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Except for pedophilia, little is known about public attitudes toward paraphilias and psychological conditions that are considered risk factors for sexual offending. In the present study we sought to compare the stigma attached to pedophilia with attitudes toward sexual sadism and antisocial tendencies (Study 1, N = 720) and with attitudes toward necrophilia and zoophilia (Study 2, N = 210) in convenience samples of community individuals. When investigating social distance intentions both studies explicitly referred to people with paraphilic sexual interests or antisocial tendencies who had not committed any crimes. In both studies, people with pedophilia emerged as highly stigmatized even though most participants showed awareness that pedophilic interests cannot be chosen or changed at will. The present studies solidify the evidence that pedophilia occupies a place in the public consciousness as less deserving of acceptance than most other sexual offending risk-relevant conditions, including ones that compare in terms of rarity.

Workplace bullying is a phenomenon that can have serious detrimental effects on health, work-related attitudes, and the behavior of the target. Particularly, workplace bullying exposure has been linked to lower level of general well-being, job satisfaction, vigor, and performance and higher level of burnout, workplace deviance, and turnover intentions. However, the psychological mechanisms behind these relations are still not well-understood. Drawing on psychological contract and self-determination theory (SDT), we hypothesized that perceptions of contract violation and the frustration of basic needs mediate the relationship between workplace bullying exposure and well-being, attitudinal, and behavioral outcomes. Self-reported data were collected among employees with different working backgrounds ( N = 1,257) via Amazon's Mechanical Turk in an online survey. Results showed that feelings of contract violation and frustration of basic needs accounted for unique variation in well-being, work satisfaction, burnout, vigor, and turnover intentions, pointing to individual contributions of both psychological mechanisms. However, when controlled for frustration of basic needs, feelings of psychological contract violation were no longer a mediator between workplace bullying exposure and work performance. Helping employees to deal effectively with workplace bullying exposure might buffer its negative effects and reduce their experienced frustration of basic needs, preserving their well-being, vigor, and work performance and, eventually, prevent burnout. The present study is the first to concurrently elucidate the proposed psychological mechanisms and unique contributions of psychological contract violation and frustration of basic needs in the context of workplace bullying., 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 Sischka, Melzer, Schmidt and Steffgen.)

This chapter on therapeutic drift with antenatal steroids will make the case that this pilar of treatment to improve the outcomes of preterm infants, despite multiple Randomized Control Trials (RCTs) and meta-analysis, has multiple gaps in solid clinical data to support any expanded use of Antenatal Corticosteroids (ACS). A basic problem is that agents used for ACS have never been evaluated to minimize fetal exposures. Based on the premise that all drug exposure to the fetus should be minimized and only used when necessary, ACS is a potent developmental modulator that has never been evaluated to minimize the dose and duration of fetal exposure. The use of ACS is expanding to late preterm infants where the benefit is modest, to elective C-sections, and periviable fetuses, with minimal RCT data of long-term benefit. Relevant animal experiments demonstrate that much lower doses will induce lung maturation in sheep and primates. Another area of drift in the use of ACS is based on the assumption that the old RCT data accurately predict the magnitude of benefit when ACS is used today with entirely different OB and neonatal care strategies to improve outcomes. We do not have data that demonstrate the effectiveness of ACS in very low resource environments, where most of the preterm mortality occurs. The final concern is the risk of ACS to the infant and child. Short-term risks are minimal but dysmaturation effects of ACS on multiple organ systems (lung, heart, brain, and kidney) may result in disease presentation in later life., (Copyright © 2021. Published by Elsevier Ltd.)

The Explicit and Implicit Sexual Interest Profile (EISIP) is a multimethod measure of sexual interest in children and adults. It combines indirect latency-based measures such as the Implicit Association Test (IAT), Viewing Time (VT), and explicit self-report measures. This study examined test-retest reliability and absolute temporal agreement of the EISIP over a 2-week interval in persons who were convicted of sexual offenses against children ( n = 33) and nonoffending controls ( n = 48). Test-retest reliability of the aggregated EISIP measures was high across the whole sample ( r tt = .90, intraclass correlation coefficient [ICC] = .90) with the IAT yielding the lowest retest correlations ( r tt = .66, ICC = .66). However, these indicators of relative reliability only quantify the temporal stability of individual differences within the group, not the detectability of individual change. Absolute temporal agreement as assessed via Bland-Altman plots ranged from one fourth to three thirds of a standardized unit in the sexual preference scores. This implies that individual change has to exceed medium to large standardized effect sizes to be distinguishable from spontaneous temporal variation in the EISIP measures. Overall, scores of combined measures were largely superior to single measures in terms of both absolute and relative reliability.

Background: Reduced heart rate (HR) increase (HRI), recovery (HRR), and higher resting HR are associated with cardiovascular (CV) disease, but causal inferences have not been deduced. We investigated causal effects of HRI, HRR, and resting HR on CV risk, all-cause mortality (ACM), atrial fibrillation (AF), coronary artery disease (CAD), and ischemic stroke (IS) using Mendelian Randomization., Methods: 11 variants for HRI, 11 for HRR, and two sets of 46 and 414 variants for resting HR were obtained from four genome-wide association studies (GWASs) on UK Biobank. We performed a lookup on GWASs for CV risk and ACM in UK Biobank ( N = 375,367, 5.4% cases and N = 393,165, 4.4% cases, respectively). For CAD, AF, and IS, we used publicly available summary statistics. We used a random-effects inverse-variance weighted (IVW) method and sensitivity analyses to estimate causality., Results: IVW showed a nominally significant effect of HRI on CV events (odds ratio [OR] = 1.0012, P = 4.11 × 10 -2 ) and on CAD and AF. Regarding HRR, IVW was not significant for any outcome. The IVW method indicated statistically significant associations of resting HR with AF (OR = 0.9825, P = 9.8 × 10 -6 ), supported by all sensitivity analyses, and a nominally significant association with IS (OR = 0.9926, P = 9.82 × 10 -3 )., Conclusion: Our findings suggest no strong evidence of an association between HRI and HRR and any outcome and confirm prior work reporting a highly significant effect of resting HR on AF. Future research is required to explore HRI and HRR associations further using more powerful predictors, when available., Competing Interests: AS has received unrestricted funding from Servier. 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 © 2021 Mensah-Kane, Schmidt, Hingorani, Finan, Chen, van Duijvenboden, Orini, Lambiase, Tinker, Marouli, Munroe and Ramírez.)

Drugs whose targets have genetic evidence to support efficacy and safety are more likely to be approved after clinical development. In this paper, we provide an overview of how natural sequence variation in the genes that encode drug targets can be used in Mendelian randomization analyses to offer insight into mechanism-based efficacy and adverse effects. Large databases of summary level genetic association data are increasingly available and can be leveraged to identify and validate variants that serve as proxies for drug target perturbation. As with all empirical research, Mendelian randomization has limitations including genetic confounding, its consideration of lifelong effects, and issues related to heterogeneity across different tissues and populations. When appropriately applied, Mendelian randomization provides a useful empirical framework for using population level data to improve the success rates of the drug development pipeline., Competing Interests: Competing interests: DG is employed part-time by Novo Nordisk. DFF is an employee of Bayer AG, Germany. JMMH is an employee of Novo Nordisk. DIS is an employee of Silence Therapeutics plc. MVH has collaborated with Boehringer Ingelheim in research, and in accordance with the policy of the Clinical Trial Service Unit and Epidemiological Studies Unit (University of Oxford), did not accept any personal payment. RAS is an employee and shareholder in GlaxoSmithKline. BMP serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. NMD reports funding from the Global Research Awards into Nicotine Dependence (GRAND) which is an independent grant awarding body funded by Pfizer. All other authors declare no conflicts of interest., (Copyright: © 2021 Gill D et al.)

