Prevalence and Psychiatric Correlates of Illicit Substance Use in UK Undergraduate Students.

This study examined the prevalence of illegal drug use in UK students and motivators behind such behavior. Additionally, we explored possible relationships between substance use, psychosocial motivators, and psychiatric distress. A group (n = 543) of students completed online measures of substance use, anxiety, depression, perceived stress, and insomnia. A series of reasons behind their use were ranked based on importance. Reported cannabis, cocaine, nitrous oxide, ketamine, and MDMA use were most prevalent based on lifetime, past year, and month assessments. The experience of anxiety, depression, perceived stress, and insomnia were related to increased reports of substance use. Poor self-confidence and self-medication were key motivators of illicit drug use in those presenting greater psychiatric distress. These outcomes add to the sparse body of literature concerning illicit substance use in relation to psychiatric distress amongst UK students. Furthermore, we provided novel insight into the psychosocial motivators of such use.

Association between intergenerational violence exposure and maternal age of menopause.

OBJECTIVE: To investigate whether maternal violence exposure personally and through her child is associated with an earlier age of menopause, controlling for covariates. METHODS: Analyses used merged data from two related sources. Although mothers (n = 1,466) were interviewed in 1995 and then 20 years later (2015-17), their children were interviewed in the National Longitudinal Study of Adolescent to Adult Health repeatedly (Waves 1-4, 1994/5 to 2008-2009). Mothers reported their own age of menopause, and mothers and adolescents each reported their own exposure to violence as children and adults. RESULTS: A mother's own childhood physical abuse (b = -1.60, P < .05) and her child's sexual abuse (b = -1.39, P < .01) both were associated with an earlier age of menopause. Mothers who were physically abused in childhood and have a child who experienced regular sexual abuse reached menopause 8.78 years earlier than mothers without a history of personal abuse or abuse of their child. CONCLUSIONS: Our study is the first to find that age of natural menopause is associated with intergenerational violence exposures.

A Comparative Assessment Study of Known Small-molecule GPVI Modulators.

The GPVI platelet receptor was recently validated as a safe antiplatelet target for the treatment of thrombosis using several peptidic modulators. In contrast, few weakly potent small-molecule GPVI antagonists have been reported. Those that have been published often lack evidence for target engagement, and their biological efficacy cannot be compared because of the natural donor variability associated with the assays implemented. Herein, we present the first side-by-side assessment of the reported GPVI small-molecule modulators. We have characterized their functional activities on platelet activation and aggregation using flow cytometry as well as light transmission and electrical impedance aggregometry. We also utilized microscale thermophoresis (MST) and saturation transfer difference (STD) NMR to validate GPVI binding and have used this along with molecular modeling to suggest potential binding interactions. We conclude that of the compounds examined, losartan and compound 5 are currently the most viable GPVI modulators.

Transfer to the clinic: refining forward programming of hPSCs to megakaryocytes for platelet production in bioreactors.

The production of in vitro-derived platelets has great potential for transfusion medicine. Here, we build on our experience in the forward programming (FoP) of human pluripotent stem cells (hPSCs) to megakaryocytes (MKs) and address several aspects of the complex challenges to bring this technology to the bedside. We first identify clinical-grade hPSC lines that generate MKs efficiently. We design a bespoke media to maximize both production and maturity of MKs and improve platelet output. Crucially, we transition the lentiviral-based FoP of hPSCs to a nonviral inducible system. We also show how small molecules promote a definitive hematopoiesis phenotype during the differentiation process, thereby increasing the quality of the final product. Finally, we generate platelets using a bioreactor designed to reproduce the physical cues that promote platelet production in the bone marrow. We show that these platelets are able to contribute to both thrombus formation in vitro and have a hemostatic effect in thrombocytopenic mice in vivo.

Progress toward a Glycoprotein VI Modulator for the Treatment of Thrombosis.

Pathogenic thrombus formation accounts for the etiology of many serious conditions including myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism. Despite the development of numerous anticoagulants and antiplatelet agents, the mortality rate associated with these diseases remains high. In recent years, however, significant epidemiological evidence and clinical models have emerged to suggest that modulation of the glycoprotein VI (GPVI) platelet receptor could be harnessed as a novel antiplatelet strategy. As such, many peptidic agents have been described in the past decade, while more recent efforts have focused on the development of small molecule modulators. Herein the rationale for targeting GPVI is summarized and the published GPVI modulators are reviewed, with particular focus on small molecules. A qualitative pharmacophore hypothesis for small molecule ligands at GPVI is also presented.

