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OBJECTIVE: Genome-wide association studies (GWASs) of the Alcohol Use Disorders Identification Test (AUDIT), a 10-item screen for alcohol use disorder (AUD), have elucidated novel loci for alcohol consumption and misuse. However, these studies also revealed that GWASs can be influenced by numerous biases (e.g., measurement error, selection bias), which may have led to inconsistent genetic correlations between alcohol involvement and AUD, as well as paradoxically negative genetic correlations between alcohol involvement and psychiatric disorders and/or medical conditions. The authors used genomic structural equation modeling to elucidate the genetics of alcohol consumption and problematic consequences of alcohol use as measured by AUDIT. METHODS: To explore these unexpected differences in genetic correlations, the authors conducted the first item-level and the largest GWAS of AUDIT items (N=160,824) and applied a multivariate framework to mitigate previous biases. RESULTS: The authors identified novel patterns of similarity (and dissimilarity) among the AUDIT items and found evidence of a correlated two-factor structure at the genetic level ("consumption" and "problems," rg=0.80). Moreover, by applying empirically derived weights to each of the AUDIT items, the authors constructed an aggregate measure of alcohol consumption that was strongly associated with alcohol dependence (rg=0.67), moderately associated with several other psychiatric disorders, and no longer positively associated with health and positive socioeconomic outcomes. Lastly, by conducting polygenic analyses in three independent cohorts that differed in their ascertainment and prevalence of AUD, the authors identified novel genetic associations between alcohol consumption, alcohol misuse, and health. CONCLUSIONS: This work further emphasizes the value of AUDIT for both clinical and genetic studies of AUD and the importance of using multivariate methods to study genetic associations that are more closely related to AUD.

Individuals with sickle cell disease (SCD) and individuals with sickle cell trait (SCT) have different health trajectories, but it is unknown whether sociodemographic and clinical characteristics are associated with their likelihood to be a parent. The purpose of this study was to examine the sociodemographic and clinical characteristics associated with perceived likelihood-to-parent among a cohort of young adults with SCD or SCT in the USA. The participants were 234 young adults (82 males, 152 females) who had either SCD (n = 138) or SCT (n = 96). The average age was 25.9 years (SD = 4.9), and most participants (87%) were single. Study participants completed the likelihood-to-parent item (0-4 scale) included in the valid and reliable Sickle Cell Reproductive Health Knowledge Parenting Intent and Behavior Questionnaire (SCKnowIQ). The mean likelihood-to-parent score was M = 2.3 (SD = 1.1) and 41% indicated that they were 'very' or 'extremely' likely to be a parent. Bivariate analysis showed that likelihood-to-parent was associated with the participant's sickle cell genotype (p = .03), age (p = .003), educational level (p = .04), income (p = .01), employment (p = .04), number of children (p < .001), health insurance (p = .02), and influenced by others (p < .001). In multiple regression analysis, participants reported higher likelihood-to-parent scores if they had at most 2 children (p = .03), higher income (p = .03), had no insurance (p = .01), and reported higher levels of being influenced by others (p = .001). Additional research is needed to confirm these findings in larger representative samples with more young adult males and to understand the likelihood to become parents over time by implementing longitudinal studies in the SCD and SCT populations. Such research is needed to guide appropriate education and genetic counseling for reproductive decision-making among young adults with SCD or SCT.

Deliberating on the state of the science underlying the prediction of dangerousness and the application of that science is a weight carried by the law. Over the past few decades new technologies have allowed neuroscience to document intricacies of the developing brain. As neuroscience has expanded and refined the evidence of biopsychosocial influences on brain development, neurolaw has considered the implications of the scientific research for criminal law. Assigning an age for the onset of adulthood is a sociolegal construct. Science cannot assign an exact age to adulthood. Neuroscience has established that brain development continues through the mid-twenties, but exposure to adverse childhood experiences, perinatal exposures and conditions, and genetic pre-disposition to mental illness changes this trajectory so that neither the course nor endpoints are fixed. The Court holds the responsibility to apply the law to an individual set of circumstances but often asks psychiatrists what factors help explain an individual’s actions or state of mind and to apply the science and the art of medicine to help explain the individual. However, a psychiatrist’s testimony is a tool used by attorneys to further an argument. Is the law ready to accept the neuroscience of emerging adulthood and does it meet Daubert are ever-evolving question and answer sets as studies are repeated and the evidence mounts regarding brain development. Even so, at the end of the day, what psychiatrists know to be true or science accepts to be fact is not the same as policy or law. Many other factors are at play.

The fetus is strongly dependent on nutrients from the mother, including polyunsaturated fatty acids (PUFA). In adult animals, n-3 PUFA ameliorates stroke-mediated brain injury, but the modulatory effects of different PUFA content in maternal diet on focal arterial stroke in neonates are unknown. This study explored effects of maternal n-3 or n-6 enriched PUFA diets on neonatal stroke outcomes. Pregnant mice were assigned three isocaloric diets until offspring reached postnatal day (P) 10–13: standard, long-chain n-3 PUFA (n-3) or n-6 PUFA (n-6) enriched. Fatty acid profiles in plasma and brain of mothers and pups were determined by gas chromatography–mass spectrometry and cytokines/chemokines by multiplex protein analysis. Transient middle cerebral artery occlusion (tMCAO) was induced in P9-10 pups and cytokine and chemokine accumulation, caspase-3 and calpain-dependent spectrin cleavage and brain infarct volume were analyzed. The n-3 diet uniquely altered brain lipid profile in naïve pups. In contrast, cytokine and chemokine levels did not differ between n-3 and n-6 diet in naïve pups. tMCAO triggered accumulation of inflammatory cytokines and caspase-3-dependent and -independent cell death in ischemic-reperfused regions in pups regardless of diet, but magnitude of neuroinflammation and caspase-3 activation were attenuated in pups on n-3 diet, leading to protection against neonatal stroke. In conclusion, maternal/postnatal n-3 enriched diet markedly rearranges neonatal brain lipid composition and modulates the response to ischemia. While standard diet is sufficient to maintain low levels of inflammatory cytokines and chemokines under physiological conditions, n-3 PUFA enriched diet, but not standard diet, attenuates increases of inflammatory cytokines and chemokines in ischemic-reperfused regions and protects from neonatal stroke. Graphic Abstract

Contains fulltext : 237013.pdf (Publisher’s version ) (Closed access) Behaviors and disorders related to self-regulation, such as substance use, antisocial behavior and attention-deficit/hyperactivity disorder, are collectively referred to as externalizing and have shared genetic liability. We applied a multivariate approach that leverages genetic correlations among externalizing traits for genome-wide association analyses. By pooling data from ~1.5 million people, our approach is statistically more powerful than single-trait analyses and identifies more than 500 genetic loci. The loci were enriched for genes expressed in the brain and related to nervous system development. A polygenic score constructed from our results predicts a range of behavioral and medical outcomes that were not part of genome-wide analyses, including traits that until now lacked well-performing polygenic scores, such as opioid use disorder, suicide, HIV infections, criminal convictions and unemployment. Our findings are consistent with the idea that persistent difficulties in self-regulation can be conceptualized as a neurodevelopmental trait with complex and far-reaching social and health correlates. 27 p.

Background Sleep is essential for wellbeing, yet sleep disturbance is a common problem linked to a wide range of health conditions. Palmitoylethanolamide (PEA) is an endogenous fatty acid amide proposed to promote better sleep via potential interaction with the endocannabinoid system. Methods This double-blind, randomised study on 103 adults compared the efficacy and tolerability of 8 weeks of daily supplemented PEA formulation (350 mg Levagen + ®) to a placebo. Sleep quality and quantity were measured using wrist actigraphy, a sleep diary and questionnaires. Results At week 8, PEA supplementation reduced sleep onset latency, time to feel completely awake and improved cognition on waking. After 8 weeks, both groups improved their sleep quality and quantity scores similarly. There was no difference between groups at baseline or week 8 for sleep quantity or quality as measured from actigraphy or sleep diaries. Conclusion These findings support PEA as a potential sleeping aid capable of reducing sleep onset time and improving cognition on waking. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12618001339246. Registered 9th August 2018.