Background: Cardiomyopathies, defined as diseases involving mainly the heart muscles, are linked to an estimated 5.9 of 100,000 deaths globally. In sub-Saharan Africa, cardiomyopathies constitute 21.4% of heart failure cases, with dilated cardiomyopathy (DCM) being the most common form. The etiology of DCM is heterogeneous and is broadly categorized as genetic or nongenetic, as well as a mixed disease in which genetics interact with intrinsic and environmental factors. Factors such as age, gender, family history, and ethnicity are nonmodifiable, whereas modifiable risk factors include poor nutrition, physical inactivity, and excessive alcohol consumption, among others. However, the relative contribution of the different risk factors to the etiology of DCM is not known in sub-Saharan Africa, and the prevalence of DCM among heart failure patients has not been systematically studied in the region., Objective: The aim of this review is to synthesize available literature from sub-Saharan Africa on the prevalence of DCM among patients with heart failure, as well as the literature on factors associated with DCM. This paper outlines the protocol that will be followed to conduct the systematic review., Methods: A limited search of the PubMed database will be performed to identify relevant keywords contained in the title, abstract, and subject descriptors using initial search terms "heart failure," "cardiomyopathy," and "sub-Saharan Africa." These search terms and their synonyms will then be used in an extensive search in PubMed, and will address the first research question on prevalence. To address the second research question on risk factors, the terms "heart failure," "cardiomyopathy," and "cardiovascular risk factors" in "Sub-Saharan Africa" will be used, listing them one by one. Articles published from 2000 and in the English language will be included. Indexed articles in PubMed and Embase will be included, as well as the first 300 articles retrieved from a Google Scholar search. Collected data will be organized in Endnote and then uploaded to the Rayyan web app for systematic reviews. Two reviewers will independently select articles against the inclusion criteria. Discrepancies in reviewer selections will be resolved by an arbitrator. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines for reporting systematic reviews will be applied. A map of sub-Saharan Africa with colors to show disease prevalence in each country will be included. For quantitative data, where possible, odds ratios (for categorical outcome data) or standardized mean differences (for continuous data) and their 95% CIs will be calculated., Results: The primary outcomes will be the prevalence of DCM among patients with heart failure and cardiovascular risk factors associated with DCM in sub-Saharan Africa. The literature search will begin on January 1, 2021, and data analysis is expected to be completed by April 30, 2021., Conclusions: This review will provide information on the current status of the prevalence and associated factors of DCM, and possibly identify gaps, including paucity of data or conflicting results that need to be addressed to improve our understanding of DCM in sub-Saharan Africa., International Registered Report Identifier (irrid): PRR1-10.2196/18229., (©Lulu Said Fundikira, Pilly Chillo, Linda W van Laake, Reuben Kato Mutagaywa, Amand Floriaan Schmidt, Appolinary Kamuhabwa, Gideon Kwesigabo, Folkert W Asselbergs. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 21.01.2021.)

Background: Nuclear magnetic resonance (NMR) spectroscopy allows triglycerides to be subclassified into 14 different classes based on particle size and lipid content. We recently showed that these subfractions have differential associations with cardiovascular disease events. Here we report the distributions and define reference interval ranges for 14 triglyceride-containing lipoprotein subfraction metabolites., Methods: Lipoprotein subfractions using the Nightingale NMR platform were measured in 9073 participants from four cohort studies contributing to the UCL-Edinburgh-Bristol consortium. The distribution of each metabolite was assessed, and reference interval ranges were calculated for a disease-free population, by sex and age group (<55, 55-65, >65 years), and in a subgroup population of participants with cardiovascular disease or type 2 diabetes. We also determined the distribution across body mass index and smoking status., Results: The largest reference interval range was observed in the medium very-low density lipoprotein subclass (2.5th 97.5th percentile; 0.08 to 0.68 mmol/L). The reference intervals were comparable among male and female participants, with the exception of triglyceride in high-density lipoprotein. Triglyceride subfraction concentrations in very-low density lipoprotein, intermediate-density lipoprotein, low-density lipoprotein and high-density lipoprotein subclasses increased with increasing age and increasing body mass index. Triglyceride subfraction concentrations were significantly higher in ever smokers compared to never smokers, among those with clinical chemistry measured total triglyceride greater than 1.7 mmol/L, and in those with cardiovascular disease, and type 2 diabetes as compared to disease-free subjects., Conclusion: This is the first study to establish reference interval ranges for 14 triglyceride-containing lipoprotein subfractions in samples from the general population measured using the nuclear magnetic resonance platform. The utility of nuclear magnetic resonance lipid measures may lead to greater insights for the role of triglyceride in cardiovascular disease, emphasizing the importance of appropriate reference interval ranges for future clinical decision making.

Respiratory complicˆations are the major cause of morbidity and mortality among preterm infants, which is partially prevented by the administration of antenatal corticosteroids (ACS). Most very preterm infants are exposed to chorioamnionitis, but short- and long-term effects of ACS treatment in this setting are not well defined. In low-resource settings, ACS increased neonatal mortality by perhaps increasing infection. We report that treatment with low-dose ACS in the setting of inflammation induced by intraamniotic lipopolysaccharide (LPS) in rhesus macaques improves lung compliance and increases surfactant production relative to either exposure alone. RNA sequencing shows that these changes are mediated by suppression of proliferation and induction of mesenchymal cellular death via TP53. The combined exposure results in a mature-like transcriptomic profile with inhibition of extracellular matrix development by suppression of collagen genes COL1A1, COL1A2, and COL3A1 and regulators of lung development FGF9 and FGF10. ACS and inflammation also suppressed signature genes associated with proliferative mesenchymal progenitors similar to the term gestation lung. Treatment with ACS in the setting of inflammation may result in early respiratory advantage to preterm infants, but this advantage may come at a risk of abnormal extracellular matrix development, which may be associated with increased risk of chronic lung disease.

Background: Administration of antenatal steroids is standard of care for women assessed to be at imminent risk of preterm delivery. There is a marked variation in antenatal steroid dosing strategy, selection for treatment criteria, and agent choice worldwide. This, combined with very limited optimization of antenatal steroid use per se, means that treatment efficacy is highly variable, and the rate of respiratory distress syndrome is decreased to perhaps as low as 40%. In some cases, antenatal steroid use is associated with limited benefit and potential harm., Objective: We hypothesized that individual differences in maternofetal steroid exposure would contribute to observed variability in antenatal steroid treatment efficacy. Using a chronically catheterized sheep model of pregnancy, we aimed to explore the relationship between maternofetal steroid exposure and antenatal steroid treatment efficacy as determined by functional lung maturation in preterm lambs undergoing ventilation., Study Design: Ewes carrying a single fetus underwent surgery to catheterize a fetal and maternal jugular vein at 119 days' gestation. Animals recovered for 24 hours before being randomized to either (1) a single maternal intramuscular injection of 2 mL saline (negative control group, n=10) or (2) a single maternal intramuscular injection of 0.25 mg/kg betamethasone phosphate plus acetate (antenatal steroid group, n=20). Serial maternal and fetal plasma samples were collected from each animal after 48 hours before fetuses were delivered and ventilated for 30 minutes. Total and free plasma betamethasone concentration was measured by mass spectrometry. Fetal lung tissue was collected for analysis using quantitative polymerase chain reaction., Results: One animal from the control group and one animal from the antenatal steroid group did not complete their treatment protocol and were removed from analyses. Animals in the antenatal steroid group were divided into a responder subgroup (n=12/19) and a nonresponder subgroup (n=7/19) using a cutoff of partial pressure of arterial CO 2 at 30-minute ventilation within 2 standard deviations of the mean value from saline-treated negative control group animals. Although antenatal steroid improved fetal lung maturation in the undivided antenatal steroid group and in the responder subgroup both physiologically (blood gas- and ventilation-related data) and biochemically (messenger ribonucleic acid expression related to fetal lung maturation), these values did not improve relative to saline-treated control group animals in the antenatal steroid nonresponder subgroup. No differences in betamethasone distribution, clearance, or protein binding were identified between the antenatal steroid responder and nonresponder subgroups., Conclusion: This study correlated individual maternofetal steroid exposures with preterm lung maturation as determined by pulmonary ventilation. Herein, approximately 40% of preterm lambs exposed to antenatal steroids had lung maturation that was not significantly different to saline-treated control group animals. These nonresponsive animals received maternal and fetal betamethasone exposures identical to animals that had a significant improvement in functional lung maturation. These data suggest that the efficacy of antenatal steroid therapy is not solely determined by maternofetal drug levels and that individual fetal or maternal factors may play a role in determining treatment outcomes in response to glucocorticoid signaling., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The addition of budesonide (Bud) 0.25 mg/kg to surfactant decreased the lung and systemic responses to mechanical ventilation in preterm sheep and the rates and severity of bronchopulmonary dysplasia (BPD) in preterm infants. We hypothesized that lower budesonide concentrations in surfactant will decrease injury while decreasing systemic corticosteroid exposure., Methods: Preterm lambs received either (1) protective tidal volume (V T ) ventilation with surfactant from birth or (2) injurious V T ventilation for 15 min and then surfactant treatment. Lambs were further assigned to surfactant mixed with (i) Saline, (ii) Bud 0.25 mg/kg, (iii) Bud 0.1 mg/kg, or (iv) Bud 0.04 mg/kg. All lambs were then ventilated with protective V T for 6 h., Results: Plasma Bud levels were proportional to the dose received and decreased throughout ventilation. In both protective and injurious V T ventilation, <4% of Bud remained in the lung at 6 h. Some of the improvements in physiology and markers of injury with Bud 0.25 mg/kg were also found with 0.1 mg/kg, whereas 0.04 mg/kg had only minimal effects., Conclusions: Lower doses of Bud were less effective at decreasing lung and systemic inflammation from mechanical ventilation. The plasma Bud levels were proportional to dose given and the majority left the lung.

