Motivation and accessing care among drug treatment court involved women: A sequential, mixed-methods approach.

Drug treatment courts (DTC) address substance use disorders (SUD) but not cooccurrencing HIV or hepatitis C virus (HCV). This pilot explored feasibility and preliminary outcomes of the Women's Initiative Supporting Health (WISH) intervention and health-related motivation, both based in self-determination theory (SDT) regarding HIV/HCV and SUD treatment. WISH feasibility study: 79 DTC women completed a one-time survey regarding motivation and willingness to engage in future interventions. WISH intervention: 22 women from DTC with SUD and HIV or HCV received a 6-session, peer motivational enhancement health behavior-oriented interventions. Recruitment strategies were feasible. SDT-based measures demonstrated internal consistency in this under-studied population, with perceived competence/autonomy associationed with motivation to reduce HIV/HCV/SUD risk. Women DTC participants indicated acceptance and showed internally consistent results in SDT-based motivation measures These WISH feasibility and intervention pilot studies lay a foundation for future studies addressing motivation to access healthcare among women DTC participants.

Characterizing Emerging Canine H3 Influenza Viruses.

The continual emergence of novel influenza A strains from non-human hosts requires constant vigilance and the need for ongoing research to identify strains that may pose a human public health risk. Since 1999, canine H3 influenza A viruses (CIVs) have caused many thousands or millions of respiratory infections in dogs in the United States. While no human infections with CIVs have been reported to date, these viruses could pose a zoonotic risk. In these studies, the National Institutes of Allergy and Infectious Diseases (NIAID) Centers of Excellence for Influenza Research and Surveillance (CEIRS) network collaboratively demonstrated that CIVs replicated in some primary human cells and transmitted effectively in mammalian models. While people born after 1970 had little or no pre-existing humoral immunity against CIVs, the viruses were sensitive to existing antivirals and we identified a panel of H3 cross-reactive human monoclonal antibodies (hmAbs) that could have prophylactic and/or therapeutic value. Our data predict these CIVs posed a low risk to humans. Importantly, we showed that the CEIRS network could work together to provide basic research information important for characterizing emerging influenza viruses, although there were valuable lessons learned.

Temporal Dysbiosis of Infant Nasal Microbiota Relative to Respiratory Syncytial Virus Infection.

BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of infant respiratory disease. Infant airway microbiota has been associated with respiratory disease risk and severity. The extent to which interactions between RSV and microbiota occur in the airway, and their impact on respiratory disease susceptibility and severity, are unknown. METHODS: We carried out 16S rRNA microbiota profiling of infants in the first year of life from (1) a cross-sectional cohort of 89 RSV-infected infants sampled during illness and 102 matched healthy controls, and (2) a matched longitudinal cohort of 12 infants who developed RSV infection and 12 who did not, sampled before, during, and after infection. RESULTS: We identified 12 taxa significantly associated with RSV infection. All 12 taxa were differentially abundant during infection, with 8 associated with disease severity. Nasal microbiota composition was more discriminative of healthy vs infected than of disease severity. CONCLUSIONS: Our findings elucidate the chronology of nasal microbiota dysbiosis and suggest an altered developmental trajectory associated with RSV infection. Microbial temporal dynamics reveal indicators of disease risk, correlates of illness and severity, and impact of RSV infection on microbiota composition.

Broad Hemagglutinin-Specific Memory B Cell Expansion by Seasonal Influenza Virus Infection Reflects Early-Life Imprinting and Adaptation to the Infecting Virus.

