Faculty Bibliography

Maternal prenatal stress influences offspring neurodevelopment and birth outcomes including the ratio of males to females born; however, there is limited understanding of what types of stress matter, and for whom. Using a data-driven approach with 27 variables from questionnaires, ambulatory diaries, and physical assessments collected early in the singleton pregnancies of 187 women, 3 latent profiles of maternal prenatal stress emerged that were differentially associated with sex at birth, birth outcomes, and fetal neurodevelopment. Most women (66.8%) were in the healthy group (HG); 17.1% were in the psychologically stressed group (PSYG), evidencing clinically meaningful elevations in perceived stress, depression, and anxiety; and 16% were in the physically stressed group (PHSG) with relatively higher ambulatory blood pressure and increased caloric intake. The population normative male:female secondary sex ratio (105:100) was lower in the PSYG (2:3) and PHSG (4:9), and higher in the HG (23:18), consistent with research showing diminished male births in maternal stress contexts. PHSG versus HG infants were born 1.5 wk earlier (P < 0.05) with 22% compared to 5% born preterm. PHSG versus HG fetuses had decreased fetal heart rate-movement coupling (P < 0.05), which may indicate slower central nervous system development, and PSYG versus PHSG fetuses had more birth complications, consistent with previous findings among offspring of women with psychiatric illness. Social support most strongly differentiated the HG, PSYG, and PHSG groups, and higher social support was associated with increased odds of male versus female births. Stress phenotypes in pregnant women are associated with male vulnerability and poor fetal outcomes.

The sparse activity of hippocampal dentate gyrus (DG) granule cells (GCs) is thought to be critical for cognition and behavior, whereas excessive DG activity may contribute to disorders such as temporal lobe epilepsy (TLE). Glutamatergic mossy cells (MCs) of the DG are potentially critical to normal and pathological functions of the DG because they can regulate GC activity through innervation of GCs or indirectly through GABAergic neurons. Here, we test the hypothesis that MC excitation of GCs is normally weak, but under pathological conditions, MC excitation of GCs is dramatically strengthened. We show that selectively inhibiting MCs during severe seizures reduced manifestations of those seizures, hippocampal injury, and chronic epilepsy. In contrast, selectively activating MCs was pro-convulsant. Mechanistic in vitro studies using optogenetics further demonstrated the unanticipated ability of MC axons to excite GCs under pathological conditions. These results demonstrate an excitatory and epileptogenic effect of MCs in the DG.

OBJECTIVE/UNASSIGNED:This cross-sectional study examined the relationship between antipsychotic medication adherence and preventable diabetes-related hospitalizations for individuals with diabetes and schizophrenia. METHODS/UNASSIGNED:Hospitalizations related to diabetes, an ambulatory care sensitive condition, were assessed among Medicaid recipients in New York State with comorbid diabetes and schizophrenia (N=14,365) for three levels of antipsychotic medication adherence: very low to no engagement (two or fewer prescriptions or none in first 6 months), moderate to low adherence, and adherent (proportion of days covered ≥80%). RESULTS/UNASSIGNED:Rates of preventable diabetes hospitalization were highest among individuals with very low to no engagement in antipsychotic treatment (4.7%), followed by those with moderate to low adherence (3.3%). Diabetes hospitalizations among adherent individuals were comparable with those of the total diabetes population (both 2.0%). The odds of a preventable diabetes hospitalization were significantly higher among individuals with very low to no engagement in antipsychotic treatment (adjusted odds ratio [AOR]=2.42) and among those with moderate to low adherence (AOR=1.57) than among adherent individuals. Black individuals were also at increased risk of a preventable diabetes hospitalization after the analyses adjusted for antipsychotic adherence and other variables (AOR=1.38). CONCLUSIONS/UNASSIGNED:This study indicates a relationship between antipsychotic adherence and improved diabetes outcomes among individuals with schizophrenia. Engagement in mental health treatment may be a critical path toward improving health disparities for individuals with schizophrenia. Individuals with very low to no engagement were a particularly vulnerable group, and the exclusion of persons with less than two prescriptions from research and quality measures should be revisited.