Background: Despite the availability of effective drug therapies that reduce low-density lipoprotein (LDL)-cholesterol (LDL-C), cardiovascular disease (CVD) remains an important cause of mortality and morbidity. Therefore, additional LDL-C reduction may be warranted, especially for people who are unresponsive to, or unable to take, existing LDL-C-reducing therapies. By inhibiting the proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme, monoclonal antibodies (PCSK9 inhibitors) reduce LDL-C and CVD risk., Objectives: Primary To quantify the effects of PCSK9 inhibitors on CVD, all-cause mortality, myocardial infarction, and stroke, compared to placebo or active treatment(s) for primary and secondary prevention. Secondary To quantify the safety of PCSK9 inhibitors, with specific focus on the incidence of influenza, hypertension, type 2 diabetes, and cancer, compared to placebo or active treatment(s) for primary and secondary prevention., Search Methods: We identified studies by systematically searching CENTRAL, MEDLINE, Embase, and Web of Science in December 2019. We also searched ClinicalTrials.gov and the International Clinical Trials Registry Platform in August 2020 and screened the reference lists of included studies. This is an update of the review first published in 2017., Selection Criteria: All parallel-group and factorial randomised controlled trials (RCTs) with a follow-up of at least 24 weeks were eligible., Data Collection and Analysis: Two review authors independently reviewed and extracted data. Where data were available, we calculated pooled effect estimates. We used GRADE to assess certainty of evidence and in 'Summary of findings' tables., Main Results: We included 24 studies with data on 60,997 participants. Eighteen trials randomised participants to alirocumab and six to evolocumab. All participants received background lipid-lowering treatment or lifestyle counselling. Six alirocumab studies used  an active treatment comparison group (the remaining used placebo), compared to three evolocumab active comparison trials. Alirocumab compared with placebo decreased the risk of CVD events, with an absolute risk difference (RD) of -2% (odds ratio (OR) 0.87, 95% confidence interval (CI) 0.80 to 0.94; 10 studies, 23,868 participants; high-certainty evidence), decreased the risk of mortality (RD -1%; OR 0.83, 95% CI 0.72 to 0.96; 12 studies, 24,797 participants; high-certainty evidence), and MI (RD -2%; OR 0.86, 95% CI 0.79 to 0.94; 9 studies, 23,352 participants; high-certainty evidence) and for any stroke (RD 0%; OR 0.73, 95% CI 0.58 to 0.91; 8 studies, 22,835 participants; high-certainty evidence). Compared to active treatment the alirocumab effects, for CVD, the RD was 1% (OR 1.37, 95% CI 0.65 to 2.87; 3 studies, 1379 participants; low-certainty evidence); for mortality, RD was -1% (OR 0.51, 95% CI 0.18 to 1.40; 5 studies, 1333 participants; low-certainty evidence); for MI, RD was 1% (OR 1.45, 95% CI 0.64 to 3.28, 5 studies, 1734 participants; low-certainty evidence); and for any stroke, RD was less than 1% (OR 0.85, 95% CI 0.13 to 5.61; 5 studies, 1734 participants; low-certainty evidence). Compared to placebo the evolocumab, for CVD, the RD was -2% (OR 0.84, 95% CI 0.78 to 0.91; 3 studies, 29,432 participants; high-certainty evidence); for mortality, RD was less than 1% (OR 1.04, 95% CI 0.91 to 1.19; 3 studies, 29,432 participants; high-certainty evidence); for MI, RD was -1% (OR 0.72, 95% CI 0.64 to 0.82; 3 studies, 29,432 participants; high-certainty evidence); and for any stroke RD was less than -1% (OR 0.79, 95% CI 0.65 to 0.94; 2 studies, 28,531 participants; high-certainty evidence).  Compared to active treatment, the evolocumab effects, for any CVD event RD was less than -1% (OR 0.66, 95% CI 0.14 to 3.04; 1 study, 218 participants; very low-certainty evidence); for all-cause mortality, the RD was less than 1% (OR 0.43, 95% CI 0.14 to 1.30; 3 studies, 5223 participants; very low-certainty evidence); and for MI, RD was less than 1% (OR 0.66, 95% CI 0.23 to 1.85; 3 studies, 5003 participants; very low-certainty evidence). There were insufficient data on any stroke.  AUTHORS' CONCLUSIONS: The evidence for the clinical endpoint effects of  evolocumab and alirocumab were graded as high. There is a strong evidence base to prescribe PCSK9 monoclonal antibodies to people who might not be eligible for other lipid-lowering drugs, or to people who cannot meet their lipid goals on more traditional therapies, which was the main patient population of the available trials.  The evidence base of PCSK9 inhibitors compared with active treatment is much weaker (low very- to low-certainty evidence) and it is unclear whether evolocumab or alirocumab might be effectively used as replacement therapies. Related, most of the available studies preferentially enrolled people with either established CVD or at a high risk already, and evidence in low- to medium-risk settings is minimal. Finally, there is very limited evidence on any potential safety issues of both evolocumab and alirocumab. While the current evidence synthesis does not reveal any adverse signals, neither does it provide evidence against such signals. This suggests careful consideration of alternative lipid lowering treatments before prescribing PCSK9 inhibitors., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Aims: Elevated low-density lipoprotein cholesterol (LDL-C) is a risk factor for cardiovascular disease; however, there is uncertainty about the role of total triglycerides and the individual triglyceride-containing lipoprotein sub-fractions. We measured 14 triglyceride-containing lipoprotein sub-fractions using nuclear magnetic resonance and examined associations with coronary heart disease and stroke., Methods: Triglyceride-containing sub-fraction measures were available in 11,560 participants from the three UK cohorts free of coronary heart disease and stroke at baseline. Multivariable logistic regression was used to estimate the association of each sub-fraction with coronary heart disease and stroke expressed as the odds ratio per standard deviation increment in the corresponding measure., Results: The 14 triglyceride-containing sub-fractions were positively correlated with one another and with total triglycerides, and inversely correlated with high-density lipoprotein cholesterol (HDL-C). Thirteen sub-fractions were positively associated with coronary heart disease (odds ratio in the range 1.12 to 1.22), with the effect estimates for coronary heart disease being comparable in subgroup analysis of participants with and without type 2 diabetes, and were attenuated after adjustment for HDL-C and LDL-C. There was no evidence for a clear association of any triglyceride lipoprotein sub-fraction with stroke., Conclusions: Triglyceride sub-fractions are associated with increased risk of coronary heart disease but not stroke, with attenuation of effects on adjustment for HDL-C and LDL-C.