Memory B cells (MBCs) are key determinants of the B cell response to influenza virus infection and vaccination, but the effect of different forms of influenza antigen exposure on MBC populations has received little attention. We analyzed peripheral blood mononuclear cells and plasma collected following human H3N2 influenza infection to investigate the relationship between hemagglutinin-specific antibody production and changes in the size and character of hemagglutinin-reactive MBC populations. Infection produced increased concentrations of plasma IgG reactive to the H3 head of the infecting virus, to the conserved stalk, and to a broad chronological range of H3s consistent with original antigenic sin responses. H3-reactive IgG MBC expansion after infection included reactivity to head and stalk domains. Notably, expansion of H3 head-reactive MBC populations was particularly broad and reflected original antigenic sin patterns of IgG production. Findings also suggest that early-life H3N2 infection "imprints" for strong H3 stalk-specific MBC expansion. Despite the breadth of MBC expansion, the MBC response included an increase in affinity for the H3 head of the infecting virus. Overall, our findings indicate that H3-reactive MBC expansion following H3N2 infection is consistent with maintenance of response patterns established early in life, but nevertheless includes MBC adaptation to the infecting virus.IMPORTANCE Rapid and vigorous virus-specific antibody responses to influenza virus infection and vaccination result from activation of preexisting virus-specific memory B cells (MBCs). Understanding the effects of different forms of influenza virus exposure on MBC populations is therefore an important guide to the development of effective immunization strategies. We demonstrate that exposure to the influenza hemagglutinin via natural infection enhances broad protection through expansion of hemagglutinin-reactive MBC populations that recognize head and stalk regions of the molecule. Notably, we show that hemagglutinin-reactive MBC expansion reflects imprinting by early-life infection and that this might apply to stalk-reactive, as well as to head-reactive, MBCs. Our findings provide experimental support for the role of MBCs in maintaining imprinting effects and suggest a mechanism by which imprinting might confer heterosubtypic protection against avian influenza viruses. It will be important to compare our findings to the situation after influenza vaccination.

Measuring the Severity of Respiratory Illness in the First 2 Years of Life in Preterm and Term Infants.

OBJECTIVE: To develop a valid research tool to measure infant respiratory illness severity using parent-reported symptoms. STUDY DESIGN: Nose and throat swabs were collected monthly for 1 year and during respiratory illnesses for 2 years in a prospective study of term and preterm infants in the Prematurity, Respiratory Outcomes, Immune System and Microbiome study. Viral pathogens were detected using Taqman Array Cards. Parents recorded symptoms during respiratory illnesses using a Childhood Origins of Asthma (COAST) scorecard. The COAST score was validated using linear mixed effects regression modeling to evaluate associations with hospitalization and specific infections. A data-driven method was also used to compute symptom weights and derive a new score, the Infant Research Respiratory Infection Severity Score (IRRISS). Linear mixed effects regression modeling was repeated with the IRRISS illness data. RESULTS: From April 2013 to April 2017, 50 term, 40 late preterm, and 28 extremely low gestational age (<29 weeks of gestation) infants had 303 respiratory illness visits with viral testing and parent-reported symptoms. A range of illness severity was described with 39% of illness scores suggestive of severe disease. Both the COAST score and IRRISS were associated with respiratory syncytial virus infection and hospitalization. Gestational age and human rhinovirus infection were inversely associated with both scoring systems. The IRRISS and COAST scores were highly correlated (r = 0.93; P < .0001). CONCLUSIONS: Using parent-reported symptoms, we validated the COAST score as a measure of respiratory illness severity in infants. The new IRRISS score performed as well as the COAST score.

IDENTIFYING PREDICTORS OF SUBSTANCE USE AND RECIDIVISM OUTCOME TRAJECTORIES AMONG DRUG TREATMENT COURT CLIENTS.

Drug treatment court (DTC) is a diversion program for individuals with drug-related crimes. However, the DTC literature is conflicting with regard to substance use and recidivism outcomes. This study examines factors associated with improved client outcome trajectories among a multisite, national DTC sample. We conducted a secondary analysis of 2,295 participants using the Global Appraisal of Individual Needs assessment tool. Participants in community-based treatment comprised a nonequivalent comparison group. Zero-inflated Poisson (ZIP) regression examined client sociodemographics in relation to substance use and rearrest at 6-month follow-up. Employed DTC clients were more likely to abstain from substances, but among all study participants, higher baseline use, male gender, and employment predicted substance use. Similarly, among DTC clients, older age and employment predicted no rearrests, but among all study participants, older and employed individuals had worse arrest outcome trajectories. Future work is needed to better understand how client characteristics may inform individualized treatment approaches.

Phthalate exposure in the neonatal intensive care unit is associated with development of bronchopulmonary dysplasia.

