Among people experiencing homelessness, difficulty securing housing is often compounded by concurrent challenges including unemployment, chronic illness, criminal justice involvement, and ...victimization. The Moving Ahead Program (MAP) is a vocational rehabilitation program that seeks to help adults facing these challenges secure competitive employment. We prospectively studied how MAP graduates (N = 97) changed from the beginning of MAP to about 6 months after graduation. We observed a variety of positive outcomes in not just employment and housing but also health, substance use, and criminal justice involvement. However, these gains were not universal; for instance, participants were less likely to report positive outcomes at follow‐up if they started MAP with a serious mental illness, made relatively small gains in work skills, or did not seek mental health treatment during the 6 months after they completed MAP. These findings might encourage program staff to devote additional resources toward supporting at‐risk students.
Access to commercial CD19 CAR-T cells remains limited even in wealthy countries like Canada due to clinical, logistical, and financial barriers related to centrally manufactured products. We created ...a non-commercial academic platform for end-to-end manufacturing of CAR-T cells within Canada's publicly funded healthcare system. We report initial results from a single-arm, open-label study to determine the safety and efficacy of in-house manufactured CD19 CAR-T cells (entitled CLIC-1901) in participants with relapsed/refractory CD19 positive hematologic malignancies. Using a GMP compliant semi-automated, closed process on the Miltenyi Prodigy, T cells were transduced with lentiviral vector bearing a 4-1BB anti-CD19 CAR transgene and expanded. Participants underwent lymphodepletion with fludarabine and cyclophosphamide, followed by infusion of non-cryopreserved CAR-T cells. Thirty participants with non-Hodgkin's lymphoma (n=25) or acute lymphoblastic leukemia (n=5) were infused with CLIC-1901: 21 males (70%), median age 66 (range 18-75). Time from enrollment to CLIC-1901 infusion was a median of 20 days (range 15-48). The median CLIC-1901 dose infused was 2.3 × 10
CAR-T cells/kg (range 0.13-3.6 × 10
/kg). Toxicity included ≥ grade 3 cytokine release syndrome (n=2) and neurotoxicity (n=1). Median follow-up was 6.5 months. Overall response rate at day 28 was 76.7%. Median progression-free and overall survival was 6 months (95%CI 3-not estimable) and 11 months (95% 6.6-not estimable), respectively. This is the first trial of in-house manufactured CAR-T cells in Canada and demonstrates that administering fresh CLIC-1901 product is fast, safe, and efficacious. Our experience may provide helpful guidance for other jurisdictions seeking to create feasible and sustainable CAR-T cell programs in research-oriented yet resource-constrained settings.
https://clinicaltrials.gov/ct2/show/NCT03765177, identifier NCT03765177.
The environment for embryo implantation and fetal growth and development is affected by maternal nutritional, metabolic and health status. The aim of this prospective, cohort study was to test ...whether plasma metabolic and inflammatory biomarkers can predict pregnancy resulting from in vitro fertilisation (IVF). Women with a natural menstrual cycle undergoing frozen embryo transfer (FET) were recruited and fasting baseline blood samples were collected a mean of 3.4 days prior to the luteinising hormone (LH) surge and a non-fasting blood sample was taken on the day of FET. Ongoing pregnancy was defined by positive fetal heartbeat on ultrasound scan at day 45 post LH surge. Thirty-six pregnancies resulted from FET in 143 women. In an overall stepwise multivariable analysis, erythrocyte saturated to unsaturated fatty acid ratio was positively associated with ongoing pregnancy. A similar model incorporating day of FET covariates found that erythrocyte saturated to unsaturated fatty acid ratio, erythrocyte fatty acid average chain length and plasma log-triglycerides predicted ongoing pregnancy. In conclusion, a higher peri-conceptional saturated to unsaturated fatty acid ratio predicted ongoing pregnancy after natural cycle frozen embryo transfer and may reflect a maternal nutritional status that facilitates pregnancy success in this assisted conception scenario.