Introduction: Hyperprolactinaemia, a common adverse effect of antipsychotic drugs, is primarily linked to blockade of dopamine D2 receptors in the pituitary gland. Certain antipsychotic drugs, such as, for example risperidone and paliperidone, are more likely to induce hyperprolactinaemia compared to others. This effect is probably caused by a relatively high blood/brain concentration ratio, a consequence of being a substrate of P-glycoprotein. Genetic variants of P-glycoprotein with changed functional activity might influence the potential of risperidone and paliperidone to cause hyperprolactinaemia as the altered blood/brain concentration ratio would lead to a reduced therapeutic drug level within essential brain areas making dose adaptations necessary. This increases exposure of dopamine D2 receptors within the pituitary gland., Aims: To investigate possible associations between MDR1/ABCB1 gene polymorphisms and antipsychotic drug-induced hyperprolactinaemia in Russian patients with schizophrenia and to determine possible differences between risperidone/paliperidone and other antipsychotics., Methods: In total, 446 patients with schizophrenia were included from 3 psychiatric hospitals in Siberia. Blood samples were obtained in a cross-sectional study design for DNA extraction and prolactin measurement. Associations between hyperprolactinaemia and 8 MDR1/ABCB1 gene-polymorphisms were assessed using logistic regression analysis accounting for covariates. The analysis was repeated in a patient subgroup using risperidone or paliperidone., Results: We did not observe an association between any of the 8 single nucleotide polymorphisms and the prevalence of antipsychotic-induced hyperprolactinaemia in the total patient population. However, in the risperidone/paliperidone subgroup, the single nucleotide polymorphism rs2032582 (G2677T) was found to be negatively associated with risperidone/paliperidone-induced hyperprolactinaemia., Conclusion: This study revealed a significant association between the ABCB1 gene polymorphism rs2032582 (G2677T) and risperidone/paliperidone-induced hyperprolactinaemia., (© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD., Methods: We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality., Results: The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92-1.16]; I 2 =28%; P -heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity., Conclusions: Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population.

Mendelian randomisation (MR) analysis is an important tool to elucidate the causal relevance of environmental and biological risk factors for disease. However, causal inference is undermined if genetic variants used to instrument a risk factor also influence alternative disease-pathways (horizontal pleiotropy). Here we report how the 'no horizontal pleiotropy assumption' is strengthened when proteins are the risk factors of interest. Proteins are typically the proximal effectors of biological processes encoded in the genome. Moreover, proteins are the targets of most medicines, so MR studies of drug targets are becoming a fundamental tool in drug development. To enable such studies, we introduce a mathematical framework that contrasts MR analysis of proteins with that of risk factors located more distally in the causal chain from gene to disease. We illustrate key model decisions and introduce an analytical framework for maximising power and evaluating the robustness of analyses.

Background: There is growing evidence that polygenic risk scores (PRSs) can identify individuals with elevated lifetime risk of coronary artery disease (CAD). Whether they can also be used to stratify the risk of subsequent events among those surviving a first CAD event remain uncertain, with possible biological differences between CAD onset and progression, and the potential for index event bias., Methods: Using two baseline subsamples of UK Biobank: prevalent CAD cases (N = 10 287) and individuals without CAD (N = 393 108), we evaluated associations between a CAD PRS and incident cardiovascular and fatal outcomes., Results: A 1 SD higher PRS was associated with an increased risk of incident myocardial infarction (MI) in participants without CAD (OR 1.33; 95% CI 1.29, 1.38), but the effect estimate was markedly attenuated in those with prevalent CAD (OR 1.15; 95% CI 1.06, 1.25) and heterogeneity P = 0.0012. Additionally, among prevalent CAD cases, we found an evidence of an inverse association between the CAD PRS and risk of all-cause death (OR 0.91; 95% CI 0.85, 0.98) compared with those without CAD (OR 1.01; 95% CI 0.99, 1.03) and heterogeneity P = 0.0041. A similar inverse association was found for ischaemic stroke [prevalent CAD (OR 0.78; 95% CI 0.67, 0.90); without CAD (OR 1.09; 95% CI 1.04, 1.15), heterogeneity P < 0.001]., Conclusions: Bias induced by case stratification and survival into UK Biobank may distort the associations of PRS derived from case-control studies or populations initially free of disease. Differentiating between effects of possible biases and genuine biological heterogeneity is a major challenge in disease progression research., (© The Author(s) 2020. Published by Oxford University Press.)

Meta-analyses based on systematic literature reviews are commonly used to obtain a quantitative summary of the available evidence on a given topic. However, the reliability of any meta-analysis is constrained by that of its constituent studies. One major limitation is the possibility of small-study effects, when estimates from smaller and larger studies differ systematically. Small-study effects may result from reporting biases (ie, publication bias), from inadequacies of the included studies that are related to study size, or from reasons unrelated to bias. We propose two estimators based on the median and mode to increase the reliability of findings in a meta-analysis by mitigating the influence of small-study effects. By re-examining data from published meta-analyses and by conducting a simulation study, we show that these estimators offer robustness to a range of plausible bias mechanisms, without making explicit modelling assumptions. They are also robust to outlying studies without explicitly removing such studies from the analysis. When meta-analyses are suspected to be at risk of bias because of small-study effects, we recommend reporting the mean, median and modal pooled estimates., (© 2020 The Authors. Research Synthesis Methods published by John Wiley & Sons Ltd.)

Background We aimed at investigating the association of circulating fatty acids with coronary heart disease (CHD) and stroke risk. Methods and Results We conducted an individual-participant data meta-analysis of 5 UK-based cohorts and 1 matched case-control study. Fatty acids (ie, omega-3 docosahexaenoic acid, omega-6 linoleic acid, monounsaturated and saturated fatty acids) were measured at baseline using an automated high-throughput serum nuclear magnetic resonance metabolomics platform. Data from 3022 incident CHD cases (13 104 controls) and 1606 incident stroke cases (13 369 controls) were included. Logistic regression was used to model the relation between fatty acids and odds of CHD and stroke, adjusting for demographic and lifestyle variables only (ie, minimally adjusted model) or with further adjustment for other fatty acids (ie, fully adjusted model). Although circulating docosahexaenoic acid, but not linoleic acid, was related to lower CHD risk in the fully adjusted model (odds ratio, 0.85; 95% CI, 0.76-0.95 per standard unit of docosahexaenoic acid), there was evidence of high between-study heterogeneity and effect modification by study design. Stroke risk was consistently lower with increasing circulating linoleic acid (odds ratio for fully adjusted model, 0.82; 95% CI, 0.75-0.90). Circulating monounsaturated fatty acids were associated with higher CHD risk across all models and with stroke risk in the fully adjusted model (odds ratio, 1.22; 95% CI, 1.03-1.44). Saturated fatty acids were not related to increased CHD risk in the fully adjusted model (odds ratio, 0.94; 95% CI, 0.82-1.09), or stroke risk. Conclusions We found consistent evidence that linoleic acid was associated with decreased risk of stroke and that monounsaturated fatty acids were associated with increased risk of CHD. The different pattern between CHD and stroke in terms of fatty acids risk profile suggests future studies should be cautious about using composite events. Different study designs are needed to assess which, if any, of the associations observed is causal.