Umbilical cord blood transplantation (UCBT) is an alternative for patients who need hematopoietic stem cell transplant (HSCT), but lack HLA-matched adult donors. Rabbit anti-thymoglobulin (ATG) has been used in UCBT conditioning to achieve T cell depletion, but ATG-induced immunosuppression is associated with delayed immune reconstitution, increased infectious complications and higher non-relapse mortality. In a clinical trial of reduced intensity double-unit UCBT (dUCBT), we substituted low dose total body irradiation (TBI) for ATG to determine whether dUCBT without ATG would alter kinetics and quality of immune reconstitution. Thirty-one patients with hematopoietic malignancies and a median age of 58 yr were treated with Flu/Mel/TBI, followed by dUCBT and GVHD prophylaxis with tacrolimus and sirolimus. We examined reconstitution of immune cell populations, thymic regeneration by quantifying T cell receptor excision circles (TREC) and serum cytokines (IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IFN-gamma, TNF-alpha, IL-12p70, GM-CSF) using the LUNARISTM Human 11-Plex Cytokine BiochipXX from AYOXXA Biosystems. Assessments were done prior to and at 1, 2, 3, 6, 12 and 24 months after dUCBT. Results are based on 28 evaluable patients. The 2-yr overall survival and progression-free survival were 53% and 48%. Median time to neutrophil and platelet engraftment was 25 and 52 days, respectively. Before UCBT, the median values for most leukocyte subsets were below normal limits, except for monocytes. CD3XX cells remained depressed until 2 months post-transplant when gradually began to re-emerge. However, CD4XX subsets had distinct reconstitution kinetics (Figure 1). CD4XX T cells declined at 1 month but gradually increased and exceeded pre-transplant levels by 9 months after UCBT. In contrast, at 9 months, CD8XX lymphocytes remained depressed to 50% of pre-transplant levels, but increased thereafter and reached normal values by 2-yr. NK cells and monocytes reached normal values at 3 months post-UCBT. B cells were mostly undetectable for the first 6 months, followed by a 10-fold increase at 9 months and exceeded the upper normal limit by 2-yr. TREC, which were within normal range before transplant, decreased after UCBT but remained detectable between 1-6 months and recovered to normal levels by 9 months. Among cytokines, only IL-8, IL-6 and TNF-alpha displayed significant changes. IL-8 and IL-6 peaked at day 100 and 9 months, and subsequently declined. In contrast, TNF-alpha increased by day 100 and remained elevated thereafter. To evaluate functional immunity, we assessed correlations between viral reactivation and reconstitution of immune cell populations and thymic function. Nineteen patients experienced 24 clinically significant viral reactivations or infections, with 1-year cumulative incidence of 62%, which was comparable to 53% observed in dUCBT cohorts receiving ATG-containing conditioning. Although there was no difference in CMV, EBV, adenovirus and VZV reactivation, there was a significant increase in the incidence of HHV-6 reactivation. HHV-6 viremia was observed in 24 of 28 (86%) patients during the first month after dUCBT. Six of these 24 (25%) patients developed HHV-6-related encephalitis. There was a correlation between development of encephalitis and HHV-6 viral load >=50.000 copies/ml (p=0.007). Pre-transplant TREC levels >=1.200 copies/ml negatively correlated with subsequent HHV-6 reactivation (p=0.04), indicating that baseline reserve of thymic function has a significant role in post-transplant immune reconstitution. On days 30, 60 and 100 post-transplant, higher TREC levels correlated with lack of HHV-6 viremia (pXX counts in the first 100 days was also observed in patients without HHV-6 reactivation. Neutrophil and platelet engraftment, reconstitution of CD4XX T effectors, NK cells and monocytes, IL-6, IL-8 and TNF-alpha levels, and development of GVHD did not correlate with HHV-6 reactivation or its absence. Our results indicate that substitution of low dose TBI for ATG in the conditioning regimen is characterized by superior recovery of thymopoiesis and reconstitution of CD4XX T cells, both of which have a protective role against HHV-6 reactivation and end organ disease. Further studies will identify why HHV-6 reactivation is selectively increased in UCBT recipients treated with TBI-containing conditioning. [Formula presented] Disclosures: Defilipp: Incyte: Research Funding. Politikos: Angiocrine Bioscience Inc: Research Funding. Armand: Otsuka: Research Funding; Roche: Research Funding; Affimed: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Infinity: Consultancy; Sigma Tau: Research Funding; ADC Therapeutics: Consultancy; Tensha: Research Funding; Genentech: Research Funding; Pfizer: Consultancy. Ho: Jazz Pharmaceuticals: Consultancy. Koreth: Amgen: Consultancy; Equillium: Consultancy; Cugene: Consultancy. Avigan: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Partners Tx: Membership on an entity's Board of Directors or advisory committees; Partner Tx: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Parexel: Consultancy; Takeda: Consultancy. Rosenblatt: Celgene: Research Funding; Amgen: Other: Advisory Board; Merck: Other: Advisory Board; BMS: Other: Advisory Board; Parexel: Consultancy; Imaging Endpoint: Consultancy; Partner Tx: Other: Advisory Board; Dava Oncology: Other: Education; BMS: Research Funding. Chen: Abbvie: Consultancy; Incyte: Consultancy; Magenta: Consultancy; Takeda: Consultancy; Kiadis: Consultancy. Soiffer: Gilead, Mana therapeutic, Cugene, Jazz: Consultancy; Juno, kiadis: Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Mana therapeutic: Consultancy; Kiadis: Other: supervisory board; Jazz: Consultancy; Cugene: Consultancy. Cutler: Kadmon: Consultancy; Incyte: Consultancy; Pharmacyclics: Consultancy; Fate Therapeutics: Consultancy. Ritz: Equillium: Research Funding; Merck: Research Funding; Kite Pharma: Research Funding; Aleta Biotherapeutics: Consultancy; Celgene: Consultancy; Avrobio: Consultancy; LifeVault Bio: Consultancy; Draper Labs: Consultancy; Talaris Therapeutics: Consultancy; TScan Therapeutics: Consultancy.XXCopyright