During 2011, the Governor of Massachusetts signed a bill to allow casino gambling in the state (Commonwealth of Massachusetts
2011
). As a result, two resort casinos will begin operations during 2018 ...and 2019; a smaller slots parlor began operations during June 2015. Prior to this expansion, gambling was widely available in Massachusetts, through the state lottery, off-track betting, and gambling opportunities available in neighboring states. Within this context, it is important to understand the patterns of gambling involvement in the population prior to gambling expansion. The current study examined gambling involvement, patterns of play, and gambling-related problems prior to gambling expansion among a sample of 511 Massachusetts residents who were members of a statewide Internet panel. To measure patterns of play, we asked questions about past-year games played and frequency of play. To measure breadth of involvement, we assessed the number of different games played. To measure depth of involvement, we measured time spent gambling, amount wagered, and amount won or lost. Principal component analysis revealed four play pattern components accounting for more than 50% of the variance in game play frequency. Multiple regression analyses revealed that component scores composed of casino gambling and skill-based gambling (e.g., poker, sports) variables uniquely contributed to the prediction of gambling-related problems, even when depth of involvement was controlled. However, the addition of breadth of involvement to the model resulted in a model where no set of variables contributed significantly, suggesting a complex relationship among play patterns, depth, and breadth of involvement. The study established discrete and distinguishable gambling play patterns associated with gambling-related problems and identified groups of individuals potentially vulnerable to the effects of gambling expansion.
Summary
A central goal of human genetics is to identify susceptibility genes for common human diseases. An important challenge is modelling gene–gene interaction or epistasis that can result in ...nonadditivity of genetic effects. The multifactor dimensionality reduction (MDR) method was developed as a machine learning alternative to parametric logistic regression for detecting interactions in the absence of significant marginal effects. The goal of MDR is to reduce the dimensionality inherent in modelling combinations of polymorphisms using a computational approach called constructive induction. Here, we propose a Robust Multifactor Dimensionality Reduction (RMDR) method that performs constructive induction using a Fisher's Exact Test rather than a predetermined threshold. The advantage of this approach is that only statistically significant genotype combinations are considered in the MDR analysis. We use simulation studies to demonstrate that this approach will increase the success rate of MDR when there are only a few genotype combinations that are significantly associated with case‐control status. We show that there is no loss of success rate when this is not the case. We then apply the RMDR method to the detection of gene–gene interactions in genotype data from a population‐based study of bladder cancer in New Hampshire.
Given the demand to better address the principles of equity, diversity, inclusion, and accessibility in higher education, research into both barriers and promising practices to support autistic ...students on post-secondary campuses has advanced significantly in the last decade. The objective of this scoping review is to identify, map, and characterize literature that enumerates and describes supports for autistic post-secondary students. This scoping review was limited to peer-reviewed research published between January 2012 and May 2022, in these databases: Web of Science, PsycINFO, Medline, EMBASE, ERIC, Social Work Abstracts, Social Services Abstracts, and EMCARE. The review aligns to Joanna Briggs Institute methodology for scoping reviews and includes consultation with an expert panel made up of the Autistic Community Partners–four autistic individuals with postsecondary experience who acted as co-researchers. Literature on creating accessible campuses were mapped in three ways: (1) through the four domains of the PASS Taxonomy; (2) ten support categories characterizing types of supports, and (3) nine emergent themes, based on autistic experiences on support and campus navigation, were inductively and iteratively coded throughout process. This review summarizes both areas that have been researched and under-studied areas in the literature that act as contributors or challenges for autistic students on postsecondary campuses. It was also the first scoping review, to our knowledge, to integrate lived experience within the methods and results analysis to describe the current state of the evidence on post-secondary campuses. Mapping the literature in known and emerging categories indicated that broad categories of support are experienced variably by autistic students. Findings provide multiple avenues for future research.