Background: Aggressiveness resulting from inappropriately intense anger plays a major role in borderline personality disorder (BPD) and research using self-report measures has consistently found elevated levels of aggression in this condition. However, while self-report assesses explicit dimensions of the self-concept, it cannot elucidate implicit processes that are at least equally important as they guide the perceptions of the self and influence behavioral responses. The present study aimed to extend the research on aggressiveness self-concepts in BPD utilizing an indirect latency-based measure., Methods: Twenty-nine female inpatients with BPD and 21 healthy women were assessed with an aggressiveness self-concept Implicit Association Test (Agg-IAT) using reaction time measurements to determine the relative strengths of associations between the self vs. others and aggression vs. peacefulness. Additionally, participants completed self-report questionnaires capturing aggressiveness and BPD symptoms., Results: Women with BPD had a significantly more aggressive self-concept as indicated by the Agg-IAT than the control group. Moreover, they rated themselves significantly more aggressive on all dimensions than the controls. As expected, correlations between the Agg-IAT and the self-reported aggressiveness dimensions were low (mean r = -.31)., Limitations: The modest sample size and the disregard of a clinical control group limit the generalizability and specificity of our findings., Conclusions: This study extends prior findings on aggression in BPD in that women with BPD do not only explicitly conceive themselves as more aggressive, but also exhibit implicitly more aggressive self-concepts than healthy controls. Because implicit and explicit self-related operations are related, but distinct processes, our results may hold clinical and therapeutic implications., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity, and its dysregulation has been associated with the pathogenesis of mood and anxiety disorders. Prolactin (PRL) is a pituitary hormone which is also produced as a cytokine by immune cells and could be a neurotrophic factor regulating the functional activity of stress-related mechanisms., Aim: To investigate the possible relationship between depressive state and BDNF and PRL genotypes or levels with special reference to severity of depression., Methods: Participants of 18-70 years with a clinical diagnosis of depressive disorder of at least moderate severity were included. These patients had not been treated with antidepressant drugs before admission to hospital during the preceding period of the last 6 months, and 54.5% had never been treated with antidepressant drugs during their entire life. The DNA was genotyped for rs1341239 within the prolactin and for rs6265, rs7124442, and rs11030104 within the BDNF gene. Rs11030104 violated the Hardy-Weinberg equilibrium distribution and was excluded from further analyses. BDNF and prolactin concentration was measured in serum by MAGPIX multiplex analyzer (Luminex, USA) using MILLIPLEX ® MAP kit (Merck, Germany). Genetic associations were determined by sequentially regressing prolactin, BDNF, 17-items Hamilton's Depression (HAMD-17) and Clinical Global Impression scale, Severity (CGI-S) ratings, and depression (absent/present) on the available SNPs. Genetic associations were evaluated assuming an additive model., Results: A total of 186 depressed patients (of which 169 were women) and 94 healthy controls (67 women) were genotyped. After excluding subjects without genetic information on all three study SNPs, 217 remained of whom 138 suffered from depression. Within depressed patients we observed an association of rs6265 with HAMD-17: mean difference (MD) 2.33 (95%CI 0.49; 4.16; p = 0.014) and CGI-S: MD 0.38 (95%CI 0.09; 0.66; p = 0.011). No significant association was observed between the prolactin SNP rs1341239 and prolactin levels. Similarly the mean differences of BDNF SNPs did not show an association with BDNF: rs6265 -0.042 ln(pg/ml) (95%CI -0.198; 0.113), and rs7124442 0.006 ln(pg/ml) (95%CI -0.117; 0.130). No other association reached statistical significance., Conclusion: We observed a significant association between BDNF gene variant rs6265 and the severity of depression in newly admitted, antidepressant treatment-free, depressed patients. Actual PRL and BDNF levels were not elevated sufficiently in depressed patients to reach statistical significance and were not associated with the studied genotypes., (Copyright © 2020 Losenkov, Mulder, Levchuk, Vyalova, Loonen, Bosker, Simutkin, Boiko, Bokhan, Wilffert, Hak, Schmidt and Ivanova.)

It is almost a cultural truism that erotic images attract our attention, presumably because paying attention to erotic stimuli provided our ancestors with mating benefits. Attention, however, can be narrowly defined as visuospatial attention (keeping such stimuli in view) or more broadly as cognitive attention (such stimuli taking up one's thoughts). We present four independent studies aiming to test the extent to which erotic images have priority in capturing visuospatial versus cognitive attention. Whereas the former would show in quicker reactions to stimuli presented in locations where erotic images appeared previously, the latter causes delayed responding after erotic images, independent of their location). To this end, we specifically modified spatial cueing tasks to disentangle visuospatial attention capture from general sexual content-induced delay (SCID) effects-a major drawback in the previous literature. Consistently across all studies (total N = 399), we found no evidence in support of visuospatial attention capture but reliably observed an unspecific delay of responding for trials in which erotic images appeared (irrespective of cue location). This SCID is equally large for heterosexual men and women and reliably associated with their self-reported sexual excitability.

Background: Antenatal corticosteroids (ACS) are the standard of care for maturing the fetal lung and improving outcomes for preterm infants. Antenatal corticosteroid dosing remains nonoptimized, and there is little understanding of how different treatment-to-delivery intervals may affect treatment efficacy. The durability of a lung maturational response is important because the majority of women treated with antenatal corticosteroids do not deliver within the widely accepted 1- to 7-day window of treatment efficacy., Objective: We used a sheep model to test the duration of fetal exposures for efficacy at delivery intervals from 1 to 10 days., Materials and Methods: For infusion studies, ewes with single fetuses were randomized to receive an intravenous bolus and maintenance infusion of betamethasone phosphate to target 1-4 ng/mL fetal plasma betamethasone for 36 hours, with delivery at 2, 4 ,or 7 days posttreatment or sterile saline solution as control. Animals receiving the clinical treatment were randomised to receive either a single injection of 0.25 mg/kg with a 1:1 mixture of betamethasone phosphate + betamethasone acetate with delivery at either 1 or 7 days posttreatment, or 2 treatments of 0.25 mg/kg betamethasone phosphate + betamethasone acetate spaced at 24 hours (giving ∼48 hours of fetal steroid exposure) with delivery at 2, 5, 7, or 10 days posttreatment. Negative control animals were treated with saline solution. All lambs were delivered at 121 ± 3 days gestational age and ventilated for 30 minutes to assess lung function., Results: Preterm lambs delivered at 1 or 2 days post-antenatal corticosteroid treatment had significant improvements in lung maturation for both intravenous and single-dose intramuscular treatments. After 2 days, the efficacy of 36-hour betamethasone phosphate infusions was lost. The single dose of 1:1 betamethasone phosphate + betamethasone acetate also was ineffective at 7 days. In contrast, animals treated with 2 doses had significant improvements in lung maturation at 2, 5, and 7 days, with treatment efficacy reduced by 10 days., Conclusion: In preterm lambs, the durability of antenatal corticosteroids treatment depends on the duration of fetal exposure and is independent of the intravenous or intramuscular maternal route of administration. For acute 24- to 48-hour posttreatment deliveries, a 24-hour fetal antenatal corticosteroids exposure was sufficient for lung maturation. A fetal exposure duration of at least 48 hours was necessary to maintain long-term treatment durability. A single-dose ACS treatment should be sufficient for women delivering within <48 hours of antenatal corticosteroids treatment., (Copyright © 2019. Published by Elsevier Inc.)

Objective: To examine whether genetic variation affecting the expression or function of lipid-lowering drug targets is associated with Alzheimer disease (AD) risk, to evaluate the potential impact of long-term exposure to corresponding therapeutics., Methods: We conducted Mendelian randomization analyses using variants in genes that encode the protein targets of several approved lipid-lowering drug classes: HMGCR (encoding the target for statins), PCSK9 (encoding the target for PCSK9 inhibitors, eg, evolocumab and alirocumab), NPC1L1 (encoding the target for ezetimibe), and APOB (encoding the target of mipomersen). Variants were weighted by associations with low-density lipoprotein cholesterol (LDL-C) using data from lipid genetics consortia (n up to 295,826). We meta-analyzed Mendelian randomization estimates for regional variants weighted by LDL-C on AD risk from 2 large samples (total n = 24,718 cases, 56,685 controls)., Results: Models for HMGCR, APOB, and NPC1L1 did not suggest that the use of related lipid-lowering drug classes would affect AD risk. In contrast, genetically instrumented exposure to PCSK9 inhibitors was predicted to increase AD risk in both of the AD samples (combined odds ratio per standard deviation lower LDL-C inducible by the drug target = 1.45, 95% confidence interval = 1.23-1.69). This risk increase was opposite to, although more modest than, the degree of protection from coronary artery disease predicted by these same methods for PCSK9 inhibition., Interpretation: We did not identify genetic support for the repurposing of statins, ezetimibe, or mipomersen for AD prevention. Notwithstanding caveats to this genetic evidence, pharmacovigilance for AD risk among users of PCSK9 inhibitors may be warranted. ANN NEUROL 2020;87:30-39., (© 2019 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

Mechanical ventilation from birth with normal tidal volumes (V T ) causes lung injury and systemic responses in preterm sheep. The addition of budesonide to surfactant therapy decreases these injury markers. Budesonide and surfactant will decrease the injury from injurious V T ventilation in preterm sheep. Lambs at 126 ± 1 day gestational age were ventilated from birth with either: 1) Normal V T [surfactant 200 mg/kg before ventilation, positive end expiratory pressure (PEEP) 5 cmH 2 O, V T 8 mL/kg] or 2) Injury V T (high pressure, 100% oxygen, no PEEP) for 15 min, then further randomized to surfactant + saline or surfactant + 0.25 mg/kg budesonide with Normal V T for 6 h. Lung function and lung, liver, and brain tissues were evaluated for indicators of injury. Injury V T + saline caused significant injury and systemic responses, and Injury V T + budesonide improved lung physiology. Budesonide decreased lung inflammation and decreased pro-inflammatory cytokine mRNA in the lung, liver, and brain to levels similar to Normal V T + saline. Budesonide was present in plasma within 15 min of treatment in both ventilation groups, and less than 5% of the budesonide remained in the lung at 6 h. mRNA sequencing of liver and periventricular white matter demonstrated multiple pathways altered by both Injury V T and budesonide and the combination exposure. In lambs receiving Injury V T , the addition of budesonide to surfactant improved lung physiology and decreased pro-inflammatory cytokine responses in the lung, liver, and brain to levels similar to lambs receiving Normal V T .

