norway (n=59 PE; n=27 control pregnancies). Serum C1q and FH concentrations were higher in control pregnancy than in nonpregnant women. No significant differences were observed for serum C1q between preeclamptic and control pregnancy in any of the three cohorts. Serum levels of FH were lower in preeclamptic pregnancies compared to control pregnancies in two of the cohorts, this effect was driven by the early onset PE cases. Neither anti-C1q autoantibodies nor anti-FH autoantibodies levels differed between women with PE and normal pregnancies. In conclusion, levels of anti-C1q and anti-FH autoantibodies are not increased in PE. C1q and FH are increased in pregnancy, but importantly, a decrease in FH concentration is associated with PE., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dijkstra, Lokki, Gierman, Borggreven, van der Keur, Eikmans, Gelderman, Laivuori, The FINNPEC Core Investigator Group, Iversen, van der Hoorn and Trouw.)

Utero-placental development in pregnancy depends on direct maternal-fetal interaction in the uterine wall decidua. Abnormal uterine vascular remodeling preceding placental oxidative stress and placental dysfunction are associated with preeclampsia and fetal growth restriction (FGR). Oxidative stress is counteracted by antioxidants and oxidative repair mechanisms regulated by the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2). We aimed to determine the decidual regulation of the oxidative-stress response by NRF2 and its negative regulator Kelch-like ECH-associated protein 1 (KEAP1) in normal pregnancies and preeclamptic pregnancies with and without FGR. Decidual tissue from 145 pregnancies at delivery was assessed for oxidative stress, non-enzymatic antioxidant capacity, cellular NRF2- and KEAP1-protein expression, and NRF2-regulated transcriptional activation. Preeclampsia combined with FGR was associated with an increased oxidative-stress level and NRF2-regulated gene expression in the decidua, while decidual NRF2- and KEAP1-protein expression was unaffected. Although preeclampsia with normal fetal growth also showed increased decidual oxidative stress, NRF2-regulated gene expression was reduced, and KEAP1-protein expression was increased in areas of high trophoblast density. The trophoblast-dependent KEAP1-protein expression in preeclampsia with normal fetal growth indicates control of decidual oxidative stress by maternal-fetal interaction and underscores the importance of discriminating between preeclampsia with and without FGR.

Context: Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with low-grade inflammation and increased incidence of pregnancy complications, but its influence on the maternal immune system in pregnancy is unknown. Longitudinal serum cytokine profiling is a sensitive measure of the complex immunological dynamics of pregnancy., Objective: This work aimed to determine the immunological dynamics of serum cytokines throughout pregnancy in women with PCOS and compare it to pregnancy in women without PCOS., Methods: A post hoc analysis was conducted of longitudinal serum samples from 2 randomized, placebo-controlled multicenter studies of pregnant women with PCOS and 2 studies of pregnant women without PCOS. Pregnant women with PCOS (n = 358) and without PCOS (n = 258, controls) provided 1752 serum samples from 4 time points in pregnancy (weeks 10, 19, 32, and 36). Main outcome measures included maternal serum levels of 22 cytokines and C-reactive protein (CRP) at 4 time points in pregnancy., Results: Women with PCOS showed marked immunological changes in serum cytokines throughout pregnancy. Compared to controls, women with PCOS showed higher levels of 17 cytokines and CRP at week 10 of pregnancy and a distinct cytokine development throughout pregnancy. The immunological dynamics in women with PCOS was significantly affected by maternal body mass index, smoking, and fetal sex., Conclusion: Pregnancy in women with PCOS was associated with a strong early mobilization of inflammatory and other serum cytokines persisting throughout pregnancy, indicating a more activated immune status. These findings provide a novel basis for further study of PCOS and pregnancy complications., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Pregnancy implies delicate immunological balance between two individuals, with constant changes and adaptions in response to maternal capacity and fetal demands. We performed cytokine profiling of 1149 longitudinal serum samples from 707 pregnant women to map immunological changes from first trimester to term and beyond. The serum levels of 22 cytokines and C-reactive protein (CRP) followed diverse but characteristic trajectories throughout pregnancy, consistent with staged immunological adaptions. Eotaxin showed a particularly robust decrease throughout pregnancy. A strong surge in cytokine levels developed when pregnancies progressed beyond term and the increase was amplified as labor approached. Maternal obesity, smoking and pregnancies with large fetuses showed sustained increase in distinct cytokines throughout pregnancy. Multiparous women had increased cytokine levels in the first trimester compared to nulliparous women with higher cytokine levels in the third trimester. Fetal sex affected first trimester cytokine levels with increased levels in pregnancies with a female fetus. These findings unravel important immunological dynamics of pregnancy, demonstrate how both maternal and fetal factors influence maternal systemic cytokines, and serve as a comprehensive reference for cytokine profiles in normal pregnancies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Jarmund, Giskeødegård, Ryssdal, Steinkjer, Stokkeland, Madssen, Stafne, Stridsklev, Moholdt, Heimstad, Vanky and Iversen.)

Introduction: Inflammation is a normal physiological process that increases to harmful levels in preeclampsia. It affects the interaction between maternal immune cells and fetal trophoblasts at both sites of the maternal-fetal interface; decidua and placenta. The pattern recognition receptor nucleotide-binding oligomerization domain-containing protein (NOD)1 is expressed at both sites. This study aimed to characterize the cellular expression and functionality of NOD1 at the maternal-fetal interface of normal and preeclamptic pregnancies., Methods: Women with normal or preeclamptic pregnancies delivered by caesarean section were included. Decidual (n = 90) and placental (n = 91) samples were analyzed for NOD1 expression by immunohistochemistry and an automated image-based quantification method. Decidual and placental explants were incubated with or without the NOD1-agonist iE-DAP and cytokine responses measured by ELISA., Results: NOD1 was markedly expressed by maternal cells in the decidua and by fetal trophoblasts in both decidua and placenta, with trophoblasts showing the highest NOD1 expression. Preeclampsia with normal fetal growth was associated with a trophoblast-dependent increase in decidual NOD1 expression density. Compared to normal pregnancies, preeclampsia demonstrated stronger correlation between decidual and placental NOD1 expression levels. Increased production of interleukin (IL)-6 or IL-8 after in vitro explant stimulation confirmed NOD1 functionality., Discussion: These findings suggest that NOD1 contributes to inflammation at the maternal-fetal interface in normal pregnancies and preeclampsia and indicate a role in direct maternal-fetal communication. The strong expression of NOD1 by all trophoblast types highlights the importance of combined assessment of decidua and placenta for overall understanding of pathophysiological processes at the maternal-fetal interface., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Inflammation and oxidative stress at the maternal-fetal interface characterize the placental dysfunction that underlies the pregnancy disorder preeclampsia. Specialized fetal trophoblasts directly interact with leukocytes at both sites of the maternal-fetal interface; the uterine wall decidua; and the placenta. TLR3 has been implicated in the harmful inflammation at the maternal-fetal interface in preeclampsia, but the cellular involvement in the decidua and placenta has not been determined. This study aimed to characterize and quantify cell-specific TLR3 expression and function at the maternal-fetal interface in normal and preeclamptic pregnancies. TLR3 expression was assessed by immunohistochemistry and quantified by a novel image-based and cell-specific quantitation method. TLR3 was expressed at the maternal-fetal interface by all decidual and placental trophoblast types and by maternal and fetal leukocytes. Placental, but not decidual, TLR3 expression was significantly higher in preeclampsia compared to normal pregnancies. This increase was attributed to placental intravillous tissue and associated with both moderate and severe placental dysfunction. TLR3 pathway functionality in the decidua and placenta was confirmed by TLR3 ligand-induced cytokine response, but the TLR3 expression levels did not correlate between the two sites. In conclusion, functional TLR3 was broadly expressed by maternal and fetal cells at both sites of the maternal-fetal interface and the placental intravillous expression was increased in preeclampsia. This suggests TLR3-mediated inflammatory involvement with local regulation at both sites of the maternal-fetal interface in normal and preeclamptic pregnancies., (© 2020 The Authors. Journal of Leukocyte Biology published by Wiley Periodicals LLC on behalf of Society for Leukocyte Biology.)

Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia.

Preeclampsia is a hypertensive and inflammatory pregnancy disorder associated with cholesterol accumulation and inflammation at the maternal-fetal interface. Preeclampsia can be complicated with fetal growth restriction (FGR) and shares risk factors and pathophysiological mechanisms with cardiovascular disease. Cholesterol crystal mediated NLRP3 inflammasome activation is central to cardiovascular disease and the pathway has been implicated in placental inflammation in preeclampsia. Direct maternal-fetal interaction occurs both in the uterine wall decidua and at the placental surface and these aligned sites constitute the maternal-fetal interface. This study aimed to investigate cholesterol crystal accumulation and NLRP3 inflammasome expression by maternal and fetal cells in the uterine wall decidua of normal and preeclamptic pregnancies. Pregnant women with normal ( n = 43) and preeclamptic pregnancies with ( n = 28) and without ( n = 19) FGR were included at delivery. Cholesterol crystals were imaged in decidual tissue by both second harmonic generation microscopy and polarization filter reflected light microscopy. Quantitative expression analysis of NLRP3, IL-1β and cell markers was performed by immunohistochemistry and automated image processing. Functional NLRP3 activation was assessed in cultured decidual explants. Cholesterol crystals were identified in decidual tissue, both in the tissue stroma and near uterine vessels. The cholesterol crystals in decidua varied between pregnancies in distribution and cluster size. Decidual expression of the inflammasome components NLRP3 and IL-1β was located to fetal trophoblasts and maternal leukocytes and was strongest in areas of proximity between these cell types. Pathway functionality was confirmed by cholesterol crystal activation of IL-1β in cultured decidual explants. Preeclampsia without FGR was associated with increased trophoblast dependent NLRP3 and IL-1β expression, particularly in the decidual areas of trophoblast and leukocyte proximity. Our findings suggest that decidual accumulation of cholesterol crystals may activate the NLRP3 inflammasome and contribute to decidual inflammation and that this pathway is strengthened in areas with close maternal-fetal interaction in preeclampsia without FGR., (Copyright © 2020 Silva, Gierman, Rakner, Stødle, Mundal, Thaning, Sporsheim, Elschot, Collett, Bjørge, Aune, Thomsen and Iversen.)

Child welfare workers (CWWs) often work under conditions similar in nature to workers within safety critical organizations (SCOs). This is because most of their work surrounds child neglect, securing homes for foster children, haphazard, and intricate cases, among other things, and where making wrong decisions, inattention to details, and the likes could lead to adverse consequences especially for the kids within their care. Research has shown that employees who experience support at work often report less stress symptoms, burnout, and a host of other negative workplace experiences. Experience of support at work has also been found to boost employees' retention, job satisfaction, and productivity. Despite this development, research exploring the essence of workplace support among CWW is very scarce in the literature, and we know very little about the type of workplace support and their influence on a host of workplace outcomes, especially the negative ones like secondary traumatic stress, aggression, and violence toward CWWs. The purpose of the current scoping review was to uncover what is known about workplace support and their relationship with workplace outcomes among CWWs. The authors explored four databases and identified 55 primary studies investigating workplace support and workplace outcomes among CWWs in the review. Studies mostly framed support under three main support types of coworker/peer support, social/organizational/management support, and supervisor/leadership support. Findings showed that workplace support has a positive impact on workplace variables like job satisfaction, engagement, commitment, and reduces the risk of turnover, burnout, and other negative workplace variables. The review highlights possible directions for future research., (Copyright © 2020 Olaniyan, Hetland, Hystad, Iversen and Ortiz-Barreda.)

Clinical end-stage parameters define the pregnancy disorders preeclampsia and fetal growth restriction while classification of the underlying placental dysfunction is missing and urgently needed. Flt-1 (FMS-like tyrosine kinase receptor 1) is the most promising placenta-derived predictive biomarker for preeclampsia. We aimed to classify placental dysfunction in preeclampsia and fetal growth restriction at delivery by metabolic profiling and authenticate the biomarker Flt-1 for placental dysfunction. We studied 143 pregnancies with or without preeclampsia and/or fetal growth restriction delivered by cesarean section. Metabolic placenta profiles were created by high-resolution magic angle spinning nuclear magnetic resonance spectroscopy and the resulting placental phenotypes obtained by hierarchical clustering. Placental Flt-1 expression (membrane-bound and soluble isoforms combined) and maternal serum Flt-1 expression (soluble isoforms) were analyzed by immunohistochemistry and ELISA, respectively. We identified 3 distinct placenta groups by 21 metabolites and diagnostic outcome parameters; normal placentas, moderate placental dysfunction, and severe placental dysfunction. Increased placental Flt-1 was associated with severe placental dysfunction, and increased serum Flt-1 was associated with moderate and severe placental dysfunction. The preeclamptic pregnancies with and without placental dysfunction could be distinguished by 5 metabolites and placental Flt-1. Placental Flt-1 alone could separate normal pregnancies with and without placental dysfunction. In conclusion, metabolomics could classify placental dysfunction and provide information not identified by traditional diagnostics and metabolites with biomarker potential were identified. Flt-1 was confirmed as precision biomarker for placental dysfunction, substantiating its usefulness for identification of high-risk pregnancies for preeclampsia and fetal growth restriction with placental involvement.

