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Introduction: The goal of this study was to evaluate changes in knowledge, attitudes, and other key suicide prevention issues for substance use disorder (SUD) counselors trained to administer the Preventing Addiction Related Suicide (PARS) module as part of a large-scale clinical trial. PARS is a 3-hour, PowerPoint based intervention designed with and for community SUD agencies for their Intensive Outpatient (IOP) group therapy programs. A previous randomized study of 906 patients from 15 community SUD sites showed positive changes in patients' suicide prevention knowledge, attitudes, and help seeking., Methods: Counselor participants completed measures of knowledge and attitudes about suicide and their confidence treating suicidal patients at each step of a large, stepped wedge cluster randomized trial of PARS, including after the final step. Data analysis compared scores in steps prior to counselors' training in PARS with scores in the steps following counselors' PARS training., Results: A total of 126 counselors participated in the study (89 % of those approached; 89-92 % retention across follow-up). Evaluation of both PARS efficacy and the PARS training by SUD counselors was highly rated. Counselor scores after receiving PARS training (vs. scores prior to PARS training) showed greater suicide knowledge, less maladaptive attitudes about suicide, and greater confidence in working with suicidal patients., Conclusions: Based on this rigorous test of PARS training for SUD counselors working in community SUD intensive outpatient programs, PARS training, as well as doing the PARS intervention, was rated as highly effective and acceptable. PARS offers an integrated, brief, engaging, and effective training method to improve suicide care for both SUD counselors and SUD clients., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Inc.)

Background: Outcome measures that are count variables with excessive zeros are common in health behaviors research. Examples include the number of standard drinks consumed or alcohol-related problems experienced over time. There is a lack of empirical data about the relative performance of prevailing statistical models for assessing the efficacy of interventions when outcomes are zero-inflated, particularly compared with recently developed marginalized count regression approaches for such data., Methods: The current simulation study examined five commonly used approaches for analyzing count outcomes, including two linear models (with outcomes on raw and log-transformed scales, respectively) and three prevailing count distribution-based models (ie, Poisson, negative binomial, and zero-inflated Poisson (ZIP) models). We also considered the marginalized zero-inflated Poisson (MZIP) model, a novel alternative that estimates the overall effects on the population mean while adjusting for zero-inflation. Motivated by alcohol misuse prevention trials, extensive simulations were conducted to evaluate and compare the statistical power and Type I error rate of the statistical models and approaches across data conditions that varied in sample size ( N = 100 $$ N=100 $$ to 500), zero rate (0.2 to 0.8), and intervention effect sizes., Results: Under zero-inflation, the Poisson model failed to control the Type I error rate, resulting in higher than expected false positive results. When the intervention effects on the zero (vs. non-zero) and count parts were in the same direction, the MZIP model had the highest statistical power, followed by the linear model with outcomes on the raw scale, negative binomial model, and ZIP model. The performance of the linear model with a log-transformed outcome variable was unsatisfactory., Conclusions: The MZIP model demonstrated better statistical properties in detecting true intervention effects and controlling false positive results for zero-inflated count outcomes. This MZIP model may serve as an appealing analytical approach to evaluating overall intervention effects in studies with count outcomes marked by excessive zeros., (© 2024 The Author(s). Statistics in Medicine published by John Wiley & Sons Ltd.)

Self-stigma-the internalization of negative community attitudes and beliefs about a disease or condition-represents an important barrier to improving patient care outcomes for people living with common mental disorders and diabetes. Integrated behavioral healthcare interventions are recognized as evidence-based approaches to improve access to behavioral healthcare and for improving patient outcomes, including for those with comorbid diabetes, yet their impact on addressing self-stigma remains unclear. Using secondary data from the Integrating Depression and Diabetes Treatment (INDEPENDENT) study-a trial that aimed to improve diabetes outcomes for people with undertreated and comorbid depression in four urban Indian cities via the Collaborative Care Model-we longitudinally analyzed self-stigma scores and evaluated whether change in total self-stigma scores on diabetes outcomes is mediated by depressive symptom severity. Self-stigma scores did not differ longitudinally comparing Collaborative Care Model participants to enhanced standard-of-care participants (mean monthly rate of change in Self-Stigma Scale for Chronic Illness-4 Item scores; B = 0.0087; 95% CI: -0.0018, 0.019, P = .10). Decreases in total self-stigma scores over 12 months predicted diabetes outcomes at 12 months (HbA1c, total effect; B = 0.070 95%CI: 0.0032, 0.14; P < .05), however depressive symptoms did not mediate this relationship (average direct effect; B = 0.064; 95% CI: -0.0043, 0.13, P = .069). Considering the local and plural notions of stigma in India, further research is needed on culturally grounded approaches to measure and address stigma in India, and on the role of integrated care delivery models alongside multi-level stigma reduction interventions. Trial registration : ClinicalTrials.gov, NCT02022111. https://clinicaltrials.gov/study/NCT02022111., Competing Interests: SH is a technical adviser for the non-profit organization Possible for which he receives no compensation. The authors have declared that no competing interests exist., (Copyright: © 2024 Halliday et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Little is known about the impacts of living in diaspora from the Hawaiian Islands on Native Hawaiian health. To address this, the authors conducted an exploratory analysis using cross-sectional data from the 2021 Native American COVID-19 Alliance Needs Assessment. A total of 1418 participants identified as Native Hawaiian (alone or in any combination), of which 1222 reported residency in the continental US and 196 in Hawai'i. Residency status in the continental US vs Hawai'i was evaluated as a predictor of survey outcomes using likelihood ratio tests on linear and logistic regression models for linear and binary outcomes, respectively. Results showed that NH residency in the continental US was significantly associated with increased odds of reporting fair or poor self-rated health; increased odds for screening positive for anxiety, depression, and suicidality; and increased odds of health insurance loss ( P 's < .05). Residency in the continent was also associated with lower odds of reporting a diagnosed chronic health condition ( P < .05). Residency in the continental US had no observed effect on the odds that participants engaged cultural activities or cultural coping strategies. These results support the role of place of residency as an important Native Hawaiian health predictor during and beyond the COVID-19 pandemic., Competing Interests: This article was prepared, in part, while Dr. Walters was employed at the University of Washington, Indigenous Wellness Research Institute. The present study was internally funded by the Ola Pasifika Lab. The authors claim no conflict of interest. The authors extend our gratitude to the participants, funders, and partners of NACA. Mahalo no ka hui pū ‘ana., (©Copyright 2024 by University Health Partners of Hawai‘i (UHP Hawai‘i).)