BACKGROUND:Despite consistent recognition of their influence, empirical study of how outer setting factors (e.g., policies, financing, stakeholder relationships) influence public systems' investment in and adoption of evidence-based treatment (EBT) is limited. This study examined associations among unmodifiable (e.g., demographic, economic, political, structural factors) and modifiable (e.g., allocation of resources, social processes, policies, and regulations) outer setting factors and adoption of behavioral health EBT by US states. METHODS:Multilevel models examined relationships between state characteristics, an array of funding and policy variables, and state adoption of behavioral health EBTs for adults and children across years 2002-2012, using data from the National Association for State Mental Health Program Directors Research Institute and other sources. RESULTS:Several unmodifiable state factors, including per capita income, controlling political party, and Medicaid expansion, predicted level of state fiscal investments in EBT. By contrast, modifiable factors, such as interagency collaboration and investment in research centers, were more predictive of state policies supportive of EBT. Interestingly, level of adult EBT adoption was associated with state fiscal supports for EBT, while child EBT adoption was predicted more by supportive policies. State per capita debt and direct state operation of services (versus contracting for services) predicted both child and adult EBT adoption. CONCLUSIONS:State-level EBT adoption and associated implementation support is associated with an interpretable array of policy, financing, and oversight factors. Such information expands our knowledge base of the role of the outer setting in implementation and may provide insight into how best to focus efforts to promote EBT for behavioral health disorders.

Sleep quality varies widely across individuals, especially during normal aging, with impaired sleep contributing to deficits in cognition and emotional regulation. Sleep can also be impacted by a variety of adverse events, including childhood adversity. Here we examined how early life adverse events impacted later life sleep structure and physiology using an animal model to test the relationship between early life adversity and sleep quality across the life span. Rat pups were exposed to an Adversity-Scarcity model from postnatal day 8-12, where insufficient bedding for nest building induces maternal maltreatment of pups. Polysomnography and sleep physiology were assessed in weaning, early adult and older adults. Early life adversity induced age-dependent disruptions in sleep and behavior, including lifelong spindle decreases and later life NREM sleep fragmentation. Given the importance of sleep in cognitive and emotional functions, these results highlight an important factor driving variation in sleep, cognition and emotion throughout the lifespan that suggest age-appropriate and trauma informed treatment of sleep problems.

The aim of this study was to assess mobility patterns among a sample of transgender women (n=14) in New York City via survey and Global Positioning System (GPS) monitoring. We found varying levels of concordance between the residential neighbourhood and each of the non-residential contexts: 64.3% considered the neighbourhood that they socialised in most often to be different from their residential neighbourhood. While participants' residences represented 10 zone improvement plan code tabulation areas (ZCTAs), GPS data were recorded in 124 of 263 ZCTAs (47.1%). Overall, 58.2% (n=373,262) were recorded in ZCTAs in the highest quartile of human immunodeficiency virus (HIV) prevalence. The association between place, community HIV prevalence, mobility, and factors that increase the vulnerability of transgender women to HIV infection are worthy of future investigation in reducing the burden of the HIV epidemic in these communities.

Social support is frequently cited as a protective factor against juvenile offending. The current study examined whether a close relationship with an adult in childhood decreases the risk for offending among individuals with a history of child maltreatment. This research utilized data from a prospective cohort design study in which children with court-substantiated cases of abuse and neglect and nonmaltreated children matched on age, sex, race, and approximate family social class were followed into adulthood (N = 1,196). Having a close relationship with an adult did not decrease risk for delinquent behavior or arrest, but a close relationship with a parent was associated with lower risk for delinquent behavior. Surprisingly, adults with no history of maltreatment who reported having a close relationship with a peer or sibling were more likely to report engaging in violent behavior in adolescence. In total, these findings point to the complexity of development and suggest that although a close relationship with an adult can be protective, the mere presence of such a relationship, without inquiry into the type of relationship, is not sufficient.