This study is a national cross-sectional survey, conducted in November 2014, of 366 dental hygienists and dentists who had suspected maltreatment but did not report it to Norwegian Child Welfare Services (CWS). The aims of the present paper are to identify the reasons why public dental healthcare professionals are reluctant to report suspected child maltreatment to CWS and to determine whether there are differences in the identified barriers according to socio-demographic variables. The questionnaire was based on earlier studies and was adapted to fit the Norwegian context. The most frequently chosen reason for not reporting was "unsure of own assessment" (90.4%). Thirteen items pertaining to not reporting were factorised into three factors of barriers. These factors were "insufficient knowledge of child maltreatment and reporting", "fear of the consequences for oneself and the dental clinic", and "fear of the consequences for the patient and their family". A t test revealed that public dental healthcare personnel who had not received training on maltreatment and reporting to CWS during their professional education scored significantly higher on the barrier "insufficient knowledge of child maltreatment and reporting" than did dental personnel who had received such training. Furthermore, dental personnel with more years of experience (11+) scored higher on this barrier than did dental personnel with less experience. No other significant differences in barriers were observed. Public dental healthcare personnel have a mandatory obligation to report to CWS if they suspect child maltreatment. Despite this obligation, the present study reveals that several barriers to reporting exist. This study underscores the importance of strengthening knowledge among dental hygienists and dentists about when and how to report, both during education and in clinical practice., (© 2018 John Wiley & Sons Ltd.)

Introduction: Human pregnancy is a state of elevated maternal systemic inflammation, and pregnancy complications are often associated with a dysfunctional immune response. The network of cytokines reflects this complex immune activity, and broad serum cytokine profiling provides a new tool to understand the changes in immune status during pregnancy., Objective: This study aimed to determine how maternal serum cytokine patterns change during the first half of pregnancy., Methods: Maternal peripheral serum samples collected at a mean gestation of 10, 13, 18 and 24 weeks were included from a prospective clinical study of healthy women (n = 110) in first half of normal pregnancy. The serum samples were analysed for 27 different cytokines using multiplex magnetic bead-based immunoassays, and high sensitivity C-reactive protein (CRP) was analysed by ELISA. Serum cytokine and CRP patterns were explored with linear mixed effects models (LMM) and multilevel partial least squares discriminant analysis (PLS-DA)., Results: Serum cytokine profiling provided partial overview of the maternal immune status and corresponding reference values for serum cytokine levels during the first half of pregnancy. Several cytokines decreased in concentration from first to second trimester. Cytokine pattern analysis revealed that chemokines provided the most sensitive measurement of variation with gestational age in normal pregnancies. The nine inflammatory cytokines showed the highest intra-group correlation during pregnancy, while CRP levels did not correlate with changes in the inflammatory cytokines., Conclusion: Chemokines showed the greatest gestational variation and inflammatory cytokines showed a strong intra-group correlation during the first half of pregnancy., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background and Aim: Hypertensive pregnancy disorders are associated with subsequent cardiovascular disease (CVD), but the extent to which this association is explained by shared risk factors is unknown. We aimed to evaluate whether hypertensive pregnancy disorder in first pregnancy is associated with increased subsequent risk of maternal CVD after adjustment for established CVD risk factors measured after pregnancy., Methods and Results: A total of 20,075 women with a first delivery registered in the Medical Birth Registry of Norway (1980-2003) participated in Cohort of Norway (CONOR) health surveys a mean (standard deviation) of 10.7 (5.5) years after delivery. They were then followed (median 11.4 years) for an incident fatal or non-fatal CVD event through linkage to the Cardiovascular Disease in Norway (CVDNOR) database and the Norwegian Cause of Death Registry. Hypertensive pregnancy disorders were associated with an increased risk of CVD [Hazard ratio (HR) 2.3; 95% confidence interval (CI) 1.9-2.8], which remained significant after adjustment for established CVD risk factors including body mass index, smoking, hypertension, diabetes, serum glucose and lipid levels (HR 1.5; 95% CI 1.2-1.8). The population attributable fraction of CVD due to hypertensive pregnancy disorder was 4.3% (95% CI 1.9-6.6) after multivariable adjustment., Conclusion: The association between hypertensive pregnancy disorders and CVD risk was mediated in part by related CVD risk factors measured 10 years following delivery. These results underline the importance of post-pregnancy follow-up of women with hypertensive pregnancy disorders focusing on modifiable, lifestyle related risk factors to prevent future CVD., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: Normal pregnancy is characterized by an elevated inflammatory state involving the placenta. The placental inflammation is further increased in preeclampsia, resulting in release of harmful danger signals to the maternal circulation. Activation of toll-like receptors (TLR)2 and TLR4 by endogenous danger signals plays a role in inflammatory diseases. Placental TLR2 and TLR4 expression has been reported, and high mobility group box 1 (HMGB1) is a likely endogenous activator of these receptors. We aimed to examine HMGB1 activation of TLR2 and TLR4 as mechanisms of placental inflammation in normal and preeclamptic pregnancies, by combined analysis of expression and function of the ligand HMGB1, the receptors TLR2 and TLR4, and the cytokine responder interleukin (IL)-8., Methods: Protein expression was analyzed in placental tissue from normal and preeclamptic pregnancies, and cytokine responses to two distinct HMGB1 isoforms were examined in placental explants and trophoblasts. Inflammatory and anti-angiogenic markers were measured in maternal serum., Results: We demonstrated strong co-localized expression of HMGB1, TLR4 and IL-8 in the syncytium layer of the placenta. Syncytium TLR4 expression and maternal serum levels of IL-8 were significantly increased in preeclamptic compared to normal pregnancies. Functionality was confirmed by TLR4-dependent release of IL-8 from placental explants and trophoblasts in response to the inflammatory isoform of HMGB1., Discussion: This demonstrates a role for the HMGB1-TLR4 pathway at the syncytium layer and suggests involvement in placental inflammation and preeclampsia., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Pre-eclampsia is associated with increased levels of cholesterol and uric acid and an inflamed placenta expressing danger-sensing pattern recognition receptors (PRRs). Crystalline cholesterol and uric acid activate the PRR Nod-like receptor protein (NLRP)3 inflammasome to release interleukin (IL)-1β and result in vigorous inflammation. We aimed to characterize crystal-induced NLRP3 activation in placental inflammation and examine its role in pre-eclampsia. We confirmed that serum total cholesterol and uric acid were elevated in pre-eclamptic compared to healthy pregnancies and correlated positively to high sensitivity C-reactive protein (hsCRP) and the pre-eclampsia marker soluble fms-like tyrosine kinase-1 (sFlt-1). The NLRP3 inflammasome pathway components (NLRP3, caspase-1, IL-1β) and priming factors [complement component 5a (C5a) and terminal complement complex (TCC)] were co-expressed by the syncytiotrophoblast layer which covers the placental surface and interacts with maternal blood. The expression of IL-1β and TCC was increased significantly and C5a-positive regions in the syncytiotrophoblast layer appeared more frequent in pre-eclamptic compared to normal pregnancies. In-vitro activation of placental explants and trophoblasts confirmed NLRP3 inflammasome pathway functionality by complement-primed crystal-induced release of IL-1β. This study confirms crystal-induced NLRP3 inflammasome activation located at the syncytiotrophoblast layer as a mechanism of placental inflammation and suggests contribution of enhanced NLRP3 activation to the harmful placental inflammation in pre-eclampsia., (© 2018 British Society for Immunology.)