Small non-coding RNAs can be secreted through a variety of mechanisms, including exosomal sorting, in small extracellular vesicles, and within lipoprotein complexes. However, the mechanisms that govern their sorting and secretion are not well understood. Here, we present ExoGRU, a machine learning model that predicts small RNA secretion probabilities from primary RNA sequences. We experimentally validated the performance of this model through ExoGRU-guided mutagenesis and synthetic RNA sequence analysis. Additionally, we used ExoGRU to reveal cis and trans factors that underlie small RNA secretion, including known and novel RNA-binding proteins (RBPs), e.g., YBX1, HNRNPA2B1, and RBM24. We also developed a novel technique called exoCLIP, which reveals the RNA interactome of RBPs within the cell-free space. Together, our results demonstrate the power of machine learning in revealing novel biological mechanisms. In addition to providing deeper insight into small RNA secretion, this knowledge can be leveraged in therapeutic and synthetic biology applications., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: This study examines the rates and trends of faculty promotions within the field of ophthalmology, with comparative emphasis on the rates of promotion among underrepresented in medicine (URiM) faculty., Design: A retrospective panel study was conducted using the Association of American Medical Colleges Faculty Roster database., Methods: We used the Association of American Medical Colleges Faculty Roster data to assess trends in academic faculty promotions within U.S. ophthalmology departments. Full-time assistant and associate professors appointed between 2000 and 2010 were included in the analysis, and tracked until November 2021 to determine promotion rates. Pearson χ 2 and Fisher exact tests were used to evaluate differences in promotion and retention rates based on gender, race and ethnicity, advanced degree, and tenure status., Results: The demographics of 1436 assistant and 680 associate faculty members were obtained for analysis through the Association of American Medical Colleges. Black faculty had lower promotion rates when compared with White faculty (20% vs 37%, P < .001). Faculty with MD and PhD degrees demonstrated higher promotion rates than faculty with MD degrees alone (59% vs 36%, P < .001). In addition, faculty not on tenure track had lower rates of promotion than those on tenure track (35% vs 48%, P < .001). With respect to faculty retention, among assistant and associate professors combined, Black faculty and faculty without tenure track appointments were more likely to leave academic medicine (46% vs 33%, P < .001) and (36% vs 27%, P < .001), respectively., Conclusion: In this study, promotion rates varied significantly by race/ethnicity. Specifically, Black faculty had lower rates of promotion and retention in academic medicine. These findings underscore the need to explore and implement strategies and policies to address equity in promotion rates and retention of URiM faculty within academic ophthalmology., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Microglia are the resident immune cells in the brain that play a key role in driving neuroinflammation, a hallmark of neurodegenerative disorders. Inducible microglia-like cells have been developed as an in vitro platform for molecular and therapeutic hypothesis generation and testing. However, there has been no systematic assessment of similarity of these cells to primary human microglia along with their responsiveness to external cues expected of primary cells in the brain. In this study, we performed transcriptional characterization of commercially available human inducible pluripotent stem cell (iPSC)-derived microglia-like (iMGL) cells by bulk and single cell RNA sequencing to assess their similarity with primary human microglia. To evaluate their stimulation responsiveness, iMGL cells were treated with Liver X Receptor (LXR) pathway agonists and their transcriptional responses characterized by bulk and single cell RNA sequencing. Bulk transcriptome analyses demonstrate that iMGL cells have a similar overall expression profile to freshly isolated human primary microglia and express many key microglial transcription factors and functional and disease-associated genes. Notably, at the single-cell level, iMGL cells exhibit distinct transcriptional subpopulations, representing both homeostatic and activated states present in normal and diseased primary microglia. Treatment of iMGL cells with LXR pathway agonists induces robust transcriptional changes in lipid metabolism and cell cycle at the bulk level. At the single cell level, we observe heterogeneity in responses between cell subpopulations in homeostatic and activated states and deconvolute bulk expression changes into their corresponding single cell states. In summary, our results demonstrate that iMGL cells exhibit a complex transcriptional profile and responsiveness, reminiscent of in vivo microglia, and thus represent a promising model system for therapeutic development in neurodegeneration., (© 2024. The Author(s).)

Understanding the efficacy and relative effectiveness of a brief alcohol intervention (BAI) relies on obtaining a credible intervention effect estimate. Outcomes in BAI trials are often count variables, such as the number of drinks consumed, which may be overdispersed (i.e., greater variability than expected based on a given model) and zero-inflated (i.e., greater probability of zeros than expected based on a given model). Ignoring such distribution characteristics can lead to biased estimates and invalid statistical conclusions. In this critical review, we identified and reviewed 64 articles that reported count outcomes from a systematic review of BAI trials for adolescents and young adults from 2013 to 2018. Given many statistical models to choose from when analyzing count outcomes, we reviewed the models used and reporting practices in the BAI trial literature. A majority (61.3%) of analyses with count outcomes used linear models despite violations of normality assumptions; 75.6% of outcome variables demonstrated clear overdispersion. We provide an overview of available count models (Poisson, negative binomial, zero-inflated or hurdle, and marginalized zero-inflated Poisson regression) and formulate practical guidelines for reporting outcomes of BAIs. We provide a visual step-by-step decision guide for selecting appropriate statistical models and reporting results for count outcomes. We list accessible resources to help researchers select an appropriate model with which to analyze their data. Recent advances in count distribution-based models hold promise for evaluating count outcomes to gauge the efficacy and effectiveness of BAIs and identify critical covariates in alcohol epidemiologic research. We recommend that researchers report the distributional properties of count outcomes, such as the proportion of zero counts, and select an appropriate statistical analysis for count outcomes using the provided decision tree. By following these recommendations, future research may yield more accurate, transparent, and reproducible results., (© 2023 The Authors. Alcohol: Clinical and Experimental Research published by Wiley Periodicals LLC on behalf of Research Society on Alcohol.)

Native American (NA) populations in the USA (i.e., those native to the USA which include Alaska Natives, American Indians, and Native Hawaiians) have confronted unique historical, sociopolitical, and environmental stressors born of settler colonialism. Contexts with persistent social and economic disadvantage are critical determinants of substance misuse and co-occurring sexual risk-taking and suicide outcomes, as well as alcohol exposed pregnancy among NA young people (i.e., adolescents and young adults). Despite intergenerational transmission of resistance and resiliencies, NA young people face continued disparities in substance misuse and co-occurring outcomes when compared to other racial and ethnic groups in the USA. The failure in progress to address these inequities is the result of a complex set of factors; many of which are structural and rooted in settler colonialism. One of these structural factors includes barriers evident in health equity research intended to guide solutions to address these disparities yet involving maintenance of a research status quo that has proven ineffective to developing these solutions. Explicitly or implicitly biased values, perspectives, and practices are deeply rooted in current research design, methodology, analysis, and dissemination and implementation efforts. This status quo has been supported, intentionally and unintentionally, by researchers and research institutions with limited experience or knowledge in the historical, social, and cultural contexts of NA communities. We present a conceptual framework illustrating the impact of settler colonialism on current research methods and opportunities to unsettle its influence. Moreover, our framework illustrates opportunities to resist settler colonialism in research. We then focus on case examples of studies from the Intervention Research to Improve Native American Health program, funded by the NIH, that impact substance use and co-occurring health conditions among NA young people., Competing Interests: Competing Interests The authors declare no competing interests.