ImportanceCharacterizing whether genetic variants for psychiatric outcomes operate via specific versus general pathways provides more informative measures of genetic risk, and, potentially, allows us to design more targeted prevention and interventions.ObjectiveEmploy multivariate methods to tease apart variants associated with problematic alcohol use through either general or specific pathways and compare results to standard univariate genetic analysis of problematic alcohol use.DesignWe compared results from a univariate genome wide association study (GWAS) of problematic alcohol use to those from a previous multivariate GWAS of externalizing phenotypes. We identified genetic variants associated with problematic alcohol use through a broad liability to externalizing, and those that remain after removing shared variance with externalizing. We compared these results across SNP overlap, bioannotations, genetic correlations, and polygenic scores.SettingWe included GWAS summary statistics from existing GWAS, and two US based hold out samples: The National Longitudinal Study of Adolescent to Adult Health (Add Health) and the Collaborative Study on the Genetics of Alcoholism (COGA).ParticipantsPublicly available GWAS of externalizing behaviors and participants in Add Health (N=5,107) and COGA (N=7,483), limited to individuals of European ancestries.Exposure(s)N/AMain Outcome(s) and Measure(s)Outcomes included problematic alcohol use (ALCP-O), shared risk for externalizing (EXT), and problematic alcohol use-specific risk (ALCP-S) for the GWASs; a preregistered list of 99 available phenotypes for genetic correlations; and substance use, substance use disorder criteria, and alcohol misuse in the polygenic score analyses.ResultsThe analysis differentiated SNPs operating through common versus specific risk pathways. While ALCP-O was associated with multiple phenotypes, ALCP-S was predominantly associated with alcohol use and other forms of psychopathology. Polygenic scores for ALCP-O were associated with a variety of other forms of substance use and substance use disorders, polygenic scores for ALCP-S were only associated with alcohol phenotypes. Polygenic scores for both ALCP-S and EXT show differential patterns of associations with alcohol misuse across development.Conclusions and RelevanceFocusing on the differential impacts of shared and specific risk can better characterize pathways of risk for alcohol use disorders. Multivariate methods can be a useful tool for studying many psychiatric conditions. Parsing risk pathways will become increasingly relevant as genetic information is incorporated into clinical practice for psychiatric outcomes.

Objective To describe the clinical course of a dog with a pheochromocytoma multisystem crisis that exhibited autoresuscitation after cardiac arrest. Case summary An approximately 10-year-old male neutered terrier mix dog presented for collapse. Abdominal imaging was suggestive of a pheochromocytoma, and clinical pathology data and thoracic imaging suggested the presence of a multisystem crisis. The dog developed cardiopulmonary arrest that was followed by autoresuscitation. New or unique information provided To the authors' knowledge, this is the first report of autoresuscitation in a dog. The phenomenon may have been associated with a pheochromocytoma multisystem crisis.

The purpose of this article is to describe the method of developing an internet-based reproductive options intervention to increase informed reproductive decision-making among individuals with sickle cell disease (SCD) or sickle cell trait (SCT). An interprofessional team of graphics and media specialist, nurses, physicians, and researchers collaborated to develop the intervention. Individuals from the community served as advisory board members who reviewed and advised on webpage design, content, delivery, and media. The intervention was theory based, delivered online, and experientially oriented for young adults of reproductive age with SCD or SCT. The intervention was culturally specific, supporting individuals with SCD or SCT in making informed reproductive decisions about transmission of SCD or SCT to their offspring. The intervention could be strengthened to include content on implementing behaviors concordant with informed reproductive decisions. Health care providers can use the result of this study to enhance their knowledge about the complexity of parenting options.

Purpose One of the most downloaded articles in 2017 from the International Journal of Radiation Oncology, Biology, and Physics was a study suggesting that music therapy during radiation therapy (RT) simulation substantially reduces anxiety. To further evaluate the potential of music's clinical efficacy in the context of radiation therapy, we conducted a randomized trial evaluating the influence of genre-based music chosen by the study participant on anxiety during the first RT treatment session with a method that is applicable to routine clinical practice. Methods and Materials We conducted a prospective randomized trial of music versus no music during the first RT treatment for cancer. We limited the study to women because prior studies document a higher rate of anxiety in female patients with cancer. Anxiety was evaluated before and after the first RT treatment using the State-Trait Anxiety Inventory (STAI) and Symptom Distress Thermometer (SDT). Patients randomized to music had their preferred genre of music played from a web-based application while in the treatment vault. Results In the study, 102 females were enrolled (51 with and 51 without music). Baseline high anxiety score before RT was recorded in 48% of patients using the STAI and 58% using the SDT. The percent decrease in mean STAI score was 16% with music versus 10% without music (P = .2197). The mean SDT percent changes were a 13% decrease with music versus a 2% increase without music (P = .3298). Conclusions This study documents that high anxiety is common in women receiving RT for cancer and that music, as used in this study, does not reduce anxiety to a meaningful degree.

A single dimension of general psychopathology, p , has been hypothesized to represent a general liability that spans multiple types of psychiatric disorders and non-clinical variation in psychiatric symptoms across the lifespan. We conducted genome-wide association analyses of lifetime symptoms of mania, psychosis, irritability in 124,952 to 208,315 individuals from UK Biobank, and then applied Genomic SEM to model the genetic relationships between these psychiatric symptoms and clinically-defined psychiatric disorders (schizophrenia, bipolar disorder, major depressive disorder). Two dimensions of cross-cutting genetic liability emerged: general vulnerability to self-reported symptoms ( p self ) versus transdiagnostic vulnerability to clinically-diagnosed disease ( p clinician ). These were only modestly correlated ( r g = .344). Multivariate GWAS identified 145 and 11 independent and genome-wide significant loci for p clinician and p self , respectively, and improved polygenic prediction, relative to univariate GWAS, in hold-out samples. Despite the severe impairments in occupational and educational functioning seen in patients with schizophrenia and bipolar disorder, p self showed stronger and more pervasive genetic correlations with facets of socioeconomic disadvantage (educational attainment, income, and neighborhood deprivation), whereas p clinician was more strongly associated with medical disorders unrelated to the brain. Genetic variance in p clinician that was unrelated to general vulnerability to psychiatric symptoms was associated with less socioeconomic disadvantage, suggesting positive selection biases in clinical samples used in psychiatric GWAS. These findings inform criticisms of psychiatric nosology by suggesting that cross-disorder genetic liabilities identified in GWASs of clinician-defined psychiatric disease are relatively distinct from genetic liabilities operating on self-reported symptom variation in the general population.

Highlights • Lumbar spinal epidural lipomatosis (SEL) is a rare cause of low back and lower extremity pain. • Magnetic resonance imaging is considered as the reference standard for the diagnosis. • The therapeutic approach of patients with SEL can be either surgical or conservative depending on the etiology and the severity of the condition., Introduction Lumbar spinal epidural lipomatosis (SEL) is a rare condition defined by an excessive deposition of adipose tissue in the lumbar spinal canal. The objective of this case report is to document a clinical case of SEL presenting within a multidisciplinary spine clinic and to compare our clinical findings and management with the available literature. Case presentation A 51-year-old female presented at a spine clinic with low back pain, bilateral leg pain and difficulty walking. Magnetic resonance imaging of the lumbar spine showed evidence of severe central canal stenosis due to extensive epidural lipomatosis. She was initially advised to lose weight and undergo a 3-month course of physiotherapy. However, because of lack of improvement, she was scheduled for and underwent L4-S1 posterior spinal decompression and L4-L5 posterior spinal instrumented fusion. At 12-month follow-up, the patient reported no pain and retained the ability to walk regular distances without experiencing discomfort. Discussion This case report describes the conservative and surgical management of a case of lumbar spinal stenosis due to SEL. The therapeutic approach of patients with this condition is not standardized. As such, a discussion of the literature with respect to the diagnosis, clinical presentation, epidemiology, imaging appearance, risk factors, etiology, and management of SEL is also presented.

Adults with congenital heart disease represent a complex and growing patient population. By virtue of their variant anatomy and the complex surgical repair often required in infancy, these patients are at risk of developing unique atrial and ventricular arrhythmias throughout their lifetimes. Electrophysiologists involved in the care of these patients should have a detailed understanding of their underlying anatomy and any prior surgical procedures to guide procedural planning and should have knowledge of the range of possible arrhythmia mechanisms that may differ from patients without structural heart disease. Despite this complexity, standard mapping techniques and electrophysiologic maneuvers may still be used to elucidate arrhythmia mechanisms, map tachycardia circuits, and guide catheter ablation. We report a case of two different macroreentrant right atrial tachycardias that were successfully ablated in a patient with congenitally-corrected transposition of the great arteries.