Supplemental oxygen (O 2 ) therapy in preterm infants impairs lung development, but the impact of O 2 on long-term systemic vascular structure and function has not been well-explored. The present study tested the hypothesis that neonatal O 2 therapy induces long-term structural and functional alterations in the systemic vasculature, resulting in vascular stiffness observed in children and young adults born preterm. Newborn Sprague-Dawley rats were exposed to normoxia (21% O 2 ) or hyperoxia (85% O 2 ) for 1 and 3 weeks. A subgroup exposed to 3 weeks hyperoxia was recovered in normoxia for an additional 3 weeks. Aortic stiffness was assessed by pulse wave velocity (PWV) using Doppler ultrasound and pressure myography. Aorta remodeling was assessed by collagen deposition and expression. Left ventricular (LV) function was assessed by echocardiography. We found that neonatal hyperoxia exposure increased vascular stiffness at 3 weeks, which persisted after normoxic recovery at 6 weeks of age. These findings were accompanied by increased PWV, aortic remodeling, and altered LV function as evidenced by decreased ejection fraction, cardiac output, and stroke volume. Importantly, these functional changes were associated with increased collagen deposition in the aorta. Together, these findings demonstrate that neonatal hyperoxia induces early and sustained biomechanical alterations in the systemic vasculature and impairs LV function. Early identification of preterm infants who are at risk of developing systemic vascular dysfunction will be crucial in developing targeted prevention strategies that may improve the long-term cardiovascular outcomes in this vulnerable population., (© 2020 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Dendritic cells (DCs) activated via TLR ligation experience metabolic reprogramming, in which the cells are heavily dependent on glucose and glycolysis for the synthesis of molecular building blocks essential for maturation, cytokine production, and the ability to stimulate T cells. Although the TLR-driven metabolic reprogramming events are well documented, fungal-mediated metabolic regulation via C-type lectin receptors such as Dectin-1 and Dectin-2 is not clearly understood. Here, we show that activation of DCs with fungal-associated β-glucan ligands induces acute glycolytic reprogramming that supports the production of IL-1β and its secretion subsequent to NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation. This acute glycolytic induction in response to β-glucan ligands requires spleen tyrosine kinase signaling in a TLR-independent manner, suggesting now that different classes of innate immune receptors functionally induce conserved metabolic responses to support immune cell activation. These studies provide new insight into the complexities of metabolic regulation of DCs immune effector function regarding cellular activation associated with protection against fungal microbes., (©2019 The Authors. Society for Leukocyte Biology Published by Wiley Periodicals, Inc.)

Background: The use of antenatal corticosteroids (ACS) in low-resource environments is sporadic. Further, drug choice, dose, and route of ACS are not optimized. We report the pharmacokinetics and pharmacodynamics of oral dosing of ACS using a preterm sheep model., Methods: We measured pharmacokinetics of oral betamethasone-phosphate (Beta-P) and dexamethasone-phosphate (Dex-P) using catheterized pregnant sheep. We compared fetal lung maturation responses of oral Beta-P and Dex-P to the standard treatment with 2 doses of the i.m. mixture of Beta-P and betamethasone-acetate at 2, 5, and 7 days after initiation of ACS., Results: Oral Dex-P had lower bioavailability than Beta-P, giving a lower maximum maternal and fetal concentration. A single oral dose of 0.33 mg/kg of Beta-P was equivalent to the standard clinical treatment assessed at 2 days; 2 doses of 0.16 mg/kg of oral Beta-P were equivalent to the standard clinical treatment at 7 days as assessed by lung mechanics and gas exchange after preterm delivery and ventilation. In contrast, oral Dex-P was ineffective because of its decreased bioavailability., Conclusion: Using a sheep model, we demonstrate the use of pharmacokinetics to develop oral dosing strategies for ACS. Oral dosing is feasible and may facilitate access to ACS in low-resource environments.

Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9., Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration., Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable., Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.

Antenatal corticosteroids (ACS) are standard of care for women at risk of preterm delivery, although choice of drug, dose or route have not been systematically evaluated. Further, ACS are infrequently used in low resource environments where most of the mortality from prematurity occurs. We report proof of principle experiments to test betamethasone-phosphate (Beta-P) or dexamethasone-phosphate (Dex-P) given orally in comparison to the clinical treatment with the intramuscular combination drug beta-phosphate plus beta-acetate in a Rhesus Macaque model. First, we performed pharmacokinetic studies in non-pregnant monkeys to compare blood levels of the steroids using oral dosing with Beta-P, Dex-P and an effective maternal intramuscular dose of the beta-acetate component of the clinical treatment. We then evaluated maternal and fetal blood steroid levels with limited fetal sampling under ultrasound guidance in pregnant macaques. We found that oral Beta is more slowly cleared from plasma than oral Dex. The blood levels of both drugs were lower in maternal plasma of pregnant than in non-pregnant macaques. Using the pharmacokinetic data, we treated groups of 6-8 pregnant monkeys with oral Beta-P, oral Dex-P, or the maternal intramuscular clinical treatment and saline controls and measured pressure-volume curves to assess corticosteroid effects on lung maturation at 5d. Oral Beta-P improved the pressure-volume curves similarly to the clinical treatment. Oral Dex-P gave more variable and nonsignificant responses. We then compared gene expression in the fetal lung, liver and hippocampus between oral Beta-P and the clinical treatment by RNA-sequencing. The transcriptomes were largely similar with small gene expression differences in the lung and liver, and no differences in the hippocampus between the groups. As proof of principle, ACS therapy can be effective using inexpensive and widely available oral drugs. Clinical dosing strategies must carefully consider the pharmacokinetics of oral Beta-P or Dex-P to minimize fetal exposure while achieving the desired treatment responses., Competing Interests: The authors have declared that no competing interests exist.

Background: Increasingly, genetic analyses are conducted using information from subjects with established disease, who often receive concomitant treatment. We determined when treatment may bias genetic associations with a quantitative trait., Methods: Graph theory and simulated data were used to explore the impact of drug prescriptions on (longitudinal) genetic effect estimates. Analytic derivations of longitudinal genetic effects are presented, accounting for the following scenarios: 1) treatment allocated independently of a genetic variant, 2) treatment that mediates the genetic effect, 3) treatment that modifies the genetic effect. We additionally evaluate treatment modelling strategies on bias, the root mean squared error (RMSE), coverage, and rejection rate., Results: We show that in the absence of treatment by gene effect modification or mediation, genetic effect estimates will be unbiased. In simulated data we found that conditional models accounting for treatment, confounding, and effect modification were generally unbiased with appropriate levels of confidence interval coverage. Ignoring the longitudinal nature of treatment prescription, however (e.g. because of incomplete records in longitudinal data), biased these conditional models to a similar degree (or worse) as simply ignoring treatment., Conclusion: The mere presence of (drug) treatment affecting a GWAS phenotype is insufficient to bias genetic associations with quantitative traits. While treatment may bias associations through effect modification and mediation, this might not occur frequently enough to warrant general concern at the presence of treated subjects in GWAS. Should treatment by gene effect modification or mediation be present however, current GWAS approaches attempting to adjust for treatment insufficiently account for the multivariable and longitudinal nature of treatment trajectories and hence genetic estimates may still be biased., Competing Interests: The authors have declared that no competing interests exist.