Meta-analysis using individual participant data (IPD) is an important methodology in intervention research because it (a) increases accuracy and precision of estimates, (b) allows researchers to investigate mediators and moderators of treatment effects, and (c) makes use of extant data. IPD meta-analysis can be conducted either via a one-step approach that uses data from all studies simultaneously, or a two-step approach, which aggregates data for each study and then combines them in a traditional meta-analysis model. Unfortunately, there are no evidence-based guidelines for how best to approach IPD meta-analysis for count outcomes with many zeroes, such as alcohol use. We used simulation to compare the performance of four hurdle models (3 one-step and 1 two-step models) for zero-inflated count IPD, under realistic data conditions. Overall, all models yielded adequate coverage and bias for the treatment effect in the count portion of the model, across all data conditions. However, in the zero portion, the treatment effect was underestimated in most models and data conditions, especially when there were fewer studies. The performance of both one- and two-step approaches depended on the formulation of the treatment effects, suggesting a need to carefully consider model assumptions and specifications when using IPD.

To evaluate and optimize brief alcohol interventions (BAIs), it is critical to have a credible overall effect size estimate as a benchmark. Estimating such an effect size has been challenging because alcohol outcomes often represent responses from a mixture of individuals: those at high risk for alcohol misuse, occasional nondrinkers, and abstainers. Moreover, some BAIs exclusively focus on heavy drinkers, whereas others take a universal prevention approach. Depending on sample characteristics, the outcome distribution might have many zeros or very few zeros and overdispersion; consequently, the most appropriate statistical model may differ across studies. We synthesized individual participant data (IPD) from 19 studies in Project INTEGRATE (Mun et al., 2015b) that randomly allocated participants to intervention and control groups (N = 7,704 participants, 38.4% men, 74.7% White, 58.5% first-year students). We sequentially estimated marginalized zero-inflated Poisson (Long et al., 2014) or negative binomial regression models to obtain covariate-adjusted, study-specific intervention effect estimates in the first step, which were subsequently combined in a random-effects meta-analysis model in the second step. BAIs produced a statistically significant 8% advantage in the mean number of drinks at both 1-3 months (RR = 0.92, 95% CI = [0.85, 0.98]) and 6 months (RR = 0.92, 95% CI = [0.85, 0.99]) compared to controls. At 9-12 months, there was no statistically significant difference in the mean number of drinks between BAIs and controls. In conclusion, BAIs are effective at reducing the mean number of drinks through at least 6 months post intervention. IPD can play a critical role in deriving findings that could not be obtained in original individual studies or standard aggregate data meta-analyses., (© 2022. The Author(s).)

Background: Brief motivational interventions (BMIs) are one of the most effective individually focused alcohol intervention strategies for college students. Despite the central theoretical role of motivation for change in BMIs, it is unclear whether BMIs increase motivation to change drinking behavior. We conducted a two-step meta-analysis of individual participant data (IPD) to examine whether BMIs increase motivation for change. N = 5903;59% women, 72% White) from Project INTEGRATE. The BMIs included individually delivered motivational interviewing with personalized feedback (MI + PF), stand-alone personalized feedback (PF), and group-based motivational interviewing (GMI)., Methods: We included 15 trials of BMI (N = 5903;59% women, 72% White) from Project INTEGRATE. The BMIs included individually-delivered motivational interviewing with personalized feedback (MI + PF), stand-alone personalized feedback (PF), and group-based motivational interviewing (GMI). Different measures and responses used in the original trials were harmonized. Effect size estimates were derived from a model that adjusted for baseline motivation and demographic variables for each trial (step 1) and subsequently combined in a random-effects meta-analysis (step 2)., Results: The overall intervention effect of BMIs on motivation for change was not statistically significant (standard mean difference [SMD]: 0.026, 95% CI: [-0.001, 0.053], p = 0.06, k = 19 comparisons). Of the three subtypes of BMIs, GMI, which tended to provide motivation-targeted content, had a statistically significant intervention effect on motivation, compared with controls (SMD: 0.055, 95% CI: [0.007, 0.103], p = 0.025, k = 5). By contrast, there was no evidence that MI + PF (SMD = 0.04, 95% CI: [-0.02, 0.10], k = 6, p = 0.20) nor PF increased motivation (SMD = 0.005, 95% CI: [-0.028, 0.039], k = 8, p = 0.75), compared with controls. Post hoc meta-regression analysis suggested that motivation sharply decreased each month within the first 3 months postintervention (b = -0.050, z = -2.80, p = 0.005 for k = 14)., Conclusions: Although BMIs provide motivational content and normative feedback and are assumed to motivate behavior change, the results do not wholly support the hypothesis that BMIs improve motivation for change. Changing motivation is difficult to assess during and following interventions, but it is still a theoretically important clinical endpoint. Further, the evidence cautiously suggests that changing motivation may be achievable, especially if motivation-targeted content components are provided., (© 2023 The Authors. Alcohol: Clinical and Experimental Research published by Wiley Periodicals LLC on behalf of Research Society on Alcohol.)

Objective: American Indian and Alaskan Natives (AIAN) are regenerating cultural knowledge and practices to adapt westernized evidence-based interventions to address health concerns such as substance use. This study describes the process of selecting, adapting, and implementing motivational interviewing plus cognitive behavior therapy (motivational interviewing + Skills Training; MIST) for use in a combined substance use intervention with a rural, Northwest tribal community., Methods: An established community and academic partnership worked together to make culturally mindful changes to MIST. The partnership incorporated community leaders/Elders (n = 7), providers (n = 9), and participants (n = 50) to implement an iterative process of adapting and implementing the adapted form of MIST., Results: Key adaptations included presenting concepts grounded in tribal values, providing examples from the community perspective, and incorporating cultural customs and traditions. Overall, the MIST adaptation was favorably received by participants, and the adaptation appeared feasible., Conclusions: Adapted MIST appeared to be an acceptable intervention for this Native American community. Future research should evaluate the interventions efficacy in reducing substance use among this and other Native American communities. Future clinical research should consider strategies outlined in this adaptation as a potential process for working with Native American communities to implement culturally appropriate interventions.