Background: Little is known about the social and emotional well-being of children whose fathers have been deployed to the conflicts in Iraq/Afghanistan or who have post-traumatic stress disorder (PTSD).AimsTo examine the emotional and behavioural well-being of children whose fathers are or have been in the UK armed forces, in particular the effects of paternal deployment to the conflicts in Iraq or Afghanistan and paternal PTSD., Method: Fathers who had taken part in a large tri-service cohort and had children aged 3-16 years were asked about the emotional and behavioural well-being of their child(ren) and assessed for symptoms of PTSD via online questionnaires and telephone interview., Results: In total, 621 (67%) fathers participated, providing data on 1044 children. Paternal deployment to Iraq or Afghanistan was not associated with childhood emotional and behavioural difficulties. Paternal probable PTSD were associated with child hyperactivity. This finding was limited to boys and those under 11 years of age., Conclusions: This study showed that adverse childhood emotional and behavioural well-being was not associated with paternal deployment but was associated with paternal probable PTSD.Declaration of interestN.T.F. is a trustee of the Warrior Programme, a charity supporting ex-service personnel and their families. She is also a member of the Independent Group Advising on the Release of Data (IGARD). S.W. is a trustee of Combat Stress, a charity supporting ex-service personnel and their families, and President of the Royal Society of Medicine. S.W. is partially funded by the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Emergency Preparedness and Response at King's College London in partnership with Public Health England (PHE), in collaboration with the University of East Anglia and Newcastle University.

Background: Preeclampsia and gestational hypertension (GH) are the most common hypertensive pregnancy disorders. Preeclampsia has been linked to increased risk of cardiovascular disease (CVD), but a similar association for GH has not been established. We aimed to determine the association between GH and subsequent CVD, and explore the additional role of small-for-gestational-age infants, preterm delivery, and parity., Methods and Results: Data from the Medical Birth Registry of Norway were linked to the Cardiovascular Disease in Norway project and the Norwegian Cause of Death Registry. Hazard ratios and 95% confidence intervals were computed using Cox proportional hazard regression, comparing women with and without GH during their first and/or second pregnancy. We included all women with a first delivery from 1980 through 2009 (n=617 589) and followed them for a median of 14.3 (quartile 1-quartile 3: 6.9-21.5) years. Women with GH in the first pregnancy had 1.8-fold (95% confidence interval, 1.7-2.0) higher risk of subsequent CVD compared with women without any hypertensive pregnancy disorder. When GH occurred in combination with small-for-gestational-age infants and/or preterm delivery, the hazard ratio was 2.6 (95% confidence interval, 2.3-3.0). When women with GH were compared with women with preeclampsia, the risk of CVD was comparable when the pregnancy complications occurred in either the first or second pregnancy but was significantly higher for preeclampsia without complications when the disorder occurred in both pregnancies., Conclusions: GH was associated with increased risk of subsequent CVD, and the highest risk was observed when GH was combined with small-for-gestational-age infants and/or preterm delivery., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: Previous research has shown a link between parental mental illness and adverse development in their offspring. In Norway, it is mandatory for health professionals to identify if patients in adult mental health services have children, and subsequently to provide support for the children. An important tool to detect if families are affected by parental mental illness and to assess if there is a need for further intervention is the Family Assessment Conversation. Family Assessment Conversations is potentially a powerful tool for communication with families affected by parental mental illness because it facilitates early identification of children at risk of various adversities due to the family situation. Additionally the tool may initiate processes that enable children and parents to cope with the situation when a parent becomes seriously ill. Little is however known about how the mental health practitioners use the family assessment form in conversations, and to what extent they record relevant information in the electronic patient journals., Methods: The main aim of the study was to provide information about the existing practice within mental health services for adults in terms of parental mental illness and family assessment conversations. The project is a retrospective journal review. The data base consists of relevant journal data from 734 patients aged 20-60 years admitted. In total, 159 recordings of family assessment conversations were discovered., Results: The main result in this study was that many of the questions in the family assessment form lacked documented responses and assessments from the healthcare professionals. Only 17% of the participants had been assessed with the total family assessment form. Additionally, there was a lack of documentation about whether or not the children had been informed in a large proportion of the assessment forms (31%). A total of 55% say that the child has not been informed. This implies that there is still a long way to go in order to make sure that children of parents with a mental illness are given relevant information and support., Conclusions: The documentation and family assessment frequency is low and reflects the challenges healthcare professionals and patient experience when the child's situation becomes the topic of assessment. There is a need to further investigate the challenges of changing the mental health systems to incorporate the children and families of patients. More research should promote knowledge on what may facilitate family assessment dialogue.

Preeclampsia, which affects approximately 5% of pregnancies, is a leading cause of maternal and perinatal death. The causes of preeclampsia remain unclear, but there is evidence for inherited susceptibility. Genome-wide association studies (GWAS) have not identified maternal sequence variants of genome-wide significance that replicate in independent data sets. We report the first GWAS of offspring from preeclamptic pregnancies and discovery of the first genome-wide significant susceptibility locus (rs4769613; P = 5.4 × 10 -11 ) in 4,380 cases and 310,238 controls. This locus is near the FLT1 gene encoding Fms-like tyrosine kinase 1, providing biological support, as a placental isoform of this protein (sFlt-1) is implicated in the pathology of preeclampsia. The association was strongest in offspring from pregnancies in which preeclampsia developed during late gestation and offspring birth weights exceeded the tenth centile. An additional nearby variant, rs12050029, associated with preeclampsia independently of rs4769613. The newly discovered locus may enhance understanding of the pathophysiology of preeclampsia and its subtypes.