Background Infant adiposity is linked to both high maternal fat mass (FM) and excessive gestational FM gain, whereas the association with maternal adipokines is less clear. The aim was to determine how levels of maternal leptin, the soluble leptin receptor (sOB-R), adiponectin, and FM during pregnancy were linked to infant FM in normal-weight (NW) women and women with obesity (OB). Methods Body composition and serum levels of leptin, adiponectin, and sOB-R were determined three times during pregnancy in 80 NW and 46 OB women. For infants, body composition was measured at 1 and 12 weeks of age. Results Maternal leptin and sOB-R levels increased during pregnancy. For NW women, infant FM at 1 week was inversely associated with changes in maternal leptin and at 12 weeks inversely associated with absolute maternal sOB-R levels throughout pregnancy, as well as changes in sOB-R levels in early pregnancy. For OB women, infant FM at both 1 and 12 weeks were best explained by maternal FM. Conclusions Leptin and sOB-R, thought to regulate leptin bioavailability, are associated with fat accumulation in infants born to NW women. In OB women, maternal FM in early pregnancy is more important than leptin in determining infant fat accumulation. Impact In normal-weight women, the regulation of maternal leptin bioavailability during pregnancy has a role in infant fat mass accumulation.In women with obesity, however, pre-pregnancy maternal fat mass seems more important for infant fat mass.This is the first study of maternal adipokines and fat mass including longitudinal measurements in both mothers and their children.Understanding the relationship between maternal factors and infant fat mass is of great importance as obesity is programmed over the generations, and it is important to learn what regulates this programming.Fig. 1Study visits and participating numbers for normal-weight women (n = 80) or women with obesity (n = 46) and their infants. ADP air displacement plethysmography, NW women of normal weight, OB women with obesity.Fig. 2Strongest explanatory variables of infant outcomes at 1 and 12 weeks using adjusted stepwise linear regression for the a normal weight (NW) group and b obese (OB) group. Estimates per 1 SD increase and 95% CI are shown to allow comparison between different variables and outcomes. FM fat mass, FFM fat-free mass, sOB-R soluble leptin receptor, T1 trimester 1, T2 trimester 2, T3 trimester 3.

We examined the acute effects of l-theanine, caffeine and their combination on sustained attention, inhibitory control and overall cognition in boys with attention deficit hyperactivity disorder (ADHD). l-Theanine (2.5 mg/kg), caffeine (2.0 mg/kg), their combination and a placebo were administered in a randomized four-way repeated-measures crossover with washout, to five boys (8–15 years) with ADHD. Functional magnetic resonance imaging (fMRI) was performed during a Go/NoGo task and a Stop-signal task ~ 1 h post-dose. NIH Cognition Toolbox was administered ~ 2 h post-dose. Treatment vs. placebo effects were examined in multi-level mixed-effects models. l-Theanine improved total cognition composite in NIH Cognition Toolbox (p = 0.040) vs. placebo. Caffeine worsened and l-theanine had a trend of worsening inhibitory control (i.e. increased Stop-signal reaction time; p = 0.031 and p = 0.053 respectively). l-Theanine–caffeine combination improved total cognition composite (p = 0.041), d-prime in the Go/NoGo task (p = 0.033) and showed a trend of improvement of inhibitory control (p = 0.080). l-Theanine–caffeine combination was associated with decreased task-related reactivity of a brain network associated with mind wandering (i.e. default mode network). l-Theanine–caffeine combination may be a potential therapeutic option for ADHD-associated impairments in sustained attention, inhibitory control and overall cognitive performance.

Objective: Assess the variability and differences in oxidative stress, antioxidant, and inflammatory biomarkers in people with type 2 diabetes mellitus (T2D) and healthy controls. Methods:: Ten men and women diagnosed with T2D and ten healthy matched controls (CON) were recruited. Participants had venous blood taken at six different time points on different days, three in the morning (after overnight fast) and three in the afternoon. Inflammation (IL-6, 8, 10 and TNF-α), oxidative stress/antioxidant biomarkers (F2-isoprostanes, protein carbonyls, total antioxidant capacity (TAC), glutathione peroxidase activity, IL-6, 8 & 10 and TNF-α) were assessed. Results:: Biomarker concentrations were similar between groups. There was large variability in nearly all biomarkers for both groups. For inflammatory measures, intra-individual coefficients of variation (CV) ranged from 64.0–92.1% and 100.9–259.0% for inter-individual differences. CVs for oxidative stress markers were lower (7.4–31.2% for intra-individual and 8.6–43.0% for inter-individual). TAC had the lowest intra-individual CV – 7% for T2D and 8% for CON. Protein carbonyls were more variable in the afternoon (34% CV) compared to morning (24% CV) in CON. IL-6 intra-individual CV was different between groups for afternoon measurements (93% T2D, 60% CON). Conclusion:: Oxidative stress and inflammatory biomarkers show considerable variation in both T2D and healthy populations. Trial registration: ClinicalTrials.gov identifier: NCT01206725.

Over the past three decades, the legal profession has experienced globalization, the rise of mega-law firms, and intensified competition. These transformations have been associated with declining career perspectives, the hyper-specialization of legal work, and increased levels of stress. We argue that the concept of alienation offers valuable insights into these changes by providing an original analysis of the objective and subjective experiences of early career lawyers at work. We elaborate a multidimensional typology that covers the content and retributions of legal work. By categorizing experiences of alienation along these two axes, we identify four ideal-types of alienation: powerlessness, purposelessness, time deprivation, and unfairness. Based on qualitative studies carried out in France and Switzerland, we illustrate how young lawyers differentially experience each type of alienation, according to gender, status, and firm size. We conclude by suggesting how these factors combine to produce long-terms effects, such as the high female attrition rates observed in the Swiss and French legal professions.

Stroke is among the top ten causes of death in children but has received disproportionally little attention. Cerebral arteriopathies account for up to 80% of childhood arterial ischemic stroke (CAIS) cases and are strongly predictive of CAIS recurrence and poorer outcomes. The underlying mechanisms of sensitization of neurovasculature by viral infection are undefined. In the first age-appropriate model for childhood arteriopathy—by administration of viral mimetic TLR3-agonist Polyinosinic:polycytidylic acid (Poly-IC) in juvenile mice—we identified a key role of the TLR3-neutrophil axis in disrupting the structural-functional integrity of the blood-brain barrier (BBB) and distorting the developing neurovascular architecture and vascular networks. First, using an array of in-vivo/post-vivo vascular imaging, genetic, enzymatic and pharmacological approaches, we report marked Poly-IC-mediated extravascular leakage of albumin (66kDa) and of a small molecule DiI (∼934Da) and disrupted tight junctions. Poly-IC also enhanced the neuroinflammatory milieu, promoted neutrophil recruitment, profoundly upregulated neutrophil elastase (NE), and induced neutrophil extracellular trap formation (NETosis). Finally, we show that functional BBB disturbances, NETosis and neuroinflammation are markedly attenuated by pharmacological inhibition of NE (Sivelestat). Altogether, these data reveal NE/NETosis as a novel therapeutic target for viral-induced cerebral arteriopathies in children.

BackgroundElectronic health records (EHR) are useful tools for understanding complex medical phenotypes, but they have been underutilized for opioid use disorders (OUD). Patterns of prescription opioid use might provide an objective measure of OUD risk.MethodsWe extracted data for over 2.6 million patients across three health registries (Vanderbilt University Medical Center, Mass General Brigham, Geisinger) between 2005 and 2018. We defined three groups based on levels of opioid exposure: No Prescription, Minimal Exposure (2 prescriptions within 90 days at least once, but never 3 prescriptions ResultsThe prevalence of substance (alcohol, tobacco, cannabis) use disorders was higher in patients with OUD and Chronic Exposure than those with No Prescription or Minimal Exposure. Patients in the OUD and Chronic Exposure groups had more psychiatric (anxiety, depression, schizophrenia, bipolar disorder) and medical comorbidities (pain, hepatitis C, HIV) than those in the Minimal Exposure group. Notably, patients in the Minimal Exposure group had different comorbidity profiles (higher rates of substance use and psychiatric disorders, more pain conditions) than those in the Unscreened or No Prescription groups, highlighting the value of including opioid exposure in studies of OUD.ConclusionsLong-term opioid prescription use may serve as an additional tool to characterize OUD risk.