Study Question: How does an altered maternal hormonal environment, such as that seen during superovulation with gonadotropins in ART, impact human uterine immune cell distribution and function during the window of implantation?, Summary Answer: Hormonal stimulation with gonadotropins alters abundance of maternal immune cells including uterine natural killer (uNK) cells and reduces uNK cell ability to promote extravillous trophoblast (EVT) invasion., What Is Known Already: An altered maternal hormonal environment, seen following ART, can lead to increased risk for adverse perinatal outcomes associated with disordered placentation. Maternal immune cells play an essential role in invasion of EVTs, a process required for proper establishment of the placenta, and adverse perinatal outcomes have been associated with altered immune cell populations. How ART impacts maternal immune cells and whether this can in turn affect implantation and placentation in humans remain unknown., Study Design, Size, Duration: A prospective cohort study was carried out between 2018 and 2021 on 51 subjects: 20 from natural cycles 8 days after LH surge; and 31 from stimulated IVF cycles 7 days after egg retrieval., Participants/materials, Setting, Methods: Endometrial biopsies and peripheral blood samples were collected during the window of implantation in subjects with regular menstrual cycles or undergoing superovulation. Serum estradiol and progesterone levels were measured by chemiluminescent competitive immunoassay. Immune cell populations in blood and endometrium were analyzed using flow cytometry. uNK cells were purified using fluorescence-activated cell sorting and were subjected to RNA sequencing (RNA-seq). Functional changes in uNK cells due to hormonal stimulation were evaluated using the implantation-on-a-chip (IOC) device, a novel bioengineered platform using human primary cells that mimics early processes that occur during pregnancy in a physiologically relevant manner. Unpaired t-tests, one-way ANOVA, and pairwise multiple comparison tests were used to statistically evaluate differences., Main Results and the Role of Chance: Baseline characteristics were comparable for both groups. As expected, serum estradiol levels on the day of biopsy were significantly higher in stimulated (superovulated) patients (P = 0.0005). In the setting of superovulation, we found an endometrium-specific reduction in the density of bulk CD56+ uNK cells (P < 0.05), as well as in the uNK3 subpopulation (P = 0.025) specifically (CD103+ NK cells). In stimulated samples, we also found that the proportion of endometrial B cells was increased (P < 0.0001). Our findings were specific to the endometrium and not seen in peripheral blood. On the IOC device, uNK cells from naturally cycling secretory endometrium promote EVT invasion (P = 0.03). However, uNK cells from hormonally stimulated endometrium were unable to significantly promote EVT invasion, as measured by area of invasion, depth of invasion, and number of invaded EVTs by area. Bulk RNA-seq of sorted uNK cells from stimulated and unstimulated endometrium revealed changes in signaling pathways associated with immune cell trafficking/movement and inflammation., Limitations, Reasons for Caution: Patient numbers utilized for the study were low but were enough to identify significant overall population differences in select immune cell types. With additional power and deeper immune phenotyping, we may detect additional differences in immune cell composition of blood and endometrium in the setting of hormonal stimulation. Flow cytometry was performed on targeted immune cell populations that have shown involvement in early pregnancy. A more unbiased approach might identify changes in novel maternal immune cells not investigated in this study. We performed RNA-seq only on uNK cells, which demonstrated differences in gene expression. Ovarian stimulation may also impact gene expression and function of other subsets of immune cells, as well as other cell types within the endometrium. Finally, the IOC device, while a major improvement over existing in vitro methods to study early pregnancy, does not include all possible maternal cells present during early pregnancy, which could impact functional effects seen. Immune cells other than uNK cells may impact invasion of EVTs in vitro and in vivo, though these remain to be tested., Wider Implications of the Findings: These findings demonstrate that hormonal stimulation affects the distribution of uNK cells during the implantation window and reduces the proinvasive effects of uNK cells during early pregnancy. Our results provide a potential mechanism by which fresh IVF cycles may increase risk of disorders of placentation, previously linked to adverse perinatal outcomes., Study Funding/competing Interest(s): Research reported in this publication was supported by the University of Pennsylvania University Research Funding (to M.M.), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD068157 to M.M., S.S., and S.M.), National Center for Advancing Translational Sciences of the National Institutes of Health (TL1TR001880 to J.K.), the Institute for Translational Medicine and Therapeutics of the Perelman School of Medicine at the University of Pennsylvania, the Children's Hospital of Philadelphia Research Institute (to S.M.G.), and the National Institute of Allergy and Infectious Diseases (K08AI151265 to S.M.G.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. All authors declare no conflict of interest., Trial Registration Number: N/A., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Single-cell RNA sequencing is a state-of-the-art technology to understand gene expression in complex tissues. With the growing amount of data being generated, the standardization and automation of data analysis are critical to generating hypotheses and discovering biological insights., Results: Here, we present scRNASequest, a semi-automated single-cell RNA-seq (scRNA-seq) data analysis workflow which allows (1) preprocessing from raw UMI count data, (2) harmonization by one or multiple methods, (3) reference-dataset-based cell type label transfer and embedding projection, (4) multi-sample, multi-condition single-cell level differential gene expression analysis, and (5) seamless integration with cellxgene VIP for visualization and with CellDepot for data hosting and sharing by generating compatible h5ad files., Conclusions: We developed scRNASequest, an end-to-end pipeline for single-cell RNA-seq data analysis, visualization, and publishing. The source code under MIT open-source license is provided at https://github.com/interactivereport/scRNASequest . We also prepared a bookdown tutorial for the installation and detailed usage of the pipeline: https://interactivereport.github.io/scRNAsequest/tutorial/docs/ . Users have the option to run it on a local computer with a Linux/Unix system including MacOS, or interact with SGE/Slurm schedulers on high-performance computing (HPC) clusters., (© 2023. The Author(s).)

The COVID-19 pandemic has disrupted sexual health services among those most vulnerable to HIV acquisition, such as adolescent men who have sex with men (AMSM). We sought to characterize the changes in sexual-risk behaviors, HIV and other STI testing, and pre-exposure prophylaxis (PrEP) use among a longitudinal cohort of AMSM aged 13 to 18 years before and during the COVID-19 pandemic. We observed a significant decline in HIV testing and a marginal decrease in other STI testing since the pandemic began in March 2020. Outreach efforts and innovative remote delivery of sexual health services are needed to support access to healthcare services among AMSM as the pandemic persists., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In research applications, mental health problems such as alcohol-related problems and depression are commonly assessed and evaluated using scale scores or latent trait scores derived from factor analysis or item response theory models. This tutorial paper demonstrates the use of cognitive diagnosis models (CDMs) as an alternative approach to characterizing mental health problems of young adults when item-level data are available. Existing measurement approaches focus on estimating the general severity of a given mental health problem at the scale level as a unidimensional construct without accounting for other symptoms of related mental health problems. The prevailing approaches may ignore clinically meaningful presentations of related symptoms at the item level. The current study illustrates CDMs using item-level data from college students (40 items from 719 respondents; 34.6% men, 83.9% White, and 16.3% first-year students). Specifically, we evaluated the constellation of four postulated domains (i.e., alcohol-related problems, anxiety, hostility, and depression) as a set of attribute profiles using CDMs. After accounting for the impact of each attribute (i.e., postulated domain) on the estimates of attribute profiles, the results demonstrated that when items or attributes have limited information, CDMs can utilize item-level information in the associated attributes to generate potentially meaningful estimates and profiles, compared to analyzing each attribute independently. We introduce a novel visual inspection aid, the lens plot, for quantifying this gain. CDMs may be a useful analytical tool to capture respondents' risk and resilience for prevention research., (© 2022. The Author(s).)