Background: The amount of surfactant deposited in the lungs and its overall pulmonary distribution determine the therapeutic outcome of surfactant replacement therapy. Most of the currently available methods to determine the intrapulmonary distribution of surfactant are time-consuming and require surfactant labelling. Our aim was to assess the potential of Mass Spectrometry Imaging (MSI) as a label-free technique to qualitatively and quantitatively evaluate the distribution of surfactant to the premature lamb., Methods: Twelve preterm lambs (gestational age 126-127d, term ~150d) were allocated in two experimental groups. Seven lambs were treated with an intratracheal bolus of the synthetic surfactant CHF5633 (200 mg/kg) and 5 lambs were managed with mechanical ventilation for 120 min, as controls. The right lung lobes of all lambs were gradually frozen while inflated to 20 cmH 2 O pressure for lung cryo-sections for MSI analysis. The intensity signals of SP-C analog and SP-B analog, the two synthetic peptides contained in the CHF5633 surfactant, were used to locate, map and quantify the intrapulmonary exogenous surfactant., Results: Surfactant treatment was associated with a significant improvement of the mean arterial oxygenation and lung compliance (p < 0.05). Nevertheless, the physiological response to surfactant treatment was not uniform across all animals. SP-C analog and SP-B analog were successfully imaged and quantified by means of MSI in the peripheral lungs of all surfactant-treated animals. The intensity of the signal was remarkably low in untreated lambs, corresponding to background noise. The signal intensity of SP-B analog in each surfactant-treated animal, which represents the surfactant distributed to the peripheral right lung, correlated well with the physiologic response as assessed by the area under the curves of the individual arterial partial oxygen pressure and dynamic lung compliance curves of the lambs., Conclusions: Applying MSI, we were able to detect, locate and quantify the amount of exogenous surfactant distributed to the lower right lung of surfactant-treated lambs. The distribution pattern of SP-B analog correlated well with the pulmonary physiological outcomes of the animals. MSI is a valuable label-free technique which is able to simultaneously evaluate qualitative and quantitative drug distribution in the lung.

Antenatal corticosteroids (ACS) are sporadically used in low and middle income countries (LMIC), although their use is considered by the World Health Organization (WHO) as essential for decreasing infant mortality. Presently the WHO recommends the use of ACS only when gestational age is known, delivery is imminent, and the delivery will be in a facility that can provide care for the mother and the infant. We review uncertainties about ACS in high income countries that are underappreciated for anticipating their effectiveness in LMIC. We discuss the implications of a large RCT that evaluated the use of ACS in LMIC and found no benefit for presumed preterm infants and increased mortality in larger infants. The treatment schedules for ACS have not been optimized and more is now known about how to improve treatment strategies to hopefully decrease risks such as neonatal hypoglycemia in LMIC. The benefits from ACS may depend on the patient populations and health care environment in which the therapy is used. Further trials are needed to evaluate the safety and efficacy of ACS in LMIC., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background The "healthy obese" hypothesis suggests the risks associated with excess adiposity are reduced in those with higher muscle quality (mass/strength). Alternative possibilities include loss of muscle quality as people become unwell (reverse causality) or unmeasured confounding. Methods and Results We conducted a cohort study using the UK Biobank (n=452 931). Baseline body mass index ( BMI) was used to quantify adiposity and handgrip strength ( HGS ) used for muscle quality. Outcomes were fatal and non-fatal cardiovascular disease, and mortality. As a secondary analysis we used waist-hip-ratio or fat mass percentage instead of BMI , and skeletal muscle mass index instead of HGS . In a subsample, we used gene scores for BMI , waist-hip-ratio and HGS in a Mendelian randomization ( MR ). BMI defined obesity was associated with an increased risk of all outcomes (hazard ratio [ HR ] range 1.10-1.82). Low HGS was associated with increased risks of cardiovascular and all-cause mortality ( HR range 1.39-1.72). HR s for the association between low HGS and cardiovascular disease events were smaller ( HR range 1.05-1.09). There was no suggestion of an interaction between HGS and BMI to support the healthy obese hypothesis. Results using other adiposity metrics were similar. There was no evidence of an association between skeletal muscle mass index and any outcome. Factorial Mendelian randomization confirmed no evidence for an interaction. Low genetically predicted HGS was associated with an increased risk of mortality ( HR range 1.08-1.19). Conclusions Our analyses do not support the healthy obese concept, with no evidence that the adverse effect of obesity on outcomes was reduced by improved muscle quality. Lower HGS was associated with increased risks of mortality in both observational and MR analyses, suggesting reverse causality may not be the sole explanation.

Antenatal corticosteroids (ANS) are the major intervention to decrease respiratory distress syndrome and mortality from premature birth and are standard of care. The use of ANS is expanding to include new indications and gestational ages, although the recommended dosing was never optimized. The most widely used treatment is two intramuscular doses of a 1:1 mixture of betamethasone-phosphate (Beta-P) and betamethasone-acetate (Beta-Ac) - the clinical drug. We tested in a primate model the efficacy of the slow release Beta-Ac alone for enhancing fetal lung maturation and to reduce fetal corticosteroid exposure and potential toxic effects. Pregnant rhesus macaques at 127 days of gestation (80% of term) were treated with either the clinical drug (0.25 mg/kg) or Beta-Ac (0.125 mg/kg). Beta-Ac alone increased lung compliance and surfactant concentration in the fetal lung equivalently to the clinical drug. By transcriptome analyses the early suppression of genes associated with immune responses and developmental pathways were less affected by Beta-Ac than the clinical drug. Promoter and regulatory analysis prediction identified differentially expressed genes targeted by the glucocorticoid receptor in the lung. At 5 days the clinical drug suppressed genes associated with neuronal development and differentiation in the fetal hippocampus compared to control, while low dose Beta-Ac alone did not. A low dose ANS treatment with Beta-Ac should be assessed for efficacy in human trials.

Based on recent findings that interrogator intonation can enhance interrogative suggestibility during recall phases, the present study tested influences of interrogator intonation on memory performance even as early as at the encoding stage. We experimentally manipulated interrogator intonation during encoding of a story to be recalled in immediate and delayed subsequent memory tests (Experiment 1, N = 50). As expected, a symmetrically structuring vs. an isolating-emphasizing speaking style generally increased the amount of freely recalled details. In a more fine-grained experiment (N = 50), we additionally manipulated emphasized story details and tested recall rates for peripheral, neutral, and central items. We found that emphasized peripheral details of the story were easier reproduced than central details realized in a neutral fashion, whereas the opposite pattern emerged for emphasized central details. Results are discussed in terms of their implications for forensic (interrogation) contexts and their legal psychological relevance., Competing Interests: The authors have declared that no competing interests exist.

Treatment with antenatal corticosteroids (ACS) is standard of care for women at risk of preterm birth between 24 and 34 weeks' gestation. ACS are increasingly used for other indications, including threated or indicated late preterm birth, elective cesarean, and in at-risk pregnancies for periviable gestations. However, the various drugs and doses being used worldwide have not been rigorously evaluated to optimize clinical responses and to minimize potential risks. Translational research in animal models indicate that a constant, low concentration fetal exposure to ACS is sufficient for lung maturation, resulting in lower fetal exposures. Clinical trials to develop dosing strategies with inexpensive and widely available drugs could promote greater use in low resource environments., (© 2019 Published by Elsevier Ltd.)

Following numerous genome-wide association studies of disease susceptibility, there is increasing interest in genetic associations with prognosis, survival or other subsequent events. Such associations are vulnerable to index event bias, by which selection of subjects according to disease status creates biased associations if common causes of incidence and prognosis are not accounted for. We propose an adjustment for index event bias using the residuals from the regression of genetic effects on prognosis on genetic effects on incidence. Our approach eliminates this bias when direct genetic effects on incidence and prognosis are independent, and otherwise reduces bias in realistic situations. In a study of idiopathic pulmonary fibrosis, we reverse a paradoxical association of the strong susceptibility gene MUC5B with increased survival, suggesting instead a significant association with decreased survival. In re-analysis of a study of Crohn's disease prognosis, four regions remain associated at genome-wide significance but with increased standard errors.

Background: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk., Methods: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD., Results: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUS-CHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction <0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09)., Conclusions: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.

Background: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD., Methods: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events., Results: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints., Conclusions: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.