T cells engineered to express antigen-specific T cell receptors (TCRs) are potent therapies for viral infections and cancer. However, efficient identification of clinical candidate TCRs is ...complicated by the size and complexity of T cell repertoires and the challenges of working with primary T cells. Here we present a high-throughput method to identify TCRs with high functional avidity from diverse human T cell repertoires. The approach used massively parallel microfluidics to generate libraries of natively paired, full-length TCRαβ clones, from millions of primary T cells, which were then expressed in Jurkat cells. The TCRαβ-Jurkat libraries enabled repeated screening and panning for antigen-reactive TCRs using peptide major histocompatibility complex binding and cellular activation. We captured more than 2.9 million natively paired TCRαβ clonotypes from six healthy human donors and identified rare (<0.001% frequency) viral-antigen-reactive TCRs. We also mined a tumor-infiltrating lymphocyte sample from a patient with melanoma and identified several tumor-specific TCRs, which, after expression in primary T cells, led to tumor cell killing.
Abstract Objective Out-of-school time (OST) programs serve a large, diverse population of children, including those at increased obesity risk. In this study, parents' perspectives about nutrition and ...physical activity (PA) during OST were assessed. Design Survey. Setting Online. Participants Six hundred parents with a school-aged child participating in programs from selected OST organizations. Main Outcome Measures Parent perspectives about the importance and availability of different foods, beverages, and PA opportunities during OST, and OST program and parent involvement in promoting healthful environments. Analysis Frequencies were used to describe parents' perspectives. Wilcoxon tests and logistic regression analyses were conducted to test for significant differences. Results Most parents reported that it was important that their children have water (96.2%), fresh fruits and vegetables (79.0%), and PA (97.2%) during OST; fewer parents reported that these were regularly available. About two thirds of parents agreed that OST programs should promote healthy environments for children, whereas one third agreed that parents alone should be responsible for children's nutrition and PA. Conclusions and Implications Results suggest that many parents would support efforts to improve OST nutrition and PA. Yet, there is a need to further understand the perceptions and motivations of different subgroups to enact successful obesity prevention efforts during OST.
Loss of critical endothelial cell function and subsequent vascular smooth muscle cell (VSMC) migration is central to the pathology of injury-induced neointimal hyperplasia and recurrent stenosis. ...Thrombomodulin (TM), well known for its function as an endothelial surface anticoagulant, may have an unknown direct effect on VSMC physiology that would be lost after injury. Here, we examined a novel effect of TM on VSMC by testing the hypothesis that direct application of TM induces favorable changes to the morphology of VSMC and inhibits their migration.
Primary human VSMC were harvested using the explant technique and used in early passage (1-4) for all experiments. Laser-scanning confocal fluorescent imaging was performed to assess the effect of soluble TM on VSMC morphology. In vitro, migration of VSMC was measured using: (1) a 4-hr modified Boyden chemotaxis assay and (2) a 24-hr electric cell-substrate impedance sensing injury migration assay. Migration experiments were conducted with VSMC exposed to increasing doses of soluble recombinant TM. Recombinant thrombin served as a positive control and serum-free media as a negative control for all experimentation. Data were analyzed using a Student's t-test or repeated measures analysis of variance where appropriate (α < 0.05).
VSMC exposed to TM clearly demonstrated a quiescent morphology with organized stress fibers consistent with a quiescent, differentiated, contractile phenotype; whereas, thrombin stimulation led to an activated, dedifferentiated, synthetic phenotype. VSMC demonstrated a low, baseline level of migration in unstimulated serum-free conditions. Thrombin significantly stimulated VSMC migration as expected. TM, independent of thrombin, significantly inhibited baseline VSMC migration in a dose-response fashion. The maximal inhibition was observed at (5 μg/mL) with 70% reduction (56 ± 1.7 vs. 18 ± 3.5 cells/5 high-power fields, P = 0.0005).
TM has a direct effect on VSMC resulting in a quiescent, differentiated and contractile phenotype, and inhibition of migration. This effect is independent of the presence of thrombin. These findings provide new knowledge in understanding the pathophysiology of vascular injury and support a strategy focused on restoring key endothelial function to prevent intimal hyperplasia.
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