We examined prevalence of mental health treatment utilization among 447 lesbian, gay, bisexual, transgender, and Two-Spirit (LGBTT-S) American Indian/Alaska Native (AI/AN) adults and the association of mental health treatment utilization with socio-demographic factors, social support, and mental health diagnoses. We derived data from the HONOR Project, a multi-site cross-sectional survey of Native LGBTT-S adults from seven U.S. metropolitan cities. Rates of lifetime mental health treatment utilization were higher for women (87%), those who were college educated (84%), and homeowners (92%). Cisgender women and transgender AI/AN adults had a higher prevalence than cisgender men of major depression, generalized anxiety, and panic disorder. Rates of subthreshold and threshold posttraumatic stress disorder were significantly higher for transgender adults. Lower positive social support and higher emotional social support were associated with greater odds of mental health treatment utilization. Mental health diagnoses and lifetime mental health treatment utilization was positively associated.

Brief motivational intervention (BMI) and personalized feedback intervention (PFI) are individual-focused brief alcohol intervention approaches that have been proven efficacious for reducing alcohol use among college students and young adults. Although the efficacy of these two intervention approaches has been well established, little is known about the factors that may modify their effects on alcohol outcomes. In particular, high school drinking may be a risk factor for continued and heightened use of alcohol in college, and thus may influence the outcomes of BMI and PFI. The purpose of this study was to investigate whether high school drinking was associated with different intervention outcomes among students who received PFI compared to those who received BMI. We conducted moderation analyses examining 348 mandated students (60.1% male; 73.3% White; and 61.5% first-year student) who were randomly assigned to either a BMI or a PFI and whose alcohol consumption was assessed at 4-month and 15-month follow-ups. Results from marginalized zero-inflated Poisson models showed that high school drinking moderated the effects of PFI and BMI at the 4-month follow-up but not at the 15-month follow-up. Specifically, students who reported no drinking in their senior year of high school consumed a 49% higher mean number of drinks after receiving BMI than PFI at the 4-month follow-up. The results suggest that alcohol consumption in high school may be informative when screening and allocating students to appropriate alcohol interventions to meet their different needs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tan, Friedman, Zhou, Huh, White and Mun.)

Objective: American Indian (AI) individuals are at increased risk for present-day trauma exposure and associated negative outcomes, as well as ongoing effects of intergenerational trauma exposure and adversity. However, few empirically supported treatments exist that are specifically tailored and/or tested with AI communities. This study describes the process of selecting, adapting, and implementing narrative exposure therapy (NET) with an AI community., Methods: A community and academic partnership was formed and worked together to make culturally mindful changes to NET to best fit the needs of the community. The partnership incorporated community leaders/Elders (n = 7), providers (n = 11), and participants seeking treatment (n = 50) to implement an iterative process of adapting and implementing the adapted form of NET., Results: Key adaptions included addressing historical and intergenerational trauma, greater protections for confidentiality in a small community, and incorporation of cultural customs and traditions. Overall, the adapted form of NET was favorably received by the participants, and the implementation appeared to be feasible, with improved retention over past trials of adapted trauma-focused treatments with this community and with highly positive satisfaction ratings and feedback., Conclusions: NET was shown to be an appropriate approach for this AI community and should be considered as a treatment option for other AI communities. Future work should consider strategies outlined in this adaption as well as following a similar process for working with AI communities to implement culturally appropriate interventions for trauma-related symptoms., (© 2022 Wiley Periodicals LLC.)

Introduction: Pasifika (Native Hawaiian and Pacific Islander) people living in the United States experience health, economic, and social inequities, and a disproportionate burden of COVID-19 cases and deaths. This study examines employment among Pasifika living in the 10 US states with the largest Pasifika populations during the COVID-19 pandemic., Methods: We use the Current Population Survey to examine racial differences in employment status, paid work from home (PWFH), and industry telework friendliness. We use data from the Washington Office of Fiscal Management and the Washington State (WA) Employment Security Department to examine county-level unemployment claims., Results: Nationally, Pasifika did not self-report unemployment significantly more than Black, Latino, Asian, and American Indian/Alaska Native respondents, but in WA counties with high Pasifika concentrations, unemployment insurance claim rates were higher compared with all other racial groups, particularly Whites and Asians. Surprisingly, Pasifika had more PWFH opportunities, but worked in less telework-friendly industries nationally., Discussion: This study demonstrates the complexity of employment among Pasifika during the COVID-19 pandemic. The findings correspond with national reports of racialized communities impacted by unemployment, including Pasifika. Marginally significant differences in unemployment nationally may be due to Pasifika working largely in essential industries requiring workplace attendance., Health Equity Implications: Although overlooked or overshadowed by size, our findings highlight the need for continued advocacy to support data disaggregation and Pasifika data sovereignty. This can be achieved through collaborations between researchers as well as local and community organizations to address data needs of Pasifika communities., Competing Interests: No competing financial interests exist., (© Santino G. Camacho et al., 2022; Published by Mary Ann Liebert, Inc.)

In this study, a different number of indium zinc oxide (IZO) interlayers are fabricated into Al 2 O 3 -based transparent resistive switching memory on a transparent indium tin oxide (ITO)/glass substrate at room temperature. Al 2 O 3 /IZO multilayer transparent memory has a transmittance of at least 65% in the wavelength range of 400-900 nm. In addition, the Al 2 O 3 /IZO multilayer transparent memory can achieve an electroforming voltage that is 35.7% lower than that of ITO/pure-Al 2 O 3 /IZO transparent memory. The fabricated Al 2 O 3 /IZO multilayer transparent memory exhibits typical bipolar resistive switching behavior, regardless of the number of IZO interlayers. Also, the fabricated Al 2 O 3 /IZO multilayer transparent memory has a low operating voltage within ±1.5 V. In addition, a flexible Al 2 O 3 /IZO multilayer transparent memory is fabricated using the same process on ITO-coated polyethylene terephthalate. The fabricated flexible transparent memory also maintains the resistive switching characteristics during the bending state., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors. Global Challenges published by Wiley‐VCH GmbH.)