A tale half told: State exclusionary and inclusionary regimes, incarceration of fathers, and the educational attainment of children.

Paternal incarceration leads to educational disparities among children who are innocent of their fathers' crimes. The scale and concentration of mass paternal incarceration thus harms millions of innocent American children. Current individuallevel analyses neglect the contribution of macro-level variation in responses of punitive state regimes to this social problem. We hypothesize that state as well as individual level investment in exclusionary paternal incarceration diminishes the educational attainment of children, although state inclusionary investment in welfare and education can offset some - and could potentially offset more - of this harm. Understanding intergenerational educational attainment therefore requires individual- and contextuallevel analyses. We use Hierarchical Generalized Linear Models to analyze the National Longitudinal Survey of Adolescent to Adult Health. Disparities in postsecondary educational outcomes are especially detrimental for children of incarcerated fathers located in state regimes with high levels of paternal incarceration and concentrated disadvantage. This has important implications for intergenerational occupational and status attainment.

Imprisonment, opioids and health care reform: The failure to reach a high-risk population.

The 2014 National Research Council report on American incarceration optimistically anticipated the Affordable Care Act (ACA) would be "a turning point in the nation's health care, and … will provide unprecedented access to care for many people being released from correctional facilities." However, the ACA was not designed to proactively respond to risks associated with prisoner re-entry into society. Our overarching hypothesis is that unmet health needs among previously incarcerated adults can be more fully understood by analyzing how un-prescribed use of drugs, such as opioids, is associated with economic and health problems and health care un-insurance that in turn results in exclusion from needed health care services. Using several waves of the National Longitudinal Study of Adolescent to Adult Health conducted before and after passage and implementation of ACA, our analysis indicates that the above risk factors nearly fully mediate the association between previous incarceration and failure to receive needed health care. We argue that these factors are likely intensified by a reactive approach to health care reform that not only fails to cover many former prisoners, but also is lacking in sufficient outreach programming, and as such is insufficient for adults with health problems and limited economic resources - especially those using un-prescribed opioids. Future work should address the capacity of more proactively organized public health programs to expand coverage to previously incarcerated populations - including un-prescribed opioid users - and thereby reduce their health risks and vulnerability to repeated exposure to law enforcement surveillance and criminal punishment.

Remodeling of Bone Marrow Hematopoietic Stem Cell Niches Promotes Myeloid Cell Expansion during Premature or Physiological Aging.

Hematopoietic stem cells (HSCs) residing in the bone marrow (BM) accumulate during aging but are functionally impaired. However, the role of HSC-intrinsic and -extrinsic aging mechanisms remains debated. Megakaryocytes promote quiescence of neighboring HSCs. Nonetheless, whether megakaryocyte-HSC interactions change during pathological/natural aging is unclear. Premature aging in Hutchinson-Gilford progeria syndrome recapitulates physiological aging features, but whether these arise from altered stem or niche cells is unknown. Here, we show that the BM microenvironment promotes myelopoiesis in premature/physiological aging. During physiological aging, HSC-supporting niches decrease near bone but expand further from bone. Increased BM noradrenergic innervation promotes ß2-adrenergic-receptor(AR)-interleukin-6-dependent megakaryopoiesis. Reduced ß3-AR-Nos1 activity correlates with decreased endosteal niches and megakaryocyte apposition to sinusoids. However, chronic treatment of progeroid mice with ß3-AR agonist decreases premature myeloid and HSC expansion and restores the proximal association of HSCs to megakaryocytes. Therefore, normal/premature aging of BM niches promotes myeloid expansion and can be improved by targeting the microenvironment.

Flow cytometry for near-patient testing in premature neonates reveals variation in platelet function: a novel approach to guide platelet transfusion.