OBJECTIVE: Bronchopulmonary dysplasia (BPD) is a serious yet common morbidity of preterm birth. Although prior work suggests a possible role for phthalate exposure in the development of BPD, no study has rigorously evaluated this. Our objective was to determine whether hospital-based phthalate exposure is associated with the development of BPD and to identify developmental windows sensitive to exposure. STUDY DESIGN: This is a prospective multicenter cohort study of 360 preterm infants born at 23-33 weeks gestation participating in the Developmental Impact of NICU Exposures (DINE) cohort. 939 urine specimens collected during the NICU stay were analyzed for biomarkers of phthalate exposure by liquid chromatography with tandem mass spectrometry. The modified Shennan definition was used to diagnose bronchopulmonary dysplasia. Reverse distributed-lag modeling identified developmental windows sensitive to specific phthalate exposure, controlling for relevant covariates including sex and respiratory support. RESULTS: Thirty-five percent of participants were diagnosed with BPD. Exposure to specific phthalate mixtures at susceptible points in preterm infant development are associated with later diagnosis of BPD in models adjusted for use of respiratory support. The weighted influence of specific phthalate metabolites in the mixtures varied by sex. Metabolites of di(2-ethylhexyl) phthalate, a phthalate previously linked to neonatal respiratory support equipment, drove this association, particularly among female infants, at 26- to 30-weeks post-menstrual age. CONCLUSIONS: This is the largest and only multi-site study of NICU-based phthalate exposure and clinical impact yet reported. In well-constructed models accounting for infant sex and respiratory support, we found a significant positive association between ultimate diagnosis of BPD and prior exposure to phthalate mixtures with DEHP predominance at 26- to 30-weeks PMA or 34-36-weeks PMA. This information is critically important as it identifies a previously unrecognized and modifiable contributing factor to BPD.

Stroke death in patients receiving radiation for head and neck cancer in the modern era.

Objectives: Head and neck cancer is a common malignancy frequently treated with chemotherapy and radiotherapy. Studies have shown an increased risk of stroke with the receipt of radiotherapy, but data on stroke-related mortality are limited, particularly in the modern era. Evaluating stroke mortality related to radiotherapy is vital given the curative nature of head and neck cancer treatment and the need to understand the risk of severe stroke in this population. Methods: We analyzed the risk of stroke death among 122,362 patients (83,651 patients who received radiation and 38,711 patients who did not) with squamous cell carcinoma of the head and neck (HNSCC) diagnosed between 1973 and 2015 in the SEER database. Patients in radiation vs. no radiation groups were matched using propensity scores. Our primary hypothesis was that radiotherapy would increase the hazard of death from stroke. We also examined other factors impacting the hazard of stroke death, including whether radiotherapy was performed during the modern era when IMRT and modern stroke care were available as well as increased HPV-mediated cancers of the head and neck. We hypothesized that the hazard of stroke death would be less in the modern era. Results: There was an increased hazard of stroke-related death in the group receiving radiation therapy (HR 1.203, p = 0.006); however, this was a very small absolute increase, and the cumulative incidence function of stroke death was significantly reduced in the modern era (p < 0.001), cohorts with chemotherapy (p=0.003), males (p=0.002), younger cohorts (p<0.001) and subsites other than nasopharynx (p=0.025). Conclusions: While radiotherapy for head and neck cancer increases the hazard of stroke death, this is reduced in the modern era and remains a very small absolute risk.

Increased risk of high-grade prostate cancer among testicular cancer survivors.

INTRODUCTION: Testicular cancer survivors (TCS) have an increased risk of additional cancers, including prostate cancer. Our understanding of the natural history of prostate cancer in testicular cancer survivors is very limited due to its rare incidence. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) Registry from 1978 to 2011, we identified 282 TCS with subsequent prostate cancer and examined the tumor grade and clinical outcomes in contrast to men with primary prostate cancer in the general population. RESULTS: TCS with a subsequent prostate cancer diagnosis were more likely to be diagnosed at a younger age than men with primary prostate cancer (65.2% vs. 37.6% for age ≤65, 34.8% vs. 62.4% for age >65, p<0.001) and were more likely to have grade III/IV tumors (46.2% vs. 37.0%, p<0.002). Longer latency between testicular and prostate cancer diagnoses was associated with a higher risk of grade III/IV (p<0.001) cancer. Despite the increased risk for high-grade tumors, 10-year prostate cancer-specific survival and overall survival were not significantly different between TCS and men with primary prostate cancer. Based on the available information in SEER, we found that prior history of radiotherapy for testicular cancer had no impact on tumor grade or survival outcomes. CONCLUSIONS: Prostate cancer in TCS was more likely to be diagnosed at a younger age and with higher grades. Risks of grade III/IV disease increased with longer latency between testicular and prostate cancer diagnoses. Radiotherapy for testicular cancer did not appear to have a significant impact on the outcome of subsequent prostate cancer.

Aberrant newborn T cell and microbiota developmental trajectories predict respiratory compromise during infancy.

Neonatal immune-microbiota co-development is poorly understood, yet age-appropriate recognition of - and response to - pathogens and commensal microbiota is critical to health. In this longitudinal study of 148 preterm and 119 full-term infants from birth through one year of age, we found that postmenstrual age or weeks from conception is a central factor influencing T cell and mucosal microbiota development. Numerous features of the T cell and microbiota functional development remain unexplained; however, by either age metric and are instead shaped by discrete perinatal and postnatal events. Most strikingly, we establish that prenatal antibiotics or infection disrupt the normal T cell population developmental trajectory, influencing subsequent respiratory microbial colonization and predicting respiratory morbidity. In this way, early exposures predict the postnatal immune-microbiota axis trajectory, placing infants at later risk for respiratory morbidity in early childhood.

Risk of adverse pathological features for intermediate risk prostate cancer: Clinical implications for definitive radiation therapy.

BACKGROUND: Intermediate risk prostate cancer represents a largely heterogeneous group with diverse disease extent. We sought to establish rates of adverse pathological features important for radiation planning by analyzing surgical specimens from men with intermediate risk prostate cancer who underwent immediate radical prostatectomy, and to define clinical pathologic features that may predict adverse outcomes. MATERIALS AND METHODS: A total of 1552 men diagnosed with intermediate risk prostate cancer who underwent immediate radical prostatectomy between 1/1/2005 and 12/31/2015 were reviewed. Inclusion criteria included available preoperative PSA level, pathology reports of transrectal ultrasound-guided prostate biopsy, and radical prostatectomy. Incidences of various pathological adverse features were evaluated. Patient characteristics and clinical disease features were analyzed for their predictive values. RESULTS: Fifty percent of men with high risk features (defined as PSA >10 but <20 or biopsy primary Gleason pattern of 4) had pathological upstage to T3 or higher disease. The incidence of upgrade to Gleason score of 8 or higher and the incidence of lymph node positive disease was low. Biopsy primary Gleason pattern of 4, and PSA greater than 10 but less than 20, affected adverse pathology in addition to age and percent positive biopsy cores. Older age and increased percentage of positive cores were significant risk factors of adverse pathology. CONCLUSION: Our findings underscore the importance of comprehensive staging beyond PSA level, prostate biopsy, and CT/bone scan for men with intermediate risk prostate cancer proceeding with radiation in the era of highly conformal treatment.

The Biopsychosocial Model and Perinatal Health Care: Determinants of Perinatal Care in a Community Sample.

Insufficient care in the perinatal period is associated with poorer maternal health, poorer perinatal outcomes, infant mortality, and health inequalities. Identifying the sources of and reducing the rates of insufficient care is therefore a major clinical and public health objective. We propose a specific application of the biopsychosocial model that conceptualizes prenatal and postpartum care quality as health markers that are influenced by psychological factors and family and social context. Clinic attendance data were abstracted from the electronic medical records of N = 291 participants enrolled in a longitudinal pregnancy cohort study of healthy women who have been followed since the first trimester; the Kotelchuck Index (KI) was calculated as an index of perinatal care utilization. Detailed prenatal psychological, social, and sociodemographic data were collected from self-report questionnaire and interview. Bivariate analyses indicated socio-demographic (e.g., race), psychological (e.g., response to perceived racism, affective symptoms, trauma experience), and social and family context (e.g., social support, family size) significantly influenced pre- and post-natal care utilization. Multivariate logistic regression analyses, adjusting for medical complications, identified social and family context as robust predictors of perinatal care utilization. The findings underscore the need for biopsychosocial models of health care and highlight several potential strategies for improving health care utilization.

HSP27: an anti-inflammatory and immunomodulatory stress protein acting to dampen immune function.

The effects of HSP27 on human monocytes (MO) are predominantly antiinflammatory through preferential interleukin (IL)10 induction and by alteration of MO to immature dendritic cells (iDCs) or MO to macrophage (Mac) differentiation. Initial HSP27 inclusion in IL4+GM-CSF MO to iDC induction cultures allows Mac differentiation (CD14++, CD16+), decreases iDC (CD1a+) differentiation, and depresses DC induction of allogeneic T lymphocyte proliferation (MLR). HSP27 increased MO IL10 and M-CSF production but subsequent increased Mac differentiation isn't responsible for depressed MO to iDC differentiation and function. Mac function after IL10 induced MO to Mac differentiation is also altered by HSP27 inclusion so that Mac phagocytic activity and scavenger receptor expression (CD163) are depressed. HSP27, in addition to immature DCs, doesn't increase Mac differentiation but instead generates inhibitory DCs, which depress rather than stimulate T cell proliferation even during anti CD3+CD28 induction. Upon maturation, these HSP27-altered inhibitory DCs have increased production of the T cell and DC suppressive mediator, thrombospondin 1. HSP27's anti-inflammatory and immunodepressive effects include deranging MO differentiation to both Mac and DCs, altering their receptor expression, and inducing production of inhibitory mediators such as thrombospondin-1 as well as IL10. These data suggest HSP27 belongs to a new group of 'anti-danger signals'.

Neonatal gut and respiratory microbiota: coordinated development through time and space.

BACKGROUND: Postnatal development of early life microbiota influences immunity, metabolism, neurodevelopment, and infant health. Microbiome development occurs at multiple body sites, with distinct community compositions and functions. Associations between microbiota at multiple sites represent an unexplored influence on the infant microbiome. Here, we examined co-occurrence patterns of gut and respiratory microbiota in pre- and full-term infants over the first year of life, a period critical to neonatal development. RESULTS: Gut and respiratory microbiota collected as longitudinal rectal, throat, and nasal samples from 38 pre-term and 44 full-term infants were first clustered into community state types (CSTs) on the basis of their compositional profiles. Multiple methods were used to relate the occurrence of CSTs to temporal microbiota development and measures of infant maturity, including gestational age (GA) at birth, week of life (WOL), and post-menstrual age (PMA). Manifestation of CSTs followed one of three patterns with respect to infant maturity: (1) chronological, with CST occurrence frequency solely a function of post-natal age (WOL), (2) idiosyncratic to maturity at birth, with the interval of CST occurrence dependent on infant post-natal age but the frequency of occurrence dependent on GA at birth, and (3) convergent, in which CSTs appear first in infants of greater maturity at birth, with occurrence frequency in pre-terms converging after a post-natal interval proportional to pre-maturity. The composition of CSTs was highly dissimilar between different body sites, but the CST of any one body site was highly predictive of the CSTs at other body sites. There were significant associations between the abundance of individual taxa at each body site and the CSTs of the other body sites, which persisted after stringent control for the non-linear effects of infant maturity. Canonical correlations exist between the microbiota composition at each pair of body sites, with the strongest correlations between proximal locations. CONCLUSION: These findings suggest that early microbiota is shaped by neonatal innate and adaptive developmental responses. Temporal progression of CST occurrence is influenced by infant maturity at birth and post-natal age. Significant associations of microbiota across body sites reveal distal connections and coordinated development of the infant microbial ecosystem.

T cell developmental arrest in former premature infants increases risk of respiratory morbidity later in infancy.

The inverse relationship between gestational age at birth and postviral respiratory morbidity suggests that infants born preterm (PT) may miss a critical developmental window of T cell maturation. Despite a continued increase in younger PT survivors with respiratory complications, we have limited understanding of normal human fetal T cell maturation, how ex utero development in premature infants may interrupt normal T cell development, and whether T cell development has an effect on infant outcomes. In our longitudinal cohort of 157 infants born between 23 and 42 weeks of gestation, we identified differences in T cells present at birth that were dependent on gestational age and differences in postnatal T cell development that predicted respiratory outcome at 1 year of age. We show that naive CD4+ T cells shift from a CD31-TNF-α+ bias in mid gestation to a CD31+IL-8+ predominance by term gestation. Former PT infants discharged with CD31+IL8+CD4+ T cells below a range similar to that of full-term born infants were at an over 3.5-fold higher risk for respiratory complications after NICU discharge. This study is the first to our knowledge to identify a pattern of normal functional T cell development in later gestation and to associate abnormal T cell development with health outcomes in infants.

Impact of prematurity and nutrition on the developing gut microbiome and preterm infant growth.

BACKGROUND: Identification of factors that influence the neonatal gut microbiome is urgently needed to guide clinical practices that support growth of healthy preterm infants. Here, we examined the influence of nutrition and common practices on the gut microbiota and growth in a cohort of preterm infants. RESULTS: With weekly gut microbiota samples spanning postmenstrual age (PMA) 24 to 46 weeks, we developed two models to test associations between the microbiota, nutrition and growth: a categorical model with three successive microbiota phases (P1, P2, and P3) and a model with two periods (early and late PMA) defined by microbiota composition and PMA, respectively. The more significant associations with phase led us to use a phase-based framework for the majority of our analyses. Phase transitions were characterized by rapid shifts in the microbiota, with transition out of P1 occurring nearly simultaneously with the change from meconium to normal stool. The rate of phase progression was positively associated with gestational age at birth, and delayed transition to a P3 microbiota was associated with growth failure. We found distinct bacterial metabolic functions in P1-3 and significant associations between nutrition, microbiota phase, and infant growth. CONCLUSION: The phase-dependent impact of nutrition on infant growth along with phase-specific metabolic functions suggests a pioneering potential for improving growth outcomes by tailoring nutrient intake to microbiota phase.

Elevated postinjury thrombospondin 1-CD47 triggering aids differentiation of patients' defective inflammatory CD1a+dendritic cells.

A subset of Pts develops dysfunctional MO to inflammatory DC differentiation and immunosuppression. MDDC, a newly described DC subset, is pivotal in initiating antibacterial responses. Endogenous proteins are known to alter MO to MDDC differentiation. In particular, trauma-elevated TSP-1, a protein that is known to affect MO functions, could trigger MDDC differentiation defects. We hypothesized that TSP-1-deranged differentiation of inflammatory CD1a(+)MDDC would negatively alter activation of immune functions, thereby increasing the risk of postinjury infections. Post-trauma increased TSP-1 levels in patients' plasma and MO correlated with two distinct MDDC differentiation dysfunctions: the previously described decreased CD1a(+)DC yields but also, development of an immunoincompetent CD1a(+)MDDC. The Pts' development of Dysf DC correlated to increased infectious complications. TSP-1 triggered its inhibitory receptor, CD47, activating an inhibitory phosphatase, SHP-1. Increased pSHP-1, decreased antigen processing, and depressed T cell stimulation characterized Pt Dysf DC. TSP-1 mimics added during Cnt MDDC differentiation depressed CD1a(+)DC yields but more importantly, also induced defective CD1a(+)MDDC, reproducing Pts' MDDC differentiation dysfunctions. CD47 triggering during Cnt MDDC differentiation increased SHP-1 activation, inhibiting IL-4-induced STAT-6 activation (critical for CD1a(+)MDDC differentiation). SHP-1 inhibition during MDDC differentiation in the presence of TSP-1 mimics restored pSTAT-6 levels and CD1a(+)MDDC immunogenicity. Thus, postinjury-elevated TSP-1 can decrease CD1a(+)DC yields but more critically, also induces SHP-1 hyperactivity, deviating MDDC differentiation to defective CD1a(+) inflammatory MDDCs by inhibiting STAT-6.