Sensing devices have shown tremendous potential for monitoring state-of-the-art organ chip devices. However, challenges like miniaturization while maintaining higher performance, longer operating times for continuous monitoring, and fabrication complexities limit their use. Herein simple, low-cost, and solution-processible inkjet dispenser printing of embedded electrochemical sensors for dissolved oxygen (DO) and reactive oxygen species (ROS) is proposed for monitoring developmental (initially normoxia) and induced hypoxia in a custom-developed gut bilayer microfluidic chip platform for 6 days. The DO sensors showed a high sensitivity of 31.1 nA L mg -1 with a limit of detection (LOD) of 0.67 mg L -1 within the 0-9 mg L -1 range, whereas the ROS sensor had a higher sensitivity of 1.44 nA μm -1 with a limit of detection of 1.7 μm within the 0-300 μm range. The dynamics of the barrier tight junctions are quantified with the help of an in-house developed trans -epithelial-endothelial electrical impedance (TEEI) sensor. Immunofluorescence staining was used to evaluate the expressions of HIF-1α and tight junction protein (TJP) ZO-1. This platform can also be used to enhance bioavailability assays, drug transport studies under an oxygen-controlled environment, and even other barrier organ models, as well as for various applications like toxicity testing, disease modeling and drug screening.

This paper introduces a meta-analytic mediation analysis approach for individual participant data (IPD) from multiple studies. Mediation analysis evaluates whether the effectiveness of an intervention on health outcomes occurs because of change in a key behavior targeted by the intervention. However, individual trials are often statistically underpowered to test mediation hypotheses. Existing approaches for evaluating mediation in the meta-analytic context are limited by their reliance on aggregate data; thus, findings may be confounded with study-level differences unrelated to the pathway of interest. To overcome the limitations of existing meta-analytic mediation approaches, we used a one-stage estimation approach using structural equation modeling (SEM) to combine IPD from multiple studies for mediation analysis. This approach (1) accounts for the clustering of participants within studies, (2) accommodates missing data via multiple imputation, and (3) allows valid inferences about the indirect (i.e., mediated) effects via bootstrapped confidence intervals. We used data (N = 3691 from 10 studies) from Project INTEGRATE (Mun et al. Psychology of Addictive Behaviors, 29, 34-48, 2015) to illustrate the SEM approach to meta-analytic mediation analysis by testing whether improvements in the use of protective behavioral strategies mediate the effectiveness of brief motivational interventions for alcohol-related problems among college students. To facilitate the application of the methodology, we provide annotated computer code in R and data for replication. At a substantive level, stand-alone personalized feedback interventions reduced alcohol-related problems via greater use of protective behavioral strategies; however, the net-mediated effect across strategies was small in size, on average., (© 2021. The Author(s).)

Importance: Individuals with substance use disorders (SUDs) are at high risk for suicide. The Preventing Addiction Related Suicide (PARS) module is the first suicide prevention module developed in and for community substance use intensive outpatient programs (IOPs)., Objective: To evaluate the effectiveness of PARS on suicide-related outcomes (ie, knowledge, attitudes, and help-seeking behavior) compared with usual care., Design, Setting, and Participants: This stepped-wedge cluster-randomized clinical trial was conducted from 2017 to 2020, with follow-up assessments conducted after treatment and at 1, 3, and 6 months. Participants included adult outpatients in SUD treatment at community IOPs across western Washington state. Data were analyzed from July 1, 2020, to January 20, 2022., Interventions: The intervention, PARS, was a 1-session secondary prevention module administered by trained SUD counselors consisting of didactic presentations and group discussions about suicide risk factors, warning signs, and actions to take if suicide risk is observed in self or others. The control group received usual care., Main Outcomes and Measures: Primary outcomes were suicide knowledge, attitudes about suicide, and help-seeking behavior among patients enrolled in an IOP., Results: A total of 906 participants (mean [SD] age, 37.5 [12.0] years; 540 [59.6%] men) were included, with 478 participants receiving usual care and 428 participants receiving PARS. In intent-to-treat analysis from baseline to after treatment, there was a greater improvement in suicide knowledge (d = 0.15; 95% CI, 0.08 to 0.23; P < .001) and a greater reduction in maladaptive attitudes (d = 0.18; 95% CI, 0.14 to 0.25; P < .001) for PARS participants compared with those receiving usual care. Improvements were maintained at follow-up for suicide knowledge (1 month: d = 0.16; 95% CI, 0.07 to 0.22; P < .001; 3 months: d = 0.12; 95% CI, 0.05 to 0.19; P = .001; 6 months: d = 0.13; 95% CI, 0.06 to 0.20; P < .001) and reductions in maladaptive attitudes (1 month: d = 0.20; 95% CI, 0.12 to 0.23; P < .001; 3 months: d = 0.10; 95% CI, 0.05 to 0.16; P < .001; 6 months: d = 0.14; 95% CI, 0.09 to 0.19; P < .001), with 788 participants (87.0%) of the sample responding across time points. From baseline to 6 months, there was a greater improvement in help-seeking in the PARS group vs usual care (d = 0.16; 95% CI, 0.01 to 0.32; P = .04)., Conclusions and Relevance: This stepped-wedge cluster-randomized clinical trial found that PARS was superior to usual care in improving suicide knowledge, maladaptive attitudes, and help-seeking in adults undergoing community addiction treatment. As a 1-session IOP module developed in partnership with community addiction agencies, PARS has the potential for wide impact in the national suicide prevention strategy., Trial Registration: ClinicalTrials.gov Identifier: NCT03166709.

Recent developments in the field of the breath figure (BF) method have led to renewed interest from researchers in the pore-selective functionalization of honeycomb-patterned (HCP) films. The pore-selective functionalization of the HCP film gives unique properties to the film which can be used for specific applications such as protein recognition, catalysis, selective cell culturing, and drug delivery. There are several comprehensive reviews available for the pore-selective functionalization by the self-assembly process. However, considerable progress in preparation technologies and incorporation of new materials inside the pore surface for exact applications have emerged, thus warranting a review. In this review, we have focused on the pore-selective functionalization of the HCP films by the modified BF method, in which the self-assembly process is accompanied by an interfacial reaction. We review the importance of pore-selective functionalization, its applications, present limitations, and future perspectives.