Osteopontin (OPN) is a matricellular protein that mediates various physiological functions and is implicated in neuroinflammation, myelination, and perinatal brain injury. However, its expression in association with brain injury in preterm infants is unexplored. Here we examined the expression of OPN in postmortem brains of preterm infants and explored how this expression is affected in brain injury. We analyzed brain sections from cases with white matter injury (WMI) and cases with germinal matrix hemorrhage (GMH) and compared them to control cases having no brain injury. WMI cases displayed moderate to severe tissue injury in the periventricular and deep white matter that was accompanied by an increase of microglia with amoeboid morphology. Apart from visible hemorrhage in the germinal matrix, GMH cases displayed diffuse white matter injury in the periventricular and deep white matter. In non-injured preterm brains, OPN was expressed at low levels in microglia, astrocytes, and oligodendrocytes. OPN expression was significantly increased in regions with white matter injury in both WMI cases and GMH cases. The main cellular source of OPN in white matter injury areas was amoeboid microglia, although a significant increase was also observed in astrocytes in WMI cases. OPN was not expressed in the germinal matrix of any case, regardless of whether there was hemorrhage. In conclusion, preterm brain injury induces elevated OPN expression in microglia and astrocytes, and this increase is found in sites closely related to injury in the white matter regions but not with the hemorrhage site in the germinal matrix. Thus, it appears that OPN takes part in the inflammatory process in white matter injury in preterm infants, and these findings facilitate our understanding of OPN’s role under both physiological and pathological conditions in the human brain that may lead to greater elucidation of disease mechanisms and potentially better treatment strategies.

ImportanceEconomic and racial inequality is linked to disparities in children’s mental health. Biomarkers that reflect these social disparities are lacking.ObjectiveWe examined the hypothesis that salivary DNA-methylation patterns of higher inflammation and faster pace of biological aging are economically, racially and ethnically stratified and are associated with child mental health.DesignThe Texas Twin Project is an on-going, observational, longitudinal study that began in May 2012. Analyses were preregistered on May 7, 2021, and completed on August 23, 2021.SettingThe population-based study identified and recruited participants from public school rosters in the greater Austin area.ParticipantsParticipants in the analytic data set included all participants that agreed to contribute DNA samples and whose samples were assayed by January 2021.ExposuresFamily- and neighborhood-level socioeconomic inequality, racial and ethnic identities (White, Latinx, Black, Asian).Main Measure(s)Environmental exposures were analyzed in relation to salivary DNA- methylation profiles of higher inflammation (DNAm-CRP) and faster pace of biological aging (DunedinPoAm). Child internalizing problems, attention problems, aggression, rule-breaking, ADHD, oppositional defiant disorder, and conduct disorder were measured using parent-reports and self-reports on abbreviated versions of the Achenbach Child Behavior Checklist and Conners 3.The hypotheses being tested were formulated after data collection of the present data freeze and were pre-registered prior to analyses being conducted.ResultsIn a sample of N=1,183 8-to-19-year-olds (609 female, age M=13.38y), children’s salivary DNA-methylation profiles and psychiatric symptoms differed by socioeconomic conditions, race and ethnicity. Children with more parent-reported internalizing symptoms had higher DNAm-CRP (r=0.15, 95% CI=0.05 to 0.25, P=0.004) and DunedinPoAm (r=0.15, CI=0.05 to 0.25, P=0.002), and children with more parent-reported aggression problems had higher DNAm-CRP (r=0.17, CI=0.04 to 0.31, P=0.013). DNAm-CRP partially mediated advantage of higher family socioeconomic status (16% of total effect) and White racial identity (12% of total effect) on reduced internalizing symptoms. DunedinPoAm also partially mediated advantage of White racial identity on internalizing (19% of total effect).Conclusions and RelevanceSocioeconomic and racial inequality are visible in children’s epigenetic profiles of inflammation and the rate of biological aging in a manner that is tied to social disparities in mental health.Key PointsQuestionWe examined whether salivary DNA-methylation profiles are socially stratified and associated with child mental health.FindingsIn this preregistered, cross-sectional observational study of 1,183 children and adolescents, socioeconomic, racial, and ethnic disparities in mental health were associated with salivary DNA-methylation profiles of inflammation and the pace of biological aging.MeaningDNA-methylation biomarkers hold promise as tools to quantify the biological impact of socioeconomic inequality and being racially minoritized in a manner that is tied to social disparities in mental health.

Chorioamnionitis is an important cause of preterm delivery. Data on neurodevelopmental outcome in exposed infants are inconsistent due to difficulties in diagnosing intrauterine infection/inflammation and lack of detailed long-term follow-up. We investigate cognitive and motor function in preterm infants at early school age and relate the findings to bacteria in amniotic fluid obtained by amniocentesis (microbial invasion of the amniotic cavity (MIAC)) or placenta findings of histological chorioamnionitis (HCA) or fetal inflammatory response syndrome (FIRS). Sixty-six infants with gestational age

Detailed data on adipokines and body composition during and after pregnancy in women of different BMI categories are lacking. Furthermore, adipokine regulation during pregnancy and the factors contributing to gestational insulin resistance are not completely understood. The objective was to longitudinally determine adipokine levels, body composition, and insulin sensitivity during and after pregnancy in women of healthy weight (HW) and with obesity (OB), and identify factors associated with insulin resistance. Women (30 HW, 19 OB) underwent blood sampling and body composition examination, by air-displacement plethysmography, longitudinally during pregnancy (trimesters 1, 2, 3) and after pregnancy (6, 12, 18 months postpartum). Serum leptin, soluble leptin receptor (sOB-R), and adiponectin levels were measured and free leptin index (FLI) and homeostatic model assessment of insulin resistance (HOMA-IR) determined. Fat mass and leptin increased during pregnancy in the HW (p

High throughput sequencing is discovering many likely causative genetic variants in individuals with cerebral palsy. Some investigators have suggested that this changes the clinical diagnosis of cerebral palsy and that these individuals should be removed from this diagnostic category. Cerebral palsy is a neurodevelopmental disorder diagnosed on clinical signs, not etiology. All nonprogressive permanent disorders of movement and posture attributed to disturbances that occurred in the developing fetal and infant brain can be described as “cerebral palsy.” This definition of cerebral palsy should not be changed, whatever the cause. Reasons include stability, utility and accuracy of cerebral palsy registers, direct access to services, financial and social support specifically offered to families with cerebral palsy, and community understanding of the clinical diagnosis. Other neurodevelopmental disorders, for example, epilepsy, have not changed the diagnosis when genomic causes are found. The clinical diagnosis of cerebral palsy should remain, should prompt appropriate genetic studies and can subsequently be subclassified by etiology.

Autism Spectrum Disorders (ASD) are heterogeneous neurodevelopmental disorders with considerably increased risk in male infants born preterm and with neonatal infection. Here we investigated the role of postnatal immune activation on hippocampal synaptopathology by targeting Reelin+ cells in mice with ASD-like behavior. C57/Bl6 mouse pups of both sexes received lipopolysaccharide (LPS, 1mg/kg) on postnatal day (P) 5. At P45, animal behavior was examined by marble burying and sociability test, followed by ex-vivo brain MRI diffusion kurtosis imaging (DKI). Hippocampal synaptogenesis, number and morphology of Reelin+ cells, and mRNA expression of trans-synaptic genes, including neurexin-3, neuroligin-1, and cell-adhesion molecule nectin-1 were analyzed at P12 and P45. Social withdrawal and increased stereotypic activities in males were related to increased mean diffusivity on MRI-DKI and overgrowth in hippocampus together with retention of long-thin immature synapses on apical dendrites, decreased volume and number of Reelin+ cells as well as reduced expression of trans-synaptic and cell-adhesion molecules. The study provides new insights into sex-dependent mechanisms that may underlie ASD-like behavior in males following PIA. We identify GABAergic interneurons as core components of dysmaturation of excitatory synapses in the hippocampus following postnatal infection and provide cellular and molecular substrates for the MRI findings with translational value.

High intakes of added sugar from soft drinks are associated with negative health outcomes such as the increased risk of gout and type 2 diabetes, weight gain and cardiovascular disease. Fruits are naturally high in sugars but their effect on cardiometabolic risk remains unknown. We examined the effect on cardiometabolic risk factors of consuming natural sugars from fruit or added sugars from sugar-sweetened soft drinks in overweight adults. Forty-eight healthy, overweight (BMI ≥ 28 kg/m2) men (n = 21) and women (n = 20) were randomized to either a fruit (n = 19) or sugar-sweetened soft drink (n = 22) intervention for 4 weeks. The fruit group received 6 items of fresh and dried fruit per day and the sugar-sweetened soft drink group received 955 ml of sugar-sweetened soft drink per day. The interventions were matched for both energy (fruit: 1,800 kJ/d; soft drink: 1,767 kJ/d) and fructose content (fruit: 51.8 g/d; soft drink: 51.7 g/d). The soft drink intervention provided 101 g total sugars, which was all added sugar and the fruit intervention provided 97 g total sugars, which were all natural sugars. Dietary intakes were otherwise ad libitum. Despite being asked to consume additional sugar (up to 1,800 additional kJ/d), there were no changes in weight, blood pressure or other cardiometabolic risk factors, except by uric acid, in any of the intervention groups. In conclusion, our findings do not provide any evidence that short-term regular intake of added sugars is linked to higher cardiometabolic risks, with exception of uric acid in overweight men. Public health interventions to prevent obesity and related diseases should focus on the quality of the whole diet rather than only focusing on reducing sugary drinks or sugar intakes.