Background: Preeclampsia is a severe pregnancy disorder often complicated by reduced fetal growth or preterm delivery and is associated with long-term maternal morbidity and mortality. We aimed to assess the association between preeclampsia phenotypes and risk of subsequent coronary heart disease and maternal cardiovascular mortality., Methods and Results: Women aged 16 to 49 years who gave birth during 1980-2002 and registered in the Medical Birth Registry of Norway were followed prospectively (1-29 years) for an incident major coronary event and mortality through linkage with the Cardiovascular Disease in Norway 1994-2009 (CVDNOR) project and the Norwegian Cause of Death Registry. Preeclampsia was subdivided based on the presence of a child born small for gestational age or preterm delivery. Among 506 350 women with 1 to 5 singleton births, there were 1275 (0.3%) occurrences of major coronary event, 468 (0.1%) cardiovascular deaths, and 5411 (1.1%) deaths overall. Compared with women without preeclampsia, the hazard ratio (95% CI) for major coronary event was 2.1 (1.73-2.65) after preeclampsia alone, 3.3 (2.37-4.57) after preeclampsia in combination with small for gestational age, and 5.4 (3.74-7.74) after preeclampsia in combination with preterm delivery. Analyses distinguishing women with 1 (n=61 352) or >1 (n=281 069) lifetime pregnancy and analyses with cardiovascular mortality as outcome followed the same pattern., Conclusions: The occurrence of major coronary events was increased among women with preeclampsia and highest for preeclampsia combined with a child born small for gestational age and/or preterm delivery., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Objective: Preeclampsia is a complex heterogeneous disease commonly defined by new-onset hypertension and proteinuria in pregnancy. Women experiencing preeclampsia have increased risk for cardiovascular diseases (CVD) later in life. Preeclampsia and CVD share risk factors and pathophysiologic mechanisms, including dysregulated inflammation and raised blood pressure. Despite commonalities, little is known about the contribution of shared genes (pleiotropy) to these diseases. This study aimed to investigate whether genetic risk factors for hypertension or inflammation are pleiotropic by also being associated with preeclampsia., Methods: We genotyped 122 single nucleotide polymorphisms (SNPs) in women with preeclampsia (n = 1006) and nonpreeclamptic controls (n = 816) from the Norwegian HUNT Study. SNPs were chosen on the basis of previously reported associations with either nongestational hypertension or inflammation in genome-wide association studies. The SNPs were tested for association with preeclampsia in a multiple logistic regression model., Results: The minor (G) allele of the intronic SNP rs17367504 in the gene methylenetetrahydrofolate reductase (MTHFR) was associated with a protective effect on preeclampsia (odds ratio 0.65, 95% confidence interval 0.53-0.80) in the Norwegian cohort. This association did not replicate in an Australian preeclampsia case-control cohort (P = 0.68, odds ratio 1.05, 95% confidence interval 0.83-1.32, minor allele frequency = 0.15)., Conclusion: MTHFR is important for regulating transmethylation processes and is involved in regulation of folate metabolism. The G allele of rs17367504 has previously been shown to protect against nongestational hypertension. Our study suggests a novel association between this allele and reduced risk for preeclampsia. This is the first study associating the minor (G) allele of a SNP within the MTHFR gene with a protective effect on preeclampsia, and in doing so identifying a possible pleiotropic protective effect on preeclampsia and hypertension.

Objective: Detecting and responding to child-maltreatment is a serious challenge and public health concern. In Norway, public dental health personnel (PDHP) have a mandatory obligation to report to child welfare services (CWS) if they suspect child-maltreatment. This study aimed to assess PDHP's frequency of reporting and failing to report to CWS and whether the frequencies varied according to personal, organizational and external characteristics., Material and Methods: An electronic questionnaire was sent to 1542 public dental hygienists and dentists in Norway, 1200 of who responded (77.8%)., Results: The majority 60.0%, reported having sent reports of concern to CWS throughout their career, 32.6% had suspected child-maltreatment but failed to report it in their career and 42.5% had sent reports during the three-year period from 2012 to 2014. The reporting frequency to CWS was influenced by PDHP's personal, organizational and external characteristics, while failure to report was influenced by personal characteristics., Conclusions: Compared to international studies, PDHP in Norway sends reports of concern and fails to report to CWS at relatively high rates. PDHP's likelihood of reporting was influenced by age, working experience, number of patients treated, size of the municipality and geographical region, while failure to report to CWS was influenced by working experience.

Introduction: Preeclampsia is a heterogeneous gestational disease characterized by maternal hypertension and proteinuria, affecting 2-7% of pregnancies. The disorder is initiated by insufficient placental development, but studies characterizing the placental disease components are lacking., Methods: Our aim was to phenotype the preeclamptic placenta using high-resolution magic angle spinning nuclear magnetic resonance spectroscopy (HR-MAS MRS). Placental samples collected after delivery from women with preeclampsia (n = 19) and normotensive pregnancies (n = 15) were analyzed for metabolic biomarkers including amino acids, osmolytes, and components of the energy and phospholipid metabolism. The metabolic biomarkers were correlated to clinical characteristics and inflammatory biomarkers in the maternal sera., Results: Principal component analysis showed inherent differences in placental metabolic profiles between preeclamptic and normotensive pregnancies. Significant differences in metabolic profiles were found between placentas from severe and non-severe preeclampsia, but not between preeclamptic pregnancies with fetal growth restricted versus normal weight neonates. The placental metabolites correlated with the placental stress marker sFlt-1 and triglycerides in maternal serum, suggesting variation in placental stress signaling between different placental phenotypes., Discussion: HR-MAS MRS is a sensitive method for defining the placental disease component of preeclampsia, identifying several altered metabolic pathways. Placental HR-MAS MRS analysis may improve insight into processes affected in the preeclamptic placenta, and represents a novel long-required tool for a sensitive placental phenotyping of this heterogeneous disease., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: Gestational hypertension and preeclampsia involve dysregulated maternal inflammatory responses to pregnancy, but whether such responses differ between the disorders has not been determined. We aimed to investigate disease-specific early pregnancy serum cytokine profiles of women subsequently developing gestational hypertension or preeclampsia for new insight into the underlying pathogeneses and differences between the disorders., Approach and Results: The study cohort consisted of 548 pregnant Norwegian women who were either multiparous with previous gestational hypertension or preeclampsia or were nulliparous. Maternal sera at gestational weeks 11(0)-13(6) were assayed for 27 cytokines, C-reactive protein, total cholesterol, high-density lipoprotein, triglyceride, creatinine, calcium, uric acid, and placental growth factor. Compared with normotensive women, women with both hypertensive conditions presented an atherogenic lipid profile at early gestation, but only those later developing gestational hypertension had significantly higher serum levels of interleukin (IL)-5 and IL-12. Comparing the 2 hypertensive pregnancy disorders, women subsequently developing gestational hypertension had higher serum levels of IL-1β, IL-5, IL-7, IL-8, IL-13, basic fibroblast growth factor, and vascular endothelial growth factor than the women subsequently developing preeclampsia., Conclusions: This study identifies early pregnancy differences in serum cytokine profiles for gestational hypertension and preeclampsia., (© 2015 American Heart Association, Inc.)

