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The purpose of this study was to evaluate a planning strategy based on Acuros with density override in comparison with AAA without and with the override. Ten lung-tumor patients were selected with each PTV size around 2 - 4 cm and were imaged using slow scan, followed by four-dimensional (4D) imaging limited to the target. On each phase-specific image, gross tumor volume (GTV) was contoured. Summed over all phases, an integrated GTV (iGTV) was generated and copied to the slow scan. A treatment plan was created using a dynamic-conformal-arc technique with AAA to prescribe 60 Gy to 95% of PTV (iGTV + 0.5 cm). Each AAA-based plan was regenerated by overriding the density of the setup margin of PTV by GTV density (modeling tumor-position uncertainty). It was also regenerated with Acuros and the override. The three plans were validated in 4D dose to PTV, after similarly overriding PTV density (phase-specific), accurately calculating with Acuros, and summing the phase-specific plans through organ/dose registration. The Acuros-based plan with the override, the AAA-based plan, and the AAA-based plan with the override provided 4D PTV doses of 63.9, 67.9, and 62 Gy at D95%, respectively, averaged over all patients. The override with Acuros and AAA produced lesser 4D doses, closer to the associated 3D doses, respectively, than that without the override, with better conformity and inhomogeneity. With the override in common, Acuros provided a greater dose to PTV than that by AAA. The Acuros with the override, which was more accurate than the AAA without the override, is clinically recommended.

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 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.

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.

RationaleRespiratory Syncytial Virus (RSV) infection is a leading cause of infant respiratory disease and hospitalization. Infant airway microbiota occupying the nasopharynx have 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 severity and infection susceptibility, are not well understood.ObjectivesTo characterize associations between the nasal microbiota and RSV infection before, during, and after infants’ first respiratory illness.MethodsNasal 16S rRNA microbial community profiling of two cohorts of infants in the first year of life: 1) a cross-sectional cohort of 89 RSV infected infants sampled during illness and 102 population matched healthy controls, and 2) an individually matched longitudinal cohort of 12 infants who developed RSV infection and 12 who did not, sampled at time points before, during, and after infection.Measurements and Main ResultsWe identified 12 taxa significantly associated with RSV infection. All 12 were differentially abundant during infection, with seven differentially abundant prior to infection, and eight differentially abundant after infection. Eight of these taxa were associated with disease severity. Nasal microbiota composition was more discriminative of healthy vs. infected than of disease severity.ConclusionsOur findings elucidate the chronology of nasal microbiota dysbiosis and suggest an altered developmental trajectory associated with first-time RSV infection. Microbial temporal dynamics reveal indicators of disease risk, correlates of illness and severity, and the impact of RSV infection on microbiota composition. Identified taxa represent appealing targets for additional translationally-oriented research.

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., Author summary The 2009 influenza pandemic was a stark reminder that ongoing vigilance is critical to protect the public from an influenza pandemic. The continual evolution of influenza viruses and emergence from animal reservoirs, leads to the need to quickly identify strains that pose a public health risk. In these studies, members of the National Institutes of Allergy and Infectious Diseases (NIAID) Centers for Excellence in Influenza Research and Surveillance (CEIRS) network worked together to demonstrate that the emerging canine H3 influenza viruses posed a low risk to public health and identified several therapeutic options in the event of an emergence. In addition to providing important new basic research, many lessons were learned that may be important in dealing with any emerging disease outbreak.

BACKGROUND: The pathogenesis of respiratory syncytial virus (RSV) in older adults may be due to age-related T-cell immunosenescence. Thus, we evaluated CD4 and CD8 T-cell responses during RSV infection in adults across the age spectrum. METHODS: Peripheral blood mononuclear cells collected during RSV infection in adults, age 26–96 years, were stimulated with live RSV and peptide pools representing F, M, NP, and G proteins and analyzed by flow cytometry. RESULTS: There were no significant age-related differences in frequency of CD4(+) T cells synthesizing interferon (IFN)γ, interleukin (IL)2, IL4, IL10, or tumor necrosis factor (TNF)α or in CD8(+)IFNγ(+) T cells. IL4(+)CD4(+) T-cell numbers were low, as were IL13 and IL17 responses. However, in univariate analysis, CD4 T-cell IFNγ, IL2, IL4, IL10, and TNFα responses and CD8(+)IFNγ(+) T cells were significantly increased with more severe illness requiring hospitalization. In multivariate analysis, viral load was also associated with increased T-cell responses. CONCLUSIONS: We found no evidence of diminished RSV-specific CD4 or CD8 T-cell responses in adults infected with RSV. However, adults with severe disease seemed to have more robust CD4 and CD8 T-cell responses during infection, suggesting that disease severity may have a greater association with T-cell responses than age.