Background: The MR-Egger (MRE) estimator has been proposed to correct for directional pleiotropic effects of genetic instruments in an instrumental variable (IV) analysis. The power of this method is considerably lower than that of conventional estimators, limiting its applicability. Here we propose a novel Bayesian implementation of the MR-Egger estimator (BMRE) and explore the utility of applying weakly informative priors on the intercept term (the pleiotropy estimate) to increase power of the IV (slope) estimate., Methods: This was a simulation study to compare the performance of different IV estimators. Scenarios differed in the presence of a causal effect, the presence of pleiotropy, the proportion of pleiotropic instruments and degree of 'Instrument Strength Independent of Direct Effect' (InSIDE) assumption violation. Based on empirical plasma urate data, we present an approach to elucidate a prior distribution for the amount of pleiotropy., Results: A weakly informative prior on the intercept term increased power of the slope estimate while maintaining type 1 error rates close to the nominal value of 0.05. Under the InSIDE assumption, performance was unaffected by the presence or absence of pleiotropy. Violation of the InSIDE assumption biased all estimators, affecting the BMRE more than the MRE method., Conclusions: Depending on the prior distribution, the BMRE estimator has more power at the cost of an increased susceptibility to InSIDE assumption violations. As such the BMRE method is a compromise between the MRE and conventional IV estimators, and may be an especially useful approach to account for observed pleiotropy.

It may not always be possible to blind participants of a randomized controlled trial for treatment allocation. As a result, estimators of the actual treatment effect may be biased. In this paper, we will extend a novel method, originally introduced in genetic research, for instrumental variable meta-analysis, adjusting for bias due to unblinding of trial participants. Using simulation studies, this novel method, "Egger Correction for non-Adherence", is introduced and compared to the performance of the "intention-to-treat," "as-treated," and conventional "instrumental variable" estimators. Scenarios considered (time-varying) non-adherence, confounding, and between-study heterogeneity. The effect of treatment on a binary endpoint was quantified by means of a risk difference. In all scenarios with unblinded treatment allocation, the Egger Correction for non-Adherence method was the least biased estimator. However, unless the variation in adherence was relatively large, precision was lacking, and power did not surpass 0.50. As a comparison, in a meta-analysis of blinded randomized controlled trials, power of the conventional IV estimator was 1.00 versus at most 0.14 for the Egger Correction for non-Adherence estimator. Due to this lack of precision and power, we suggest to use this method mainly as a sensitivity analysis.

Objectives: Researchers often perform arbitrary outcome transformations to fulfill the normality assumption of a linear regression model. This commentary explains and illustrates that in large data settings, such transformations are often unnecessary, and worse may bias model estimates., Study Design and Setting: Linear regression assumptions are illustrated using simulated data and an empirical example on the relation between time since type 2 diabetes diagnosis and glycated hemoglobin levels. Simulation results were evaluated on coverage; i.e., the number of times the 95% confidence interval included the true slope coefficient., Results: Although outcome transformations bias point estimates, violations of the normality assumption in linear regression analyses do not. The normality assumption is necessary to unbiasedly estimate standard errors, and hence confidence intervals and P-values. However, in large sample sizes (e.g., where the number of observations per variable is >10) violations of this normality assumption often do not noticeably impact results. Contrary to this, assumptions on, the parametric model, absence of extreme observations, homoscedasticity, and independency of the errors, remain influential even in large sample size settings., Conclusion: Given that modern healthcare research typically includes thousands of subjects focusing on the normality assumption is often unnecessary, does not guarantee valid results, and worse may bias estimates due to the practice of outcome transformations., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: Improved outcomes over the past decade have increased confidence of physicians and patients in extended duration of left ventricular assist device (LVAD) support. This single-centre cohort study reports 5-year outcomes with the HeartMate II (HMII) LVAD., Methods: We describe a cohort of 89 patients who received a HMII LVAD between February 2004 and December 2010. The causes of death and adverse events were assessed by examination of medical records. A total of 202.74 patient-years were analysed., Results: After 5 years, of the 89 patients, 15 patients remained on device therapy, 39 patients died, 28 patients underwent heart transplantation and 7 patients underwent explantation of the HMII for recovery. One year after the HMII implantation, there was a survival of 71% in the study cohort. In the following years, the survival rate was 65% in the 2nd year, 63% in the 3rd year, 56% in the 4th year and 54% after 5 years of LVAD support. Ten LVAD exchanges were performed in 8 (11%) patients. Currently (March 2017), 12 patients still remain on their original device. The longest ongoing patient on the HMII has been supported for over 11 years (4097 days). The most common adverse events were bleeding (68%; 1.5837 events per patient-year) and LVAD infection [49%; 1.0666 events per patient-year]. Seven cases of pump thrombosis were described (8%; 0.1131 events per patient-year)., Conclusions: This is the first single-cohort study to describe a 5-year survival of HMII patients on extended duration of support. A 5-year survival of 54% was observed in this single-centre cohort., (© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Antenatal steroids are standard of care for women who are at risk of preterm delivery; however, antenatal steroid dosing and formulation have not been evaluated adequately. The standard clinical 2-dose treatment with betamethasone-acetate+betamethasone-phosphate is more effective than 2 doses of betamethasone-phosphate for the induction of lung maturation in preterm fetal sheep. We hypothesized that the slowly released betamethasone-acetate component induces similar lung maturation to betamethasone-phosphate+betamethasone-acetate with decreased dose and fetal exposure., Objective: The purpose of this study was to investigate pharmacokinetics and fetal lung maturation of antenatal betamethasone-acetate in preterm fetal sheep., Study Design: Groups of 10 singleton-pregnant ewes received 1 or 2 intramuscular doses 24 hours apart of 0.25 mg/kg/dose of betamethasone-phosphate+betamethasone-acetate (the standard of care dose) or 1 intramuscular dose of 0.5 mg/kg, 0.25 mg/kg, or 0.125 mg/kg of betamethasone-acetate. Fetuses were delivered 48 hours after the first injection at 122 days of gestation (80% of term) and ventilated for 30 minutes, with ventilator settings, compliance, vital signs, and blood gas measurements recorded every 10 minutes. After ventilation, we measured static lung pressure-volume curves and sampled the lungs for messenger RNA measurements. Other groups of pregnant ewes and fetuses were catheterized and treated with intramuscular injections of betamethasone-phosphate 0.125 mg/kg, betamethasone-acetate 0.125 mg/kg, or betamethasone-acetate 0.5 mg/kg. Maternal and fetal betamethasone concentrations in plasma were measured for 24 hours., Results: All betamethasone-treated groups had increased messenger RNA expression of surfactant proteins A, B, and C, ATP-binding cassette subfamily A member 3, and aquaporin-5 compared with control animals. Treatment with 1 dose of intramuscular betamethasone-acetate 0.125mg/kg improved dynamic and static lung compliance, gas exchange, and ventilation efficiency similarly to the standard treatment of 2 doses of 0.25 m/kg of betamethasone-acetate+betamethasone-phosphate. Betamethasone-acetate 0.125 mg/kg resulted in lower maternal and fetal peak plasma concentrations and decreased fetal exposure to betamethasone compared with betamethasone-phosphate 0.125 mg/kg., Conclusion: A single dose of betamethasone-acetate results in similar fetal lung maturation as the 2-dose clinical formulation of betamethasone-phosphate+betamethasone-acetate with decreased fetal exposure to betamethasone. A lower dose of betamethasone-acetate may be an effective alternative to induce fetal lung maturation with less risk to the fetus., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

We developed a cued pro- and antisaccade paradigm (CPAP) to explore automatic components of sexual interest. Heterosexual participants (n = 32 women, n = 25 men) had to perform fast eye movements toward and away from sexually relevant or irrelevant stimuli across a congruent (i.e., prosaccade toward sexually relevant stimuli, antisaccade away from sexually irrelevant stimuli) and an incongruent condition (i.e., prosaccade toward sexually irrelevant stimuli, antisaccade away from sexually relevant stimuli). We hypothesized that pro- and antisaccade performance would be influenced by the sexual interest-specific relevance of the presented stimulus (i.e., nude female or male stimulus) and the instructed task (i.e., pro- or antisaccade) and, thus, differ meaningfully between conditions. Results for prosaccades toward sexually relevant stimuli in the congruent condition showed that error rates were lower and latencies were shorter compared with prosaccades toward sexually irrelevant stimuli in the incongruent condition, but only for male participants. In addition, error rates for antisaccades away from sexually irrelevant stimuli in the congruent condition were lower than for antisaccades away from sexually relevant stimuli in the incongruent condition, for both female and male participants. Latencies of antisaccades, however, did not differ between conditions. In comparison with established indirect sexual interest paradigms, the CPAP benefits from measuring highly automated processes less prone to deliberate control. To this end, the CPAP could be applied to explore the interplay of early automatic and deliberate components of sexual information processing.