Objective: Preeclampsia is a complex genetic disease of pregnancy with a heterogenous presentation, unknown cause and potential severe outcomes for both mother and child. Preeclamptic women have increased risk for atherothrombotic cardiovascular disease. We aimed to identify heritabilities and phenotypic correlations of preeclampsia and related conditions in the Norwegian Preeclampsia Family Biobank., Methods: By applying a variance components model, a total of 493 individuals (from 138 families with increased occurrence of preeclampsia) were classified according to 30 disease-related phenotypes., Results: Of parous women, 75.7% (263/338) had experienced preeclampsia and 35.7% of women with and 22.4% without preeclampsia delivered children small for gestational age (SGA). We identified 11 phenotypes as heritable. The increased occurrence of preeclampsia was reflected by the presence [heritability (H2r) = 0.60)] and severity (H2r = 0.15) of preeclampsia and being born in a preeclamptic pregnancy (H2r = 0.25). Other heritable phenotypes identified included SGA (H2r = 0.40), chronic hypertension (H2r = 0.57), severity of atherothrombotic cardiovascular disease (H2r = 0.31), BMI (H2r = 0.60) and pulmonary disease (H2r = 0.91). The heritable phenotype preeclampsia overlapped with SGA (P = 0.03), whereas pulmonary disease was phenotypically correlated with atherothrombotic cardiovascular disease (P < 0.01), SGA (P = 0.02) and BMI (P = 0.02)., Conclusion: This is the first study identifying the H2r of a range of health-related conditions in preeclamptic families. Our study demonstrates how refinement of phenotypes leads to better H2r estimation and the identification of a biological relationship between preeclampsia and related traits.

Introduction: Excessive placental inflammation is associated with pregnancy complications. Toll-like receptors (TLRs) are sensors for danger signals from infections and damaged tissue and initiate inflammation. Trophoblasts in the placenta broadly express TLRs. Trophoblast cell lines are used as surrogates for primary trophoblasts for in vitro studies, but the inflammatory translatability of trophoblast cell lines warrants examination. We aimed to assess TLR1-10 gene expression and activation in seven trophoblast cell lines and compare this to primary trophoblasts., Methods: The five choriocarcinoma trophoblast cell lines BeWo, JAR, JEG-3, AC1M-32 and ACH-3P, and the two SV40 transfected trophoblast cell lines HTR-8/SVneo and SGHPL-5 were included and compared to primary first trimester trophoblasts (n = 6). TLR1-10 gene expression was analyzed by RT-qPCR. Cells were stimulated by specific TLR1-9 ligands for 24 h and cytokine release was measured by a 10-plex immunoassay., Results: All choriocarcinoma cell lines demonstrated broad TLR gene expression, but lacked functional cytokine response to TLR ligand activation. In contrast, SV40 transfected cell lines showed restricted TLR gene expression, but SGHPL-5 cells displayed significantly increased levels of interleukin (IL)-6, IL-8, IL-12 and vascular endothelial growth factor A after TLR3 and/or TLR4 activation (P < 0.01), while TLR2 activation increased IL-6 and IL-8 levels (P < 0.05). HTR8/SVneo cells responded to TLR3 activation by increased IL-6 and interferon (IFN)-γ (P < 0.05). The SGHPL-5 TLR profile most closely resembled primary trophoblast., Discussion: The characterized trophoblast cell line TLR profiles serve as a reference and warrant caution when selecting trophoblast cell lines as in vitro models for immune responses in primary trophoblasts., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Hypertensive disorders of pregnancy, including preeclampsia, are major contributors to maternal morbidity. The goal of this study was to evaluate the potential of metabolomics to predict preeclampsia and gestational hypertension from urine and serum samples in early pregnancy, and elucidate the metabolic changes related to the diseases. Metabolic profiles were obtained by nuclear magnetic resonance spectroscopy of serum and urine samples from 599 women at medium to high risk of preeclampsia (nulliparous or previous preeclampsia/gestational hypertension). Preeclampsia developed in 26 (4.3%) and gestational hypertension in 21 (3.5%) women. Multivariate analyses of the metabolic profiles were performed to establish prediction models for the hypertensive disorders individually and combined. Urinary metabolomic profiles predicted preeclampsia and gestational hypertension at 51.3% and 40% sensitivity, respectively, at 10% false positive rate, with hippurate as the most important metabolite for the prediction. Serum metabolomic profiles predicted preeclampsia and gestational hypertension at 15% and 33% sensitivity, respectively, with increased lipid levels and an atherogenic lipid profile as most important for the prediction. Combining maternal characteristics with the urinary hippurate/creatinine level improved the prediction rates of preeclampsia in a logistic regression model. The study indicates a potential future role of clinical importance for metabolomic analysis of urine in prediction of preeclampsia.

The non-classical major histocompatibility complex, human leukocyte antigen (HLA)-G, plays an important role in pregnancy. HLA-G mediates proper interaction between maternal immune cells and fetal trophoblasts invading the uterine wall, to ensure successful placental development and function. Several HLA-G gene variants have been shown to be associated with development of preeclampsia (PE), but the reported associations of the HLA-G 14 base pair (bp) insertion/deletion (I/D) polymorphism (rs66554220) with PE are inconsistent. In this meta-analysis of HLA-G 14 bp I/D in each member of the family triad, we estimated risk (odds ratio [OR], 95% confidence interval) of associations with PE based on nine published offspring, nine mother and three father case-control studies. No significant increased risk associations between PE and HLA-G 14 bp I/D were detected in any of the family triad members (offspring: OR = 1.08-1.21, P = 0.57-0.74; mothers: OR = 1.11-1.28, P = 0.07-0.44; fathers: OR = 1.09-1.65, P = 0.07-0.70). Of the 20 comparisons performed, 14 (70%) were non-heterogeneous and seven of these had zero heterogeneity (I(2) = 0%). Sensitivity treatment confirmed robustness for the overall lack of association for HLA-G 14 bp I/D. In subgroup analysis, significant association between HLA-G 14 bp I/D and PE was shown in offspring from primipara (OR = 1.66-1.95, P = 0.04) and European Caucasian pregnancies (OR = 1.37-2.03, P = 0.02-0.03). However, heterogeneity and sensitivity tests suggest that further investigation is needed to determine if HLA-G 14 bp I/D is involved in trophoblast HLA-G expression and PE development in these subgroups., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Toll-like receptors (TLRs) are an important part of the body's danger response system and crucial for initiating inflammation in response to cellular stress, tissue damage, and infections. Proper placental development is sensitive to inflammatory activation, and a role for TLRs in trophoblast immune activation has been suggested, but no overall examination has been performed in primary trophoblasts of early pregnancy. This study aimed to broadly examine cell surface and endosomal TLR gene expression and activation in first-trimester trophoblasts. Gene expression of all ten TLRs was examined by quantitative RT-PCR (RT-qPCR) in primary first-trimester trophoblasts (n = 6) and the trophoblast cell line BeWo, and cytokine responses to TLR ligands were detected by quantitative multiplex immunoassay. Primary first-trimester trophoblasts broadly expressed all ten TLR mRNAs; TLR1, TLR2, TLR3, TLR4, and TLR6 mRNA were expressed by all primary trophoblast populations, while TLR5, TLR7, TLR8, TLR9, and TLR10 mRNA expression was more restricted. Functional response to ligand activation of cell surface TLR2/1, TLR4, and TLR5 increased IL-6 and/or IL-8 release (P < 0.01) from primary trophoblasts. For endosomal TLRs, TLR3 and TLR9 ligand exposure increased receptor-specific production of IL-8 (P < 0.01) and IFN-γ-induced protein 10 (IP-10; P < 0.001) or vascular endothelial growth factor A (VEGFA; P < 0.01). In contrast, BeWo cells expressed lower TLR mRNA levels and did not respond to TLR activation. In conclusion, primary first-trimester trophoblasts broadly express functional TLRs, with inter-individual variation, suggesting that trophoblast TLR2, TLR3, TLR4, TLR5, and TLR9 might play a role in early placental inflammation., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Summary OBJECTIVES: To describe a successful mentoring scheme designed for mid-career clinician scientists and to examine factors associated with mentee report of positive career impact., Design: Mixed methods study including in-depth interviews and cross-sectional data collection via an online survey., Setting: Academy of Medical Sciences mentoring scheme set up in 2002 and evaluated in 2010., Participants: One hundred and forty-seven of 227 mentees took part in the study (response rate of 65%). Ten mentees, three mentors and eight stakeholders/scheme staff were selected to participate in in-depth interviews., Main Outcome Measures: Qualitative data: Interviews were transcribed, and free text was analysed to identify themes and subthemes in the narrative. Quantitative data: We examined the associations of reported positive career impact of mentoring by performing simple and multiple logistic regression analysis., Results: Mentoring success was determined by a variety of factors including reasons for selection (e.g. presence of a personal recommendation), mentee characteristics (e.g. younger age), experience and skills of the mentor (e.g. 'mentor helped me to find my own solutions') and the quality of the relationship (e.g. 'my mentor and I set out clear expectations early on')., Conclusions: Our evaluation demonstrates that both mentor and mentee value mentoring and that careful planning of a scheme including preparation, training and ongoing support of both mentor and mentee addressing expectations, building rapport and logistics are likely to be helpful in ensuring success and benefit from the intervention., (© The Royal Society of Medicine.)