BACKGROUND: Neonatal haemorrhaging is often co-observed with thrombocytopenia; however, no evidence of a causal relationship with low platelet count has been reported. Regardless, the administration of a platelet transfusion is often based upon this parameter. Accurate measurement of platelet function in small volumes of adult blood samples by flow cytometry is well established and we propose that the use of the same technology could provide complementary information to guide the administration of platelet transfusions in premature neonates. METHODS: In 28 neonates born at 27-41 weeks gestation, platelet function after stimulation agonists was measured using fibrinogen binding and P-selectin expression (a marker of degranulation). RESULTS: Platelets of neonates with gestation of ≤36 weeks (n = 20) showed reduced fibrinogen binding and degranulation with ADP, and reduced degranulation with CRP-XL. Degranulation Scores of 7837 ± 5548, 22,408 ± 5301 and 53,131 ± 12,102 (mean ± SEM) identified significant differences between three groups: <29, 29-36 and >36 weeks gestation). Fibrinogen binding and degranulation responses to ADP were significantly reduced in suspected septic neonates (n = 6) and the Fibrinogen Binding scores clearly separated the septic and healthy group (88.2 ± 10.3 vs 38.6 ± 12.2, P = 0.03). CONCLUSIONS: Flow cytometric measurement of platelet function identified clinically different neonatal groups and may eventually contribute to assessment of neonates requiring platelet transfusion.

Structurally graduated collagen scaffolds applied to the ex vivo generation of platelets from human pluripotent stem cell-derived megakaryocytes: Enhancing production and purity.

Platelet transfusions are a key treatment option for a range of life threatening conditions including cancer, chemotherapy and surgery. Efficient ex vivo systems to generate donor independent platelets in clinically relevant numbers could provide a useful substitute. Large quantities of megakaryocytes (MKs) can be produced from human pluripotent stem cells, but in 2D culture the ratio of platelets harvested from MK cells has been limited and restricts production rate. The development of biomaterial cell supports that replicate vital hematopoietic micro-environment cues are one strategy that may increase in vitro platelet production rates from iPS derived Megakaryocyte cells. In this paper, we present the results obtained generating, simulating and using a novel structurally-graded collagen scaffold within a flow bioreactor system seeded with programmed stem cells. Theoretical analysis of porosity using micro-computed tomography analysis and synthetic micro-particle filtration provided a predictive tool to tailor cell distribution throughout the material. When used with MK programmed stem cells the graded scaffolds influenced cell location while maintaining the ability to continuously release metabolically active CD41 + CD42 + functional platelets. This scaffold design and novel fabrication technique offers a significant advance in understanding the influence of scaffold architectures on cell seeding, retention and platelet production.

Maternal imprisonment, economic marginality, and unmet health needs in early adulthood.

There is relatively little research on access to the health care needed by children whose mothers have been incarcerated, and even fewer studies of how effects of lack of access continue and cumulate as these children transition from living with parents, parent surrogates, or foster care into adulthood. We find in a nationally representative U.S. panel study (n=9418 participants from 1995 to 2007-2008 in the National Longitudinal Study of Adolescent and Adult Health) that young adult children of incarcerated mothers are less likely to receive the health care they need. These effects hold in models that take into account covariates and receipt of health care in the past, a useful control for unmeasured heterogeneity. In this analysis for 2007-2008, economic marginality mediates maternal incarceration on young adult unmet health care needs. Health insurance mediates a smaller portion of this effect. The findings of this research provide important bench marks for assessing the effects of the 2010 passage and the 2013 implementation of the Affordable Care Act [ACA], as well as prospective efforts to change or repeal the ACA.

Leukotriene E4 is a full functional agonist for human cysteinyl leukotriene type 1 receptor-dependent gene expression.

Leukotriene E4 (LTE4) the most stable of the cysteinyl leukotrienes (cysLTs) binds poorly to classical type 1 (CysLT1) and 2 (CysLT2) receptors although it induces potent responses in human airways in vivo, such as bronchoconstriction, airway hyperresponsiveness and inflammatory cell influx suggesting the presence of a novel receptor that preferentially responds to LTE4. To identify such a receptor two human mast cell lines, LAD2 and LUVA, were selected that differentially responded to LTE4 when analysed by intracellular signalling and gene expression. Comparative transcriptome analysis and recombinant gene overexpression experiments revealed CysLT1 as a receptor responsible for potent LTE4-induced response in LAD2 but not in LUVA cells, an observation confirmed further by gene knockdown and selective inhibitors. Lentiviral overexpression of CysLT1 in LUVA cells augmented intracellular calcium signalling induced by LTE4 but did not restore full agonist responses at the gene expression level. Our data support a model where both an increased expression of Gαq-coupled CysLT1, and sustained intracellular calcium mobilisation and extracellular signal-regulated kinase (Erk) activation, are required for LTE4-mediated regulation of gene expression in human cells. Our study shows for the first time that CysLT1 expression is critically important for responsiveness to LTE4 within a human cell system.

Children's exposure to community and war violence and mental health in four African countries.