The purpose of this case series was to evaluate the presence of low Energy Availability (EA) and its impact on components of Relative Energy Deficiency in Sport (RED-S) in a population of female collegiate runners. Seven female NCAA Division I athletes (age: 22.3 ± 1.5 yrs; height: 169.7 ± 5.7 cm; weight: 58.3 ± 4.1 kg) were tracked from August until February, covering the beginning (Pre XC), end (Post XC) of their competitive cross country season, and beginning of the following track season (Pre Track). The athletes were assessed for female athlete triad (Triad) risk, energy availability, body composition, resting metabolic rate (RMR), nutritional intake, and blood markers (including vitamin D, ferritin, and triiodothyronine (T3)). From Pre XC to Post XC there were no significant differences in body mass, fat free mass or body fat percentage. At Pre XC, mean EA was 31.6 ± 13.3 kcal/kg FFM∙d-1. From Post XC to Pre Track, there was a significant increase in body mass (59.1 ± 5.1 to 60.6 ± 5.7 kg, p-1, pvs 39.5 ± 12.2 ng·mL-1, p=0.047,d=-0.4), and a significant increase from Post XC to Pre Track (39.5 ± 12.2 vs. 48.1 ± 10.4 ng·mL-1, p=0.014,d=0.75). For ferritin, there was a trend towards a decrease from Pre XC to Post XC (24.2 ± 13.2 vs. 15.7 ± 8.8 ng·mL-1, p=0.07, d=-0.75), as well as a trend toward an increase from Post XC to Pre Track (15.7 ± 8.8 vs. 34.1 ± 18.0 ng·mL-1, p=0.08, d=1.3). No differences in T3 were observed across time points. Average Triad risk score was 2.3 ± 1.4. Notably, 5 of 7 athletes met criteria for moderate risk. Despite many athletes meeting criteria for low EA and having elevated Triad risk assessment scores, most were able to maintain body mass and RMR. One athlete suffered severe performance decline and a reduced RMR. Surprisingly, she was the only athlete above the recommended value for ferritin. Following increased nutritional intake and reduced training volume, her performance and RMR recovered. Changes in body mass and body composition were not indicative of the presence of other concerns associated with RED-S. This exploratory work serves as a guide for future, larger studies for tracking athletes, using RMR and nutritional biomarkers to assess RED-S.

Schizophrenia (SCZ) is a psychiatric disorder that can include symptoms of disorganized speech and thoughts with uncertain underlying mechanisms possibly linked to over‐activated microglia. In this study, we used brain samples from sixteen donors with SCZ and thirteen control donors to assess the differential activation of microglia by quantifying density and 3D reconstruction of microglia stained with ionized calcium‐binding adaptor molecule‐1 (Iba1). Our samples consisted of sections from the frontal, temporal, and cingulate cortical gray matter, subcortical white matter regions (SCWM), and included the anterior corpus callosum. In the first series of studies, we performed a density analysis followed by a spatial analysis to ascertain the microglial density, distribution, and soma size in SCZ brains. Second, we performed a series of morphological quantification techniques to investigate the arborization patterns of the microglia in SCZ. The results demonstrated an increase in microglia density in the cortical gray matter regions in SCZ cases, while in the SCWM, there was a significant increase in microglia density in the frontal and temporal, but not in the other brain regions of interest (ROIs). Spatial analysis using the “nearest neighbor” demonstrated that there was no effect in “clustering”, but there were shorter distances between microglia seen in the SCZ cases. The morphological measures showed that there was a region‐dependent increase in the microglia soma size in the SCZ cases while the Sholl analysis revealed a significant decrease in the microglia arborization in the SCZ cases across all the ROI’s studied. An in‐depth 3D reconstruction of microglia in Brodmann area 9 cortical region found that there was a significant association between age and reduced microglial arborization in the SCZ cases. This region‐dependent age association can help determine whether longitudinal changes in microglial activation across age are brain region‐dependent, which may point to potential therapeutic targets., Morphological alterations seen in postmortem brain samples of people with schizophrenia may indicate a shift towards increased activation. The anatomical data shown in this study demonstrates regional changes in microglia.

Background Neonatal encephalopathy often leads to lifelong disabilities with limited treatments currently available. The brain vasculature is an important factor in many neonatal neurological disorders but there is a lack of diagnostic tools to evaluate the brain vascular dysfunction of neonates in the clinical setting. Measurement of blood–brain barrier tight-junction (TJ) proteins have shown promise as biomarkers for brain injury in the adult. Here we tested the biomarker potential of tight-junctions in the context of neonatal brain injury. Methods The levels of TJ-proteins (occluding, claudin-5, and zonula occludens protein 1) in both blood plasma and cerebrospinal fluid (CSF) as well as blood–brain barrier function via 14C-sucrose (342 Da) and Evans blue extravasation were measured in a hypoxia/ischemia brain-injury model in neonatal rats. Results Time-dependent changes of occludin and claudin-5 levels could be measured in blood and CSF after hypoxia/ischemia with males generally having higher levels than females. The levels of claudin-5 in CSF correlated with the severity of the brain injury at 24 h post- hypoxia/ischemia. Simultaneously, we detected early increase in blood–brain barrier-permeability at 6 and 24 h after hypoxia/ischemia. Conclusions Levels of circulating claudin-5 and occludin are increased after hypoxic/ischemic brain injuries and blood–brain barrier-impairment and have promise as early biomarkers for cerebral vascular dysfunction and as a tool for risk assessment of neonatal brain injuries.

Objective/aim Growth-differentiation-factor 15 (GDF15) has been suggested to improve or protect beta cell function. During pregnancy, beta cell numbers and function increase to overcome the natural rise in insulin resistance during gestation. In this study, we longitudinally measured serum GDF15 levels during and after pregnancy in women of normal weight (NW) and in women with obesity (OB) and explored associations between GDF15 and changes in beta cell function by homeostatic model assessment (HOMA). Methods The cohort participants were 38 NW (BMI 22.3 ± 1.7) and 35 OB (BMI 35.8 ± 4.2). Blood was sampled and body composition measured at each trimester (T1, T2, and T3) and at 6, 12 and 18 months postpartum. Fasting glucose, insulin and GDF15 were measured, and HOMA for insulin resistance (HOMA-IR) and beta cell function (HOMA-B) determined. Results GDF15 levels increased significantly each trimester and were ~200-fold higher at T3 than in the nonpregnant postpartum state. GDF15 was higher in NW than OB during pregnancy, but was reversed after pregnancy with a significant interaction effect. GDF15 correlated inversely with BMI and fat-free mass at T3. Low GDF15 was associated with lower incidence of nausea and with carrying a male foetus. The pregnancy induced increase in GDF15 associated with increased HOMA-B in OB and with reduced fasting glucose in all women. Conclusion Large gestational upregulation of GDF15 levels may help increase insulin secretory function to overcome pregnancy-induced insulin resistance.

International audience; Abstract Background In utero exposure to Zika virus (ZIKV) is known to be associated with birth defects. The impact of in utero ZIKV exposure on neurodevelopmental outcomes in early childhood remains unclear. The objective of this study was to determine the impact of in utero ZIKV exposure on neurodevelopment at 24 months of age among toddlers who were born normocephalic to women who were pregnant during the 2016 ZIKV outbreak in French territories in the Americas. Methods We conducted a population-based mother-child cohort study of women whose pregnancies overlapped with the 2016 ZIKV epidemic in Guadeloupe, Martinique, and French Guiana. Infants were included in this analysis if maternal ZIKV infection during pregnancy could be determined, the newborn had a gestational age ≥ 35 weeks, there were no abnormal transfontanelle cerebral ultrasound findings after delivery or no abnormal ultrasound findings on the last ultrasound performed during the third trimester of the mother’s pregnancy, there was an absence of microcephaly at birth, and the parent completed the 24-month neurodevelopment assessment of the infant at 24 months (± 1 month) of age. ZIKV exposure of the toddler was determined by evidence of maternal ZIKV infection during pregnancy. Neurodevelopment assessments included the Ages and Stages Questionnaire (ASQ) for five dimensions of general development—communication, gross motor, fine motor, problem solving, and personal-social skills; the Modified Checklist for Autism on Toddlers (M-CHAT) for behavior; and the French MacArthur Inventory Scales (IFDC) for French language acquisition. Results Between June 2018 and August 2019, 156 toddlers with and 79 toddlers without in utero ZIKV exposure completed neurodevelopment assessments. Twenty-four (15.4%) ZIKV-exposed toddlers and 20 (25.3%) ZIKV-unexposed toddlers had an ASQ result below the reference − 2SD cut-off ( P = 0.10) for at least one of the five ASQ dimensions. Conclusion In one of the largest population-based cohorts of in utero ZIKV-exposed, normocephalic newborns to date, there were minimal differences apparent in neurodevelopment outcomes at 24 months of age compared to ZIKV-unexposed toddlers at 24 months of age. Trial registration ClinicalTrials.gov, NCT02810210 . Registered 20 June 2016.