Aims: College students who drink are at an increased risk of driving after drinking and alcohol-involved traffic accidents and deaths. Furthermore, the persistence of driving after drinking over time underscores a need for effective interventions to prevent future drunk driving in adulthood. The present study examined whether brief alcohol interventions (BAIs) for college students reduce driving after drinking., Methods: A two-step meta-analysis of individual participant data (IPD) was conducted using a combined sample of 6801 college students from 15 randomized controlled trials (38% male, 72% White and 58% first-year students). BAIs included individually delivered Motivational Interviewing with Personalized Feedback (MI + PF), Group Motivational Interviewing (GMI), and stand-alone Personalized Feedback (PF) interventions. Two outcome variables, driving after two+/three+ drinks and driving after four+/five+ drinks, were checked, harmonized and analyzed separately for each study and then combined for meta-analysis and meta-regression analysis., Results: BAIs lowered the risk of driving after four+/five+ drinks (19% difference in the odds of driving after drinking favoring BAIs vs. control), but not the risk of driving after two+/three+ drinks (9% difference). Subsequent subgroup analysis indicated that the MI + PF intervention was comparatively better than PF or GMI., Conclusions: BAIs provide a harm reduction approach to college drinking. Hence, it is encouraging that BAIs reduce the risk of driving after heavy drinking among college students. However, there may be opportunities to enhance the intervention content and timing to be more relevant for driving after drinking and improve the outcome assessment and reporting to demonstrate its effect., (© The Author(s) 2021. Medical Council on Alcohol and Oxford University Press.)

Many clinical endpoint measures, such as the number of standard drinks consumed per week or the number of days that patients stayed in the hospital, are count data with excessive zeros. However, the zero-inflated nature of such outcomes is sometimes ignored in analyses of clinical trials. This leads to biased estimates of study-level intervention effect and, consequently, a biased estimate of the overall intervention effect in a meta-analysis. The current study proposes a novel statistical approach, the Zero-inflation Bias Correction (ZIBC) method, that can account for the bias introduced when using the Poisson regression model, despite a high rate of inflated zeros in the outcome distribution of a randomized clinical trial. This correction method only requires summary information from individual studies to correct intervention effect estimates as if they were appropriately estimated using the zero-inflated Poisson regression model, thus it is attractive for meta-analysis when individual participant-level data are not available in some studies. Simulation studies and real data analyses showed that the ZIBC method performed well in correcting zero-inflation bias in most situations., (© 2021 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.)

The ability to ascribe mental states, such as beliefs or desires to oneself and other individuals forms an integral part of everyday social interaction. Animations tasks, in which observers watch videos of interacting triangles, have been extensively used to test mental state attribution in a variety of clinical populations. Compared to control participants, individuals with clinical conditions such as autism typically offer less appropriate mental state descriptions of such videos. Recent research suggests that stimulus kinematics and movement similarity (between the video and the observer) may contribute to mental state attribution difficulties. Here we present a novel adaptation of the animations task, suitable to track and compare animation generator and -observer kinematics. Using this task and a population-derived stimulus database, we confirmed the hypotheses that an animation's jerk and jerk similarity between observer and animator significantly contribute to the correct identification of an animation. By employing random forest analysis to explore other stimulus characteristics, we reveal that other indices of movement similarity, including acceleration- and rotation-based similarity, also predict performance. Our results highlight the importance of movement similarity between observer and animator and raise new questions about reasons why some clinical populations exhibit difficulties with this task., (© 2021. The Author(s).)

The cellular microenvironment is influenced explicitly by the extracellular matrix (ECM), the main tissue support biomaterial, as a decisive factor for tissue growth patterns. The recent emergence of hepatic microphysiological systems (MPS) provide the basic physiological emulation of the human liver for drug screening. However, engineering microfluidic devices with standardized surface coatings of ECM may improve MPS-based organ-specific emulation for improved drug screening. The influence of surface coatings of different ECM types on tissue development needs to be optimized. Additionally, an intensity-based image processing tool and transepithelial electrical resistance (TEER) sensor may assist in the analysis of tissue formation capacity under the influence of different ECM types. The current study highlights the role of ECM coatings for improved tissue formation, implying the additional role of image processing and TEER sensors. We studied hepatic tissue formation under the influence of multiple concentrations of Matrigel, collagen, fibronectin, and poly-L-lysine. Based on experimental data, a mathematical model was developed, and ECM concentrations were validated for better tissue development. TEER sensor and image processing data were used to evaluate the development of a hepatic MPS for human liver physiology modeling. Image analysis data for tissue formation was further strengthened by metabolic quantification of albumin, urea, and cytochrome P450. Standardized ECM type for MPS may improve clinical relevance for modeling hepatic tissue microenvironment, and image processing possibly enhance the tissue analysis of the MPS.

Thermoelectrics operating at high temperature can cost-effectively convert waste heat and compete with other zero-carbon technologies. Among different high-temperature thermoelectrics materials, silicon nanowires possess the combined attributes of cost effectiveness and mature manufacturing infrastructures. Despite significant breakthroughs in silicon nanowires based thermoelectrics for waste heat conversion, the figure of merit (ZT) or operating temperature has remained low. Here, we report the synthesis of large-area, wafer-scale arrays of porous silicon nanowires with ultra-thin Si crystallite size of ~4 nm. Concurrent measurements of thermal conductivity (κ), electrical conductivity (σ), and Seebeck coefficient (S) on the same nanowire show a ZT of 0.71 at 700 K, which is more than ~18 times higher than bulk Si. This ZT value is more than two times higher than any nanostructured Si-based thermoelectrics reported in the literature at 700 K. Experimental data and theoretical modeling demonstrate that this work has the potential to achieve a ZT of ~1 at 1000 K.

Hemostasis is an innate protective mechanism that plays a central role in maintaining the homeostasis of the vascular system during vascular injury. Studying this essential physiological process is often challenged by the difficulty of modeling and probing the complex dynamics of hemostatic responses in the native context of human blood vessels. To address this major challenge, this paper describes a microengineering approach for in vitro modeling of hemostasis. This microphysiological model replicates the living endothelium, multilayered microarchitecture, and procoagulant activity of human blood vessels, and is also equipped with a microneedle that is actuated with spatial precision to simulate penetrating vascular injuries. The system recapitulates key features of the hemostatic response to acute vascular injury as observed in vivo, including i) thrombin-driven accumulation of platelets and fibrin, ii) formation of a platelet- and fibrin-rich hemostatic plug that halts blood loss, and iii) matrix deformation driven by platelet contraction for wound closure. Moreover, the potential use of this model for drug testing applications is demonstrated by evaluating the effects of anticoagulants and antiplatelet agents that are in current clinical use. The vascular injury-on-a-chip may serve as an enabling platform for preclinical investigation of hematological disorders and emerging therapeutic approaches against them., (© 2020 Wiley-VCH GmbH.)