Objective: Four putative single nucleotide polymorphism (SNP) risk variants at the preeclampsia susceptibility locus on chromosome 2q22; rs2322659 (LCT), rs35821928 (LRP1B), rs115015150 (RND3) and rs17783344 (GCA), were recently shown to associate with known cardiovascular risk factors in a Mexican American cohort. This study aimed to further evaluate the pleiotropic effects of these preeclampsia risk variants in an independent Australian population-based cohort., Methods: The four SNPs were genotyped in the Western Australian Pregnancy Cohort (Raine) Study that included DNA, clinical and biochemical data from 1246 mothers and 1404 of their now adolescent offspring. Genotype association analyses were undertaken using the SOLAR software., Results: Nominal associations (P<0.05) with cardiovascular risk factors were detected for all four SNPs. The LCT SNP was associated with decreased maternal height (P=0.005) and decreased blood glucose levels in adolescents (P=0.022). The LRP1B SNP was associated with increased maternal height (P=0.026) and decreased maternal weight (P=0.044). The RND3 SNP was associated with decreased triglycerides in adolescents (P=0.001). The GCA SNP was associated with lower risk in adolescents to be born of a preeclamptic pregnancy (P=0.003) and having a mother with prior preeclamptic pregnancy (P=0.033)., Conclusions: Our collective findings support the hypothesis that genetic mechanisms for preeclampsia and CVD are, at least in part, shared, but need to be interpreted with some caution as a Bonferroni correction for multiple testing adjusted the statistical significance threshold (adjusted P<0.001)., (Copyright © 2014 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Objective: To explore the potential of magnetic resonance (MR) metabolomics for study of preeclampsia, for improved phenotyping and elucidating potential clues to etiology and pathogenesis., Methods: Urine and serum samples from pregnant women with preeclampsia (n = 10), normal pregnancies (n = 10) and non-pregnant women (n = 10) matched by age and gestational age were analyzed with MR spectroscopy and subjected to multivariate analysis. Metabolites were then quantified and compared between groups., Results: Urine and serum samples revealed clear differences between women with preeclampsia and both control groups (normal pregnant and non-pregnant women). Nine urine metabolites were significantly different between preeclampsia and the normal pregnant group. Urine samples from women with early onset preeclampsia clustered together in the multivariate analysis. The preeclampsia serum spectra showed higher levels of low and very-low density lipoproteins and lower levels of high-density lipoproteins when compared to both non-pregnant and normal pregnant women., Conclusion: The MR determined metabolic profiles in urine and serum from women with preeclampsia are clearly different from normal pregnant women. The observed differences represent a potential to examine mechanisms underlying different preeclampsia phenotypes in urine and serum samples in larger studies. In addition, similarities between preeclampsia and cardiovascular disease in metabolomics are demonstrated.

Pre-eclampsia is a major cause of maternal and fetal mortality in pregnancy. The identification of genetic variants which predispose to pre-eclampsia demands large DNA collections from affected mothers and babies and controls, with reliable supporting phenotypic data. The InterPregGen study has assembled a consortium of researchers from Europe, Central Asia and South America with the aim of elucidating the genetic architecture of pre-eclampsia. The MoBa collection is playing a vital role in this collaborative venture, which has the potential to provide new insights into the causes of pre-eclampsia, and provide a rational basis for novel approaches to prevention and treatment.

New psychiatry residents must rapidly acquire new clinical skills and learn to work effectively with new colleagues. In medical and surgical specialties, high-fidelity simulation with structured debriefing is widely used, but so far this has not been applied to psychiatry. We have developed a one-day simulation-based training course for emergency psychiatry which incorporates clinical and team-working skills training. Five scenarios covering key psychiatric emergencies are delivered in a purpose-built simulation facility. Patients are played by an actor or a high-fidelity manikin. Each scenario is followed by a 45-minute group debrief. Evaluation of a pilot group found that the course was well received and improved participants' workplace confidence. We are now planning to expand the course, provide it to all new residents and conduct further evaluation.

Objectives: To examine cytomegalovirus (CMV) seroprevalence and associated risk factors for CMV seropositivity in pregnant Norwegian women., Design: Cross-sectional study., Setting: The Norwegian Mother and Child Cohort Study (MoBa) in addition to two random samples of pregnant women from Sør-Trøndelag County in Norway., Participants: Study group 1 were 1000 pregnant women, randomly selected among 46 127 pregnancies in the MoBa (1999-2006) at 17/18 week of gestation. Non-ethnic Norwegian women were excluded. Study groups 2 (n=1013 from 1995) and 3 (n=979 from 2009) were pregnant women at 12 weeks of gestation from Sør-Trøndelag County., Outcome Measures: CMV seropositivity in blood samples from pregnant Norwegian women., Results: CMV-IgG antibodies were detected in 59.9% and CMV-IgM antibodies in 1.3% of pregnant Norwegian women in study group 1. Women from North Norway demonstrated a higher CMV-IgG seroprevalence (72.1%) than women from South Norway (58.5%) (OR 1.83, 95% CI 1.17 to 2.88). The CMV-IgG seroprevalence was higher among women with low education (70.5%) compared to women with higher education (OR 2.20, 95% CI 1.24 to 3.90). Between 1995 and 2009 the CMV-IgG seroprevalence increased from 63.1% to 71.4% in pregnant women from Sør-Trøndelag County (study groups 2 and 3; p<0.001). The highest CMV-IgG seroprevalence (79.0%) was observed among the youngest pregnant women (<25 years) from Sør-Trøndelag County in 2009 (study group 3)., Conclusions: The CMV-IgG seroprevalence of pregnant Norwegian women varies with geographic location and educational level. Additionally, the CMV-IgG seroprevalence appears to have increased over the last years, particularly among young pregnant women.