Aim Growth differentiation factor 15 (GDF15) increases in serum during pregnancy to levels not seen in any other physiological state and is suggested to be involved in pregnancy-induced nausea, weight regulation and glucose metabolism. The main action of GDF15 is regulated through a receptor of the brainstem, i.e., through exposure of GDF15 in both blood and cerebrospinal fluid (CSF). The aim of the current study was to measure GDF15 in both CSF and serum during pregnancy, and to compare it longitudinally to non-pregnant levels. Methods Women were sampled at elective caesarean section (n = 45, BMI = 28.1±5.0) and were followed up 5 years after pregnancy (n = 25). GDF15, insulin and leptin were measured in CSF and serum. Additional measurements included plasma glucose, and serum adiponectin and Hs-CRP. Results GDF15 levels were higher during pregnancy compared with follow-up in both CSF (385±128 vs. 115±32 ng/l, PPPP = 0.98). Both CSF and serum GDF15 were highest in women carrying a female fetus (P Conclusion This, the first study to measure CSF GDF15 during pregnancy, demonstrated increased GDF15 levels in both serum and CSF during pregnancy. The results suggest that effects of GDF15 during pregnancy can be mediated by increases in both CSF and serum levels.

Germinal matrix hemorrhage (GMH) is a serious complication in extremely preterm infants associated with neurological deficits and mortality. The purpose of the present study was to develop and characterize a grade III and IV GMH model in postnatal day 5 (P5) rats, the equivalent of preterm human brain maturation. P5 Wistar rats were exposed to unilateral GMH through intracranial injection into the striatum close to the germinal matrix with 0.1, 0.2, or 0.3 U of collagenase VII. During 10 days following GMH induction, motor functions and body weight were assessed and brain tissue collected at P16. Animals were tested for anxiety, motor coordination and motor asymmetry on P22–26 and P36–40. Using immunohistochemical staining and neuropathological scoring we found that a collagenase dose of 0.3 U induced GMH. Neuropathological assessment revealed that the brain injury in the collagenase group was characterized by dilation of the ipsilateral ventricle combined with mild to severe cellular necrosis as well as mild to moderate atrophy at the levels of striatum and subcortical white matter, and to a lesser extent, hippocampus and cortex. Within 0.5 h post-collagenase injection there was clear bleeding at the site of injury, with progressive increase in iron and infiltration of neutrophils in the first 24 h, together with focal microglia activation. By P16, blood was no longer observed, although significant gray and white matter brain infarction persisted. Astrogliosis was also detected at this time-point. Animals exposed to GMH performed worse than controls in the negative geotaxis test and also opened their eyes with latency compared to control animals. At P40, GMH rats spent more time in the center of open field box and moved at higher speed compared to the controls, and continued to show ipsilateral injury in striatum and subcortical white matter. We have established a P5 rat model of collagenase-induced GMH for the study of preterm brain injury. Our results show that P5 rat pups exposed to GMH develop moderate brain injury affecting both gray and white matter associated with delayed eye opening and abnormal motor functions. These animals develop hyperactivity and show reduced anxiety in the juvenile stage.

Behaviors and disorders related to self-regulation, such as substance use, antisocial conduct, and ADHD, are collectively referred to asexternalizingand have a shared genetic liability. We applied a multivariate approach that leverages genetic correlations among externalizing traits for genome-wide association analyses. By pooling data from ~1.5 million people, our approach is statistically more powerful than single-trait analyses and identifies more than 500 genetic loci. The identified loci were enriched for genes expressed in the brain and related to nervous system development. A polygenic score constructed from our results captures variation in a broad range of behavioral and medical outcomes that were not part of our genome-wide analyses, including traits that until now lacked well-performing polygenic scores, such as opioid use disorder, suicide, HIV infections, criminal convictions, and unemployment. Our findings are consistent with the idea that persistent difficulties in self-regulation can be conceptualized as a neurodevelopmental condition.

Genome-wide association studies (GWASs) of the Alcohol Use Disorder Identification Test (AUDIT), a ten-item screener for alcohol use disorder (AUD), have elucidated novel loci for alcohol consumption and misuse. However, these studies also revealed that GWASs can be influenced by numerous biases (e.g., measurement error, selection bias), which have led to inconsistent genetic correlations between alcohol involvement and AUD, as well as paradoxically negative genetic correlations between alcohol involvement and psychiatric disorders/medical conditions. To explore these unexpected differences in genetic correlations, we conducted the first item-level and largest GWAS of AUDIT items (N=160,824), and applied a multivariate framework to mitigate previous biases. In doing so, we identified novel patterns of similarity (and dissimilarity) among the AUDIT items, and found evidence of a correlated two-factor structure at the genetic level (Consumption and Problems, rg=.80). Moreover, by applying empirically-derived weights to each of the AUDIT items, we constructed an aggregate measure of alcohol consumption that is strongly associated with alcohol dependence (rg=.67) and several other psychiatric disorders, and no longer positively associated with health and positive socioeconomic outcomes. Lastly, by performing polygenic analyses in three independent cohorts that differed in their ascertainment and prevalence of AUD, we identified novel genetic associations between alcohol consumption, alcohol misuse, and human health. Our work further emphasizes the value of AUDIT for both clinical and genetic studies of AUD, and the importance of using multivariate methods to study genetic associations that are more closely related to AUD.

Internalising symptoms in childhood and adolescence are as heritable as adult depression and anxiety, yet little is known of their molecular basis. This genome-wide association meta-analysis of internalising symptoms included repeated observations from 64,641 individuals, aged between 3 and 18. The N-weighted meta-analysis of overall internalising symptoms (INToverall) detected no genome-wide significant hits and showed low SNP heritability (1.66%, 95% confidence intervals 0.84-2.48%, Neffective=132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalising symptoms showing the highest heritability (5.63%, 95% confidence intervals 3.08-8.18%). Additive genetic effects on internalising symptoms appeared stable over age, with overlapping estimates of SNP heritability from early-childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the wellbeing spectrum (|rg|> 0.70), as well as with insomnia, loneliness, attention-deficit hyperactivity disorder, autism, and childhood aggression (range |rg|=0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa. The pattern of genetic correlations suggests that childhood and adolescent internalising symptoms share substantial genetic vulnerabilities with adult internalising disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalising symptoms over time and the high comorbidity amongst childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success.

Acute liver injury (ALI) is a highly destructive and potentially life-threatening condition, exacerbated by physical and psychological stress. The endocannabinoid system plays a key role in modulating stress and hepatic function. The aim of this study was to examine the development of acute liver injury in the genetically susceptible stress-sensitive Wistar-Kyoto (WKY) rat compared with normo-stress-sensitive Sprague Dawley (SD) rats, and associated changes in the endocannabinoid system. Administration of the hepatotoxin lipopolysaccharide/D-Galactosamine (LPS/GalN) resulted in marked liver injury in WKY, but not SD rats, with increased alanine aminotransferase (ALT), aspartate aminotransferase (AST) and glutamate dehydrogenase (GLDH) plasma levels, significant histopathological changes, increased hepatic pro-inflammatory cytokine expression and caspase-3 activity and expression and reduced Glutathione (GSH) activity. Furthermore, compared to SD controls, WKY rats display increased anandamide and 2-Arachidonoylglycerol levels concurrent with decreased expression of their metabolic enzymes and a decrease in cannabinoid (CB)1 receptor expression following LPS/GalN. CB1 antagonism with AM6545 or CB2 agonism with JWH133 did not alter LPS/GalN-induced liver injury in SD or WKY rats. These findings demonstrate exacerbation of acute liver injury induced by LPS/GalN in a stress-sensitive rat strain, with effects associated with alterations in the hepatic endocannabinoid system. Further studies are required to determine if the endocannabinoid system mediates or modulates the exacerbation of liver injury in this stress-sensitive rat strain. The authors would like to gratefully acknowledge funding received from the College of Medicine, Nursing and Health Sciences Postgraduate Research Scholarship, the Discipline of Physiology and the Research Office, National University of Ireland Galway peer-reviewed