In this article we review the mental health consequences of children's exposure to community and war violence (ETV) in four African countries: South Africa, Sierra Leone, Gambia and Rwanda. A focus on Africa is particularly pressing because of children's high levels of community and war ETV in countries therein. Regions of Africa present important macro-contexts for understanding children's various types of violence exposure amidst war and economic disadvantage. Findings of the review across 20 quantitative studies from 2004 to 2015 indicate consistent associations between exposure to war and community violence and children's symptoms of Post-traumatic Stress disorder (PTSD), depression, and aggression. School climate and family support mitigate these ETV influences upon children: however, more research is needed on the buffering effects of such resources. The effects of war violence are mediated by perceived discrimination in communities post-conflict. We integrate findings across studies to synthesize knowledge on children's ETV in Africa around a model of its correlates, mediators, and moderators in relation to mental health. Emerging research points to avenues for prevention and future inquiry.

Human-specific epigenetic variation in the immunological Leukotriene B4 Receptor (LTB4R/BLT1) implicated in common inflammatory diseases.

BACKGROUND: Common human diseases are caused by the complex interplay of genetic susceptibility as well as environmental factors. Due to the environment's influence on the epigenome, and therefore genome function, as well as conversely the genome's facilitative effect on the epigenome, analysis of this level of regulation may increase our knowledge of disease pathogenesis. METHODS: In order to identify human-specific epigenetic influences, we have performed a novel genome-wide DNA methylation analysis comparing human, chimpanzee and rhesus macaque. RESULTS: We have identified that the immunological Leukotriene B4 receptor (LTB4R, BLT1 receptor) is the most epigenetically divergent human gene in peripheral blood in comparison with other primates. This difference is due to the co-ordinated active state of human-specific hypomethylation in the promoter and human-specific increased gene body methylation. This gene is significant in innate immunity and the LTB4/LTB4R pathway is involved in the pathogenesis of the spectrum of human inflammatory diseases. This finding was confirmed by additional neutrophil-only DNA methylome and lymphoblastoid H3K4me3 chromatin comparative data. Additionally we show through functional analysis that this receptor has increased expression and a higher response to the LTB4 ligand in human versus rhesus macaque peripheral blood mononuclear cells. Genome-wide we also find human species-specific differentially methylated regions (human s-DMRs) are more prevalent in CpG island shores than within the islands themselves, and within the latter are associated with the CTCF motif. CONCLUSIONS: This result further emphasises the exclusive nature of the human immunological system, its divergent adaptation even from very closely related primates, and the power of comparative epigenomics to identify and understand human uniqueness.

Maternal and paternal imprisonment in the stress process.

Parental incarceration is now prevalent in community samples (e.g., with 11% of children reporting paternal imprisonment and 3% reporting maternal imprisonment in a national sample), pointing to a potentially important childhood trauma that should be included in work on contemporary childhood stressors in this era of mass incarceration. This paper investigates the influences of maternal and paternal imprisonment on changes in young adult mental health using a nationally representative sample. We assess four perspectives-gendered loss, same-sex role model, intergenerational stress, and maternal salience - on the joint influences of maternal and paternal incarceration within the broader stress process paradigm. The results generalize support for a gendered loss perspective developed in work on parental death and an early small study of parental incarceration. This pattern reveals maternal incarceration increases depressive symptoms while paternal incarceration increases substance role problems. Chronicity of parental imprisonment and its timing are also influential. Analyses further specify a vulnerability of male and minority young adults to high levels of mental health problems following maternal and paternal incarceration in adolescence.

Characterisation of P2Y(12) receptor responsiveness to cysteinyl leukotrienes.

Leukotriene E4 (LTE4), the most stable of the cysteinyl leukotrienes (cysLTs), binds poorly to classical type 1 and 2 cysLT receptors although in asthmatic individuals it may potently induce bronchial constriction, airway hyperresponsiveness and inflammatory cell influx to the lung. A recent study has suggested that the purinergic receptor P2Y12 is required for LTE4 mediated pulmonary inflammation in a mouse model of asthma and signals in response to cysLTs. The aim of the study was to characterise the responsiveness of human P2Y12 to cysteinyl leukotrienes. Models of human CysLT1, CysLT2 and P2Y12 overexpressed in HEK293, CHO cells and human platelets were used and responsiveness to different agonists was measured using intracellular calcium, cAMP and ß-arrestin recruitment assays. CysLTs induced concentration dependent calcium mobilisation in cells overexpressing CysLT1 and CysLT2 but failed to induce any calcium response in cells expressing P2Y12 or P2Y12+ Gα16. In contrast, selective P2Y12 agonists ADP and 2-MeS-ADP induced specific calcium flux in cells expressing P2Y12+ Gα16. Similarly, specific response to 2-MeS-ADP, but not to cysLTs was also observed in cells expressing P2Y12 when intracellular cAMP and ß-arrestin signalling were analysed. Platelets were used as a model of human primary cells expressing P2Y12 to analyse potential signalling and cell activation through P2Y12 receptor or receptor heterodimers but no specific LTE4 responses were observed. These results show that LTE4 as well as other cysLTs do not activate intracellular signalling acting through P2Y12 and suggest that another LTE4 specific receptor has yet to be identified.