Here, we present an approach to model and adapt the mechanical regulation of morphogenesis that uses contractile cells as sculptors of engineered tissue anisotropy in vitro. Our method uses heterobifunctional cross-linkers to create mechanical boundary constraints that guide surface-directed sculpting of cell-laden extracellular matrix hydrogel constructs. Using this approach, we engineered linearly aligned tissues with structural and mechanical anisotropy. A multiscale in silico model of the sculpting process was developed to reveal that cell contractility increases as a function of principal stress polarization in anisotropic tissues. We also show that the anisotropic biophysical microenvironment of linearly aligned tissues potentiates soluble factor-mediated tenogenic and myogenic differentiation of mesenchymal stem cells. The application of our method is demonstrated by (i) skeletal muscle arrays to screen therapeutic modulators of acute oxidative injury and (ii) a 3D microphysiological model of lung cancer cachexia to study inflammatory and oxidative muscle injury induced by tumor-derived signals., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Hepatic fibrosis is a foreshadowing of future adverse events like liver cirrhosis, liver failure, and cancer. Hepatic stellate cell activation is the main event of liver fibrosis, which results in excessive extracellular matrix deposition and hepatic parenchyma's disintegration. Several biochemical and molecular assays have been introduced for in vitro study of the hepatic fibrosis progression. However, they do not forecast real-time events happening to the in vitro models. Trans-epithelial electrical resistance (TEER) is used in cell culture science to measure cell monolayer barrier integrity. Herein, we explored TEER measurement's utility for monitoring fibrosis development in a dynamic cell culture microphysiological system. Immortal HepG2 cells and fibroblasts were co-cultured, and transforming growth factor β1 (TGF-β1) was used as a fibrosis stimulus to create a liver fibrosis-on-chip model. A glass chip-based embedded TEER and reactive oxygen species (ROS) sensors were employed to gauge the effect of TGF-β1 within the microphysiological system, which promotes a positive feedback response in fibrosis development. Furthermore, albumin, Urea, CYP450 measurements, and immunofluorescent microscopy were performed to correlate the following data with embedded sensors responses. We found that chip embedded electrochemical sensors could be used as a potential substitute for conventional end-point assays for studying fibrosis in microphysiological systems.

Eukaryotic transfer RNAs can become selectively fragmented upon various stresses, generating tRNA-derived small RNA fragments. Such fragmentation has been reported to impact a small fraction of the tRNA pool and thus presumed to not directly impact translation. We report that oxidative stress can rapidly generate tyrosine-tRNA GUA fragments in human cells-causing significant depletion of the precursor tRNA. Tyrosine-tRNA GUA depletion impaired translation of growth and metabolic genes enriched in cognate tyrosine codons. Depletion of tyrosine tRNA GUA or its translationally regulated targets USP3 and SCD repressed proliferation-revealing a dedicated tRNA-regulated growth-suppressive pathway for oxidative stress response. Tyrosine fragments are generated in a DIS3L2 exoribonuclease-dependent manner and inhibit hnRNPA1-mediated transcript destabilization. Moreover, tyrosine fragmentation is conserved in C. elegans. Thus, tRNA fragmentation can coordinately generate trans-acting small RNAs and functionally deplete a tRNA. Our findings reveal the existence of an underlying adaptive codon-based regulatory response inherent to the genetic code., (© 2020 The Authors.)

Microglia are central nervous system (CNS) resident immune cells that have been implicated in neuroinflammatory pathogenesis of a variety of neurological conditions. Their manifold context-dependent contributions to neuroinflammation are only beginning to be elucidated, which can be attributed in part to the challenges of studying microglia in vivo and the lack of tractable in vitro systems to study microglia function. Organotypic brain slice cultures offer a tissue-relevant context that enables the study of CNS resident cells and the analysis of brain slice microglial phenotypes has provided important insights, in particular into neuroprotective functions. Here we use RNA sequencing, direct digital quantification of gene expression with nCounter® technology and targeted analysis of individual microglial signature genes, to characterize brain slice microglia relative to acutely-isolated counterparts and 2-dimensional (2D) primary microglia cultures, a widely used in vitro surrogate. Analysis using single cell and population-based methods found brain slice microglia exhibited better preservation of canonical microglia markers and overall gene expression with stronger fidelity to acutely-isolated adult microglia, relative to in vitro cells. We characterized the dynamic phenotypic changes of brain slice microglia over time, after plating in culture. Mechanical damage associated with slice preparation prompted an initial period of inflammation, which resolved over time. Based on flow cytometry and gene expression profiling we identified the 2-week timepoint as optimal for investigation of microglia responses to exogenously-applied stimuli as exemplified by treatment-induced neuroinflammatory changes observed in microglia following LPS, TNF and GM-CSF addition to the culture medium. Altogether these findings indicate that brain slice cultures provide an experimental system superior to in vitro culture of microglia as a surrogate to investigate microglia functions, and the impact of soluble factors and cellular context on their physiology., Competing Interests: AD is employed by Putnam Associates; MB, DH, JB, RC, PC, TC, KE, CS, H-HT, NA, NF are full-time employees and shareholders of Biogen; RR is employed by Third Rock Ventures; CR is employed by Genomics Institute of the Novartis Research Foundation; and MF is employed by bluebird bio. The authors declare that this study was funded by Biogen and designed and executed by current or former Biogen employees., (Copyright © 2020 Delbridge, Huh, Brickelmaier, Burns, Roberts, Challa, Raymond, Cullen, Carlile, Ennis, Liu, Sun, Allaire, Foos, Tsai, Franchimont, Ransohoff, Butts and Mingueneau.)

Monitoring microbial reactions in highly opaque or autofluorescent environments like soils, seawater, and wastewater remains challenging. To develop a simple approach for observing post-translational reactions within microbes situated in environmental matrices, we designed a methyl halide transferase (MHT) fragment complementation assay that reports by synthesizing an indicator gas. We show that backbone fission within regions of high sequence variability in the Rossmann domain yields split MHT (sMHT) AND gates whose fragments cooperatively associate to synthesize CH 3 Br. Additionally, we identify a sMHT whose fragments require fusion to pairs of interacting partner proteins for maximal activity. We also show that sMHT fragments fused to FKBP12 and the FKBP-rapamycin binding domain of mTOR display significantly enhanced CH 3 Br production in the presence of rapamycin. This gas production is reversed in the presence of the competitive inhibitor of FKBP12/FKPB dimerization, indicating that sMHT is a reversible reporter of post-translational reactions. This sMHT represents the first genetic AND gate that reports on protein-protein interactions via an indicator gas. Because indicator gases can be measured in the headspaces of complex environmental samples, this assay should be useful for monitoring the dynamics of diverse molecular interactions within microbes situated in hard-to-image marine and terrestrial matrices.

Bone remodeling is a renewal process regulated by bone synthesis (osteoblasts) and bone destruction (osteoclasts). A previous study demonstrated that Lycii radicis cortex (LRC) extract inhibited ovariectomized (OVX)-induced bone loss in mice. This study investigated the anti-osteoporotic effects of bioactive constituent(s) from the LRC extract. The effective compound(s) were screened, and a single compound, scopolin, which acts as a phytoalexin, was chosen as a candidate component. Scopolin treatment enhanced alkaline phosphatase activity and increased mineralized nodule formation in MC3T3-E1 pre-osteoblastic cells. However, osteoclast differentiation in