Objective/aim Growth-differentiation-factor 15 (GDF15) has been suggested to improve beta-cell function. During pregnancy, beta-cell numbers and function increase to overcome the natural rise in insulin resistance. Here, we longitudinally measured serum GDF15 levels during and after pregnancy in women of normal-weight (NW) and in women with obesity (OB) and explored associations between GDF15 and changes in homeostatic model assessment for insulin resistance (HOMA-IR) and for beta-cell function (HOMA-B).Methods Fasting blood GDF15, glucose and insulin were measured and body composition determined at each trimester (T1, T2, and T3) and at 6, 12, and 18 months postpartum in 38 NW (BMI 22.3±1.7) and 35 OB (BMI 35.8±4.2). Results GDF15 levels increased each trimester and were ~200-fold higher at T3 than in the nonpregnant postpartum state. In T3, GDF15 was higher in NW than OB and correlated inversely with BMI and fat-free mass. GDF15 at T2 and T3 and the increases between trimesters associated with increased HOMA-B over the course of pregnancy. Increases in GDF15 either early or late in pregnancy were associated with a reduction in blood glucose between T2 and T3.Conclusion Large gestational upregulation of GDF15 levels may help increase insulin secretory function to overcome pregnancy-induced insulin resistance.

Background. Cancer cachexia and exacerbated fatigue represent two hallmarks in cancer patients, negatively impacting their exercise tolerance and ultimately their quality of life. However, the characterization of patients’ physical status and exercise tolerance and, most importantly, their evolution throughout cancer treatment may represent the first step in efficiently counteracting their development with prescribed and tailored exercise training. In this context, the aim of the PROTECT-01 study will be to investigate the evolution of physical status, from diagnosis to the end of first-line treatment, of patients with one of the three most common cancers (i.e. lung, breast, and colorectal). Methods. The PROTECT-01 cohort study will include 300 patients equally divided between lung, breast and colorectal cancer. Patients will perform a series of assessments at three visits throughout the treatment: 1) between the date of diagnosis and the start of treatment, 2) 8 weeks after the start of treatment, and 3) after the completion of first-line treatment or at the 6-month mark, whichever occurs first. For each of the three visits, subjective and objective fatigue, maximal voluntary force, body composition, cachexia, physical activity level, quality of life, respiratory function, overall physical performance and exercise tolerance will be assessed. Discussion. The present study is aimed at identifying the nature and severity of maladaptation related to exercise intolerance in the three most common cancers. Therefore, our results should contribute to the delineation of the needs of each group of patients and to the determination of the most valuable exercise interventions in order to counteract these maladaptations. This descriptive and comprehensive approach is a prerequisite in order to elaborate, through future interventional research projects, tailored exercise strategies to counteract specific symptoms that are potentially cancer-type dependent and, in fine, to improve the health and quality of life of cancer patients. Moreover, our concomitant focus on fatigue and cachexia will provide insightful information about two factors that may have substantial interaction but require further investigation. Ethics and Dissemination This prospective study has been approved by the national ethics committee (2019-A00848-49) and all subjects will provide written informed consent in accordance with the Declaration of Helsinki.

There is an important unmet need to improve long term outcomes of encephalopathy for preterm and term infants. Meta-analyses of large controlled trials suggest that maternal treatment with magnesium sulfate (MgSO4) is associated with a reduced risk of cerebral palsy and gross motor dysfunction after premature birth. However, to date, follow up to school age has found an apparent lack of long-term clinical benefit. Because of this inconsistency, it remains controversial whether MgSO4 offers sustained neuroprotection. We systematically reviewed preclinical and clinical studies reported from January 1 2010, to January 31 2020 to evaluate the most recent advances and knowledge gaps relating to the efficacy of MgSO4 for the treatment of perinatal brain injury. The outcomes of MgSO4 in preterm and term-equivalent animal models of perinatal encephalopathy were highly inconsistent between studies. None of the perinatal rodent studies that suggested benefit directly controlled body or brain temperature. The majority of the studies did not control for sex, study long term histological and functional outcomes or use pragmatic treatment regimens and many did not report controlling for potential study bias. Finally, most of the recent preterm or term human studies that tested the potential of MgSO4 for perinatal neuroprotection were relatively underpowered, but nevertheless, suggest that any improvements in neurodevelopment were at best modest or absent. On balance, these data suggest that further rigorous testing in translational preclinical models of perinatal encephalopathy is essential to ensure safety and best regimens for optimal preterm neuroprotection, and before further clinical trials of MgSO4 for perinatal encephalopathy at term are undertaken.

Fifteen million babies are born preterm every year and a significant number suffer from permanent neurological injuries linked to white matter injury (WMI). A chief cause of preterm birth itself and predictor of the severity of WMI is exposure to maternal-fetal infection-inflammation such as chorioamnionitis. There are no neurotherapeutics for this WMI. To affect this healthcare need, the repurposing of drugs with efficacy in other white matter injury models is an attractive strategy. As such, we tested the efficacy of GSK247246, an H3R antagonist/inverse agonist, in a model of inflammation-mediated WMI of the preterm born infant recapitulating the main clinical hallmarks of human brain injury, which are oligodendrocyte maturation arrest, microglial reactivity, and hypomyelination. WMI is induced by mimicking the effects of maternal-fetal infection-inflammation and setting up neuroinflammation. We induce this process at the time in the mouse when brain development is equivalent to the human third trimester; postnatal day (P)1 through to P5 with i.p. interleukin-1β (IL-1β) injections. We initiated GSK247246 treatment (i.p at 7mg/kg or 20mg/kg) after neuroinflammation was well established (on P6) and it was administered twice daily through to P10. Outcomes were assessed at P10 and P30 with gene and protein analysis. A low dose of GSK247246 (7 mg/kg) lead to a recovery in protein expression of markers of myelin (density of Myelin Basic Protein, MBP & Proteolipid Proteins, PLP) and a reduction in macro- and microgliosis (density of ionising adaptor protein, IBA1 & glial fibrillary acid protein, GFAP). Our results confirm the neurotherapeutic efficacy of targeting the H3R for WMI seen in a cuprizone model of multiple sclerosis and a recently reported clinical trial in relapsing-remitting multiple sclerosis patients. Further work is needed to develop a slow release strategy for this agent and test its efficacy in large animal models of preterm infant WMI.

Sexual assault is a troubling epidemic that plagues college campuses across the United States, and is often proceeded by drinking by the perpetrator and/or victim. The goal of this study was to examine the effect of level of intoxication, history of alcohol-related blackouts, and childhood sexual abuse (CSA) on the likelihood of being a victim or perpetrator of coercive sexual activities. Participants (N = 2,244) were part of a 6-year longitudinal study which explored alcohol use and associated behavioral risks during college. A subsample (N = 1,423) completed 30 days of daily diary surveys across four years of college. Participants provided daily reports of their alcohol consumption, sexual coercion perpetration, and sexual coercion victimization. Using hierarchical linear models, results indicated that increases in daily estimated blood alcohol concentration (eBAC) were associated with a greater likelihood of being a victim and a perpetrator of sexual coercion. In addition, main effects of CSA and history of blackouts predicted a greater likelihood of being coerced into sexual activity, but blackouts were not associated with being a perpetrator. A significant interaction between blackouts and event-level eBAC indicated that individuals with a history of blackouts had a greater likelihood of sexual coercion victimization relative to those without prior blackouts. Finally, having a history of blackouts and CSA was predictive of a lower likelihood of being a perpetrator of sexual coercion at higher eBACs relative to those without a history of blackouts. Thus, prevention efforts should integrate the impact of blackouts and CSA on sexual coercion victimization and perpetration. (PsycINFO Database Record

Central nervous system homeostasis is maintained by cellular barriers that protect the brain from external environmental changes and protect the CNS from harmful molecules and pathogens in the blood. Historically, for many years these barriers were thought of as immature, with limited functions, during brain development. In this review, we will present advances in the understanding of the barrier systems during development and evidence to show that in fact the barriers serve many important neurodevelopmental functions and that fetal and newborn brains are well protected. We will also discuss how ischaemic injury or systemic inflammation may breach the integrity of the barriers in the developing brain.