Neighborhood, family and individual influences on school physical victimization.

Few studies on the correlates of school violence include school and neighborhood influences. We use ecological systems theory and social disorganization theory to simultaneously incorporate neighborhood (e.g., concentrated poverty, residential instability, and immigrant concentration), school, family, and individual predictors of physical school victimization longitudinally among a large socio-economically and ethnically diverse (49 % Hispanic; 34 % African American) sample of 6 and 9 year olds (49 % female) from the Project on Human Development in Chicago Neighborhoods. These children were followed up at Wave II at ages 8 and 11 (n = 1,425). Results of Hierarchical Generalized Linear Models reveal neighborhood residential instability increases school victimization net of family and individual correlates. Furthermore, cross-level interactions were also supported where residential family mobility has a stronger risk influence in areas of high residential instability. Also, the influence of residential family mobility is decreased in areas with higher levels of immigrant concentration. We also found cross-context connections where parent-to-child aggression in the home is connected to a higher risk of victimization at school. The role of neighborhood and family residential instability on victimization warrants further research.

Associations between menarcheal timing and behavioral developmental trajectories for girls from age 6 to age 15.

Substantial evidence from cross-sectional and short time-span longitudinal studies exists about negative associations between early pubertal maturation on a number of psychological outcomes. The objective of the present study was to assess the association between early maturation and developmental trajectories of social skills and internalizing and externalizing problems in girls from grades 1 through 9, including pre- and post-pubertal periods. The sample came from the NICHD Study of Early Child Care and Youth Development and included 398 Caucasian and 60 African American girls. Multilevel modeling revealed early maturing Caucasian girls were at risk for higher internalizing and externalizing problems and experiencing higher levels of problems pre-pubertally. African American youth had lower social skills and internalizing problems with no group differences due to early pubertal development. Findings are discussed in light of literature on continuity of girls' psychosocial development before and during the pubertal transition.

Toward a stress process model of children's exposure to physical family and community violence.

Theoretically informed models are required to further the comprehensive understanding of children's ETV. We draw on the stress process paradigm to forward an overall conceptual model of ETV (ETV) in childhood and adolescence. Around this conceptual model, we synthesize research in four dominant areas of the literature which are detailed but often disconnected including: (1) exposure to three forms of physical violence (e.g., child physical maltreatment, interparental violence, and community ETV); (2) the multilevel correlates and causes of ETV (e.g., neighborhood characteristics including concentrated disadvantage; family characteristics including socio-economic status and family stressors); (3) a range of consequences of ETV (e.g., internalizing and externalizing mental health problems, role transitions, and academic outcomes); and (4) multilevel and cross domain mediators and moderators of ETV influences (e.g., school and community factors, family social support, and individual coping resources). We highlight the range of interconnected processes through which violence exposures may influence children and suggest opportunities for prevention and intervention. We further identify needed future research on children's ETV including coping resources as well as research on cumulative contributions of violence exposure, violence exposure modifications, curvilinearity, and timing of exposure.

Growing up fast: stress exposure and subjective "weathering" in emerging adulthood.

We examine "subjective weathering" among females entering adulthood, using three waves of a national study. Subjective weathering is a social psychological component of aging that is associated with "physical weathering" previously observed in research on physical health. We examine the influence of stressors from childhood and adolescence on subjective weathering and depressive symptoms in emerging adulthood. Childhood abuse is associated with early menarche, as anticipated in research on physical weathering. Early menarche and child abuse are in turn associated with intimate partner violence exposure in adolescence. Both early menarche and intimate partner violence are associated with early parenthood and diminish the likelihood of high school graduation. These experiences culminate in subjective weathering associated with depressive symptoms in emerging adulthood. Our findings connect physical and subjective weathering within the stress process paradigm.