Objectives: To compare attitudes to mental illness in the U.K. military and in the general population in England., Methods: Using data from a cross-sectional survey of 821 U.K. military personnel and a separate cross-sectional survey of 1,729 members of the general population in England, levels of agreement with five statements about mental illness were compared in the military and the general population., Results: The majority of respondents from both populations showed positive attitudes toward mental illness. The general population showed slightly more positive attitudes toward integrating people with mental illness into the community (68.0% [65.7%-70.1%] agreed that "People with mental illness have the same rights to a job as everyone else," vs. 56.7% [51.5%-61.7%] of the military). However, the general population showed more negative attitudes about the causes of mental illness (62.4% [60.1%-64.6%] disagreed that "One of the main causes of mental illness is a lack of self-discipline and willpower," vs. 81.3% [77.0%-84.9%] of the military)., Conclusions: Overall, attitudes toward mental illness are comparable in the general population in England and the U.K. military. Differences included the military holding more positive attitudes about the causes of mental illness, but more negatives attitudes about job rights of those with mental illness. Strategies aiming to improve attitudes toward mental illness could focus particularly on personnel's concerns around mental illness impacting on their career., (Reprint & Copyright © 2013 Association of Military Surgeons of the U.S.)

Objective: To test the hypothesis that pre-eclampsia is a risk factor for cerebral palsy mediated through preterm birth and being born small for gestational age., Design: Population based cohort study., Setting: Clinical data from the Norwegian Cerebral Palsy Registry were linked with perinatal data prospectively recorded by the Medical Birth Registry of Norway., Participants: All singleton babies who survived the neonatal period during 1996-2006 (849 children with cerebral palsy and 616,658 control children)., Main Outcome Measures: Cerebral palsy and cerebral palsy subtypes., Results: Children exposed to pre-eclampsia had an excess risk of cerebral palsy (unadjusted odds ratio 2.5, 95% confidence interval 2.0 to 3.2) compared with unexposed children. Among children born at term (≥ 37 weeks), exposure to pre-eclampsia was not associated with an excess risk of cerebral palsy in babies not born small for gestational age (1.2, 0.7 to 2.0), whereas children exposed to pre-eclampsia and born small for gestational age had a significantly increased risk of cerebral palsy (3.2, 1.5 to 6.7). Non-small for gestational age babies born very preterm (<32 weeks) and exposed to pre-eclampsia had a reduced risk of cerebral palsy compared with unexposed children born at the same gestational age (0.5, 0.3 to 0.8), although the risk was not statistically significantly reduced among children exposed to pre-eclampsia and born small for gestational age (0.7, 0.4 to 1.3). Exposure to pre-eclampsia was not associated with a specific cerebral palsy subtype., Conclusions: Exposure to pre-eclampsia was associated with an increased risk of cerebral palsy, and this association was mediated through the children being born preterm or small for gestational age, or both. Among children born at term, pre-eclampsia was a risk factor for cerebral palsy only when the children were small for gestational age.

Introduction: The first trimester of pregnancy is characterised by a mild pro-inflammatory environment, however excessive inflammation threatens placental development and function. Toll-like receptors (TLRs) are crucial in initiating inflammation. TLR1, TLR2, TLR4, TLR5, TLR6 and TLR10 are expressed on the cell surface, and respond to microbial infection and cell damage and stress signals. Recent findings of TLRs in trophoblasts indicate a role in inflammation during pregnancy, but further studies are warranted., Objectives: To investigate gene expression and function of cell surface TLRs in first trimester trophoblasts, to extend knowledge on the role of trophoblast TLRs during placental development., Methods: Primary trophoblasts were isolated from first trimester placentas (n=6) by enzyme degradation and density gradient centrifugation. Gene expression of TLR1, TLR2, TLR4, TLR5, TLR6 and TLR10 was quantified by RT-qPCR in primary first trimester trophoblasts and the trophoblast cell line BeWo. Trophoblasts were stimulated with cell surface TLR ligands and pro-inflammatory cytokine release was analysed by multiplex immunoassay., Results: Primary first trimester trophoblasts expressed all cell surface TLR mRNAs, and activation of TLR2/1, TLR4 and TLR5 induced IL-6 and/or IL-8., Conclusion: The broad expression of functional cell surface TLRs in primary first trimester trophoblasts suggests a central role for trophoblasts in placental inflammation and immune activation., (Copyright © 2013. Published by Elsevier B.V.)

Introduction: It is well established that preeclampsia (PE) increases later life cardiovascular disease (CVD) risk. Consequently, PE has started to gain a role as an early screening criterion for CVD. PE and CVD share several risk factors, pathological features and metabolic abnormalities. These common antecedents have drawn attention to the likelihood of shared genetic susceptibility., Objectives: Results from our previous PE GWAS identified a significant association with the rs7579169 SNP and maternal PE susceptibility (odds ratio 1.57). This SNP resides near the Inhibin, beta B (INHBB) gene on chromosome 2q14. Therefore, this study sought to interrogate this PE susceptibility SNP against several CVD risk traits in an effort to highlight additional empirical evidence of likely shared PE/CVD genetic mechanisms., Methods: The rs7579169 SNP was genotyped in a large independent Australian cohort rich in quantitative CVD risk traits; The Western Australian Pregnancy Cohort (Raine) Study. This cohort comprises of fasting blood samples from 1246 mothers and 1461 adolescents (14- and 17-year-old) and clinical parameters pertaining, but not limited, to anthropometric measures of adiposity and lipid-related measures. Genetic association analyses of rs7579169 against the Raine CVD-related risk traits were performed using the software package R. All statistical analyses assumed an additive model of gene action., Results: Significant associations (p<0.05) for rs7579169 with CVD-related risk traits were detected, both for the mothers and the adolescents. Specifically, the minor rs7579169-T allele (MAF 0.400) was found to be significantly associated with elevated levels of triglycerides, total and LDL cholesterol, a greater average waist:hip circumference ratio and a greater average hip circumference., Conclusion: We have previously identified rs7579169 located near the INHBB gene on chromosome 2q14 to significantly associate with maternal PE susceptibility. We have now demonstrated that this SNP is also significantly associated with several CVD-related risk traits in an independent Caucasian population. We hereby present additional empirical evidence of possible shared genetic risk factors underlying both PE and CVD related traits., (Copyright © 2013. Published by Elsevier B.V.)