Marfan syndrome is characterized by manifestations in three systems: skeletal, ocular and cardiovascular. There are no publications of typical Marfan syndrome patients associated with craniosynostosis or hydrocephalus. There are a series of publications of the association between craniosynostosis and marfanoid habitus, which led to the description of new syndromes: Loeys-Dietz types IA, IIA, IB e IIB and Shprintzen-Goldberg. Among those syndromes, there are cases of hydrocephalus, but they are typically associated with craniosynostosis. We describe two cases of patients with marfanoid habitus associated with hydrocephalus without craniosynostosis. The first patient presented with skeletal malformations with arachnodactyly, camptodactyly, malar hypoplasia in association with interatrial shunt, gastroparesis, mild mental retardation and symptomatic hydrocephalus. The other patient presented with marfanoid habitus associated with mild cognitive deficit and symptomatic hydrocephalus. None of those patients had craniosynostosis. Many phenotypic characteristics our patients presented resemble the craniosynostosis-marfanoid habitus syndromes. The absence of craniosynostosis raises suspicion on the possibility of occurrence of those syndromes with atypical characteristics or a new syndrome not yet described. We believe that the description of these cases may enlighten this discussion.

GABRA2, the gene encoding the α2 subunit of the GABAA receptor, potentially plays a role in the etiology of problematic drinking, as GABRA2 genotype has been associated with subjective response to alcohol and other alcohol-related reward processes. The GABRA2 gene has also been associated with illicit drug use, but the extent to which associations with drug use are independent of associations with alcohol use remains unclear, partly because most previous research has used a cross-sectional design that cannot discriminate comorbidity at the between-person level and co-occurrence within-persons. The present study used a daily monitoring method that assessed the effects of GABRA2 variation on substance use as it occurred in the natural environment during emerging adulthood. Non-Hispanic European participants provided DNA samples and completed daily reports of alcohol and drug use for 1 month per year across 4 years (N = 28,263 unique observations of N = 318 participants). GABRA2 variants were associated with illicit drug use in both sober and intoxicated conditions. Moreover, the effect of GABRA2 variation on drug use was moderated by an individual's degree of intoxication. These findings are consistent with recent genetic and neuroscience research, and they suggest GABRA2 variation influences drug-seeking behavior through both alcohol-related and alcohol-independent pathways. (PsycINFO Database Record

To compare 12 weeks of exercise training at two intensities on oxidative stress, antioxidants and inflammatory biomarkers in patients with type 2 diabetes (T2D).Randomized trial.Thirty-six participants with T2D were randomized to complete either 12 weeks of treadmill based high-intensity interval training (HIIT) or moderate-intensity continuous training (MICT), followed by 40 weeks of home-based training at the same intensities. Plasma inflammation, oxidative stress and antioxidant biomarkers (total F2-isoprostanes, protein carbonyls, total antioxidant capacity, glutathione peroxidase activity, interleukin-10, interleukin-6, interleukin-8 and TNF-α) were measured at baseline, 12-weeks and 1-year.There were no significant changes (p0.05) in oxidative stress and inflammation biomarkers from baseline to 12-weeks in either intervention. A decrease in total antioxidant capacity in the MICT group from baseline to 1-year by 0.05mmol/L (p=0.05) was observed. There was a significant difference (p0.05) when groups were separated by sex with females in the MICT group having a 22.1% (p0.05) decrease in protein carbonyls from baseline to 1-year.HIIT and MICT had no acute effect on oxidative stress and inflammatory biomarkers in patients with T2D.

See related article, p 2341 Stroke risk and poststroke disability have steadily decreased in the United States over the past 2 decades because of improved prevention and access to reperfusion therapies for acute ischemic stroke, such as tPA (tissue-type plasminogen activator; alteplase) and endovascular thrombectomy. Despite the efficacy and safety of thrombolysis and thrombectomy, not all patients who receive the treatment improve to full, independent recovery, and most patients are ineligible for treatment. Additionally, there are no efficacious treatments to improve long-term outcomes for patients after the acute phase of ischemic stroke or to reduce brain injury induced by acute intracerebral hemorrhage. Therefore, development of new therapies for both acute and chronic stroke is sorely needed. Stroke occurs because of a variety of vascular pathologies and injury mechanisms, some of which are difficult to model in animals. With the exception of reperfusion therapy, preclinical research end points do not generally reflect clinical outcomes. Pharmacodynamics, pharmacokinetics, and target engagement in the human brain need to be further developed and optimized for stroke interventions so that drug level in brain tissue, time to initiation, and duration of treatment can be accurately measured in clinical trials. Many variables, such as heterogeneity of vascular pathologies, patient demographics, and a host of comorbid conditions, as well as the lack of validated biomarkers to stratify patient populations, limit the ability of typical stroke clinical trials to detect a treatment effect. To address these gaps, the National Institute of Neurological Disorders and Stroke organized and sponsored the workshop Translational Stroke Research: Vision and Opportunities, which was held in Bethesda, Maryland, on November 1 to 2, 2016. The workshop gathered over 180 registered participants from academia, industry, the Food and Drug Administration, and other public and private funding agencies. …

Background: High-intensity interval training (HIIT) is superior to moderate-intensity continuous training (MICT) at improving cardiometabolic risk. However, the optimal volume of HIIT to reduce the severity of the metabolic syndrome (MetS) has yet to be investigated. The aim of this study was to examine the impact of different volumes of HIIT and MICT on MetS severity (MetS z-score). Methods: This was a substudy of the “Exercise in prevention of Metabolic Syndrome” (EX-MET) multicenter trial, reporting data collected at the Brisbane site. Ninety-nine adults diagnosed with MetS were randomized to one of the following 16-week interventions: (1) MICT [n = 34, 30 min at 60%–70% heart rate (HR) peak/session, 150 min/week]; (2) 4HIIT (n = 34, 4 × 4 min bouts at 85%–95% HR peak, interspersed with 3 min active recovery at 50%–70% HR peak, 114 min/week); or (3) 1HIIT (n = 31, 1 × 4 min bout at 85%–95% HR peak, 51 min/week). Z-scores were derived from levels of MetS risk factors before and after the intervention. Results: Eighty-one participants completed post-testing (MICT, n = 26; 4HIIT, n = 28, 1HIIT, n = 27). After excluding 16 participants who had a change in medication dosage or type during the intervention, a total of 65 participants were included in the analysis [MICT, n = 22, age 55 ± 10 years, body mass index (BMI) 32 ± 6 kg/m; 4HIIT, n = 22, 56 ± 10 years, 35 ± 9 kg/m2; 1HIIT, n = 21, 57 ± 8 years, 32 ± 5 kg/m). MetS severity reduced following all interventions (pre- to post-MetS z-score: MICT, 1.80 ± 1.93 to 0.90 ± 1.93; 4HIIT, 2.75 ± 2.56 to 2.17 ± 2.71; 1HIIT, 2.48 ± 3.38 to 0.84 ± 2.98), with no significant differences between groups. There were no reported adverse events that were directly related to the exercise interventions. Conclusions: Low-volume HIIT (51 min/week) was as effective as high-volume HIIT (114 min/week) and MICT (150 min/week) in ameliorating MetS severity.

Preterm infants are highly susceptible to late-onset sepsis (LOS) and necrotizing enterocolitis (NEC), but disease pathogenesis and specific diagnostic markers are lacking. Circulating cell-free DNA (cfDNA) and immune cell-derived proteins are involved in multiple immune diseases in adults but have not been investigated in preterm neonates. We explored the relation of circulating neutrophil-associated proteins and cfDNA to LOS and/or NEC. Using a clinically relevant preterm pig model of spontaneous LOS and NEC development, we investigated neutrophil-associated proteins and cfDNA in plasma, together with cytokines in gut tissues. The changes in cfDNA levels were further studied in preterm pigs and neonatal mice with induced sepsis, and in preterm infants with or without LOS and/or NEC. Fifteen of 114 preterm pigs spontaneously developed both LOS and NEC, and they showed increased intestinal levels of IL-6 and IL-1β and plasma levels of cfDNA, neutrophil-associated proteins, and proteins involved in platelet-neutrophil interaction during systemic inflammation. The abundance of neutrophil-associated proteins highly correlated with cfDNA levels. Further, Staphylococcus epidermidis challenge of neonatal mice and preterm pigs increased plasma cfDNA levels and bacterial accumulation in the spleen. In infants, plasma cfDNA levels were elevated at LOS diagnosis and 1–6 d before NEC. In conclusion, elevated levels of plasma cfDNA and neutrophil proteins are associated with LOS and NEC diagnosis.