Neonatal immune-microbiota co-development is poorly understood, yet appropriate recognition of – and response to – pathogens and commensal microbiota is critical to health. In this longitudinal study of 148 pre- and 119 full-term infants from birth through one year of age we found that postmenstrual age, or weeks from conception, not post-natal age, is the dominant 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 peri- and post-natal 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 imprint the postnatal immune-microbiota axis and place an infant at significant risk for respiratory morbidity in early childhood.One Sentence SummaryT cells and microbiota follow predictable, coordinated trajectories in newborns, and their coordination is an important determinant of illness in the first year.Graphical AbstractNasal and rectal microbiome was assessed weekly in the NICU, monthly post-discharge, and when respiratory illness symptoms occurred. T cells were characterized at birth (cord blood), 36-42 weeks postmenstrual age, and at 12 months. Quarterly respiratory morbidity surveys determined the 12-month outcome of persistent respiratory disease. More frequent illnesses and chronic disease outcomes occurred by one year of age if development of these systems was discordant or disrupted.

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.

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.

Background:Postnatal development of the microbiota in early life influences immunity, metabolism, neurodevelopment and long-term infant health. Microbiome development occurs at multiple body sites, each 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 and risk of respiratory diseases.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 composition. Multiple methods were used to relate the occurrence of CSTs to several measures of infant maturity, including gestational age (GA) at birth, week of life (WOL), and post menstrual age (PMA: equal to GA plus WOL). Manifestation of CSTs followed one of three patterns with respect to infant maturity. First,chronological: independent of infant maturity (GA) at birth, and strongly associated with post-natal age (WOL). Second,idiosyncratic: primarily dependent on maturity (GA) at birth, with persistent differences in CST occurrence between pre- and full-term infants through the first year of life. Third,convergent: CSTs appear earlier in infants with greater maturity (GA) at birth, but after a sufficient post-natal interval their occurrence in pre-term infants reaches parity with full-term infants. 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. Significant canonical correlations exist between the microbiota composition at each pair of body sites, with the strongest correlations between more proximal locations.Conclusion:Cross-body site associations of developing infant microbiota suggest the importance of research and clinical practices that focus on dynamic interactions between multiple microbial communities to elucidate and promote systemic microbiota development.

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 (

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.

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'.

s / Drug and Alcohol Dependence 146 (2015) e34–e117 e47 Support, traumatization, and employment differences in drug court outcomes Diane Morse1, Catherine Cerulli 1, Sanjukta Bandyopadhyay2, Joseph J. Guido2, Hongmei Yang2, John L. Wilson1, F. Taxman3 1 Psychiatry, University of Rochester School of Medicine, Rochester, NY, United States 2 Biostatistics, University of Rochester School of Medicine, Rochester, NY, United States 3 Criminology, Law & Society, George Mason University, Fairfax, VA, United States Aims: Adult drug treatment court (ADTC) outcomes in relation to social support, trauma, and employment are poorly understood. We examined these outcomes and related factors. Methods: Bivariate analysis using chi square and t-test assessed the following outcomes: substance abuse, arrests, health problems, emotional problems, social risk problems, and recovery environment risk using Global Appraisal of Individual Need data collected as part of a multi-site study examining drug use, recidivism, service utilization and treatment. ADTC clients from twelve sites were included (N=666 male, 915 female). Independent variables included: gender, race, age, years of education, income, partner status, employment, social support, traumatization, and traumagenic factors. Results: Social support was associated with a decreased likelihood of arrest (p< .033), substance abuse (p< .001), recovery environment risk (p< .001) and social risk index (p< .001). Victimization within the past year was associated with increased substance use (p< .001), social risk problems (p< .008), and recovery environment risk (p< .001). Employment within the past year was associated with decreased recovery environmental risk (p< .024) and substance use (p< .001). Female gender was associated with an increased likelihood of reduction in substance abuse (p< .038). Conclusions:Desirable ADTCoutcomes derive from: Social support related to 4 of 6 outcomes. Victimization history related to 3 of 6 outcomes. Employment related to 2 of 4 outcomes. Client victimization related to ADTC outcomes. Addressing victimization and employment appear important to improve outcomes, as supported by these findings. Future analyses will examine whether these findings are robust in a multivariate analysis, controlling for trauma-informed treatment as well as a rasch based outcome model to determine factors that affect multiple outcomes. Financial support: NIDA 1K23DA031612-01A1, SAMHSA/Center for Substance Abuse Treatment 270201200001c. http://dx.doi.org/10.1016/j.drugalcdep.2014.09.498 Effect of methylphenidate preexposure on methylphenidate-induced conditioned taste avoidance Mirabella Muller, Bradley B. Wetzell, Shaun M. Flax, Heather E. King, Anthony L. Riley Psychopharmacology Laboratory, Department of Psychology, American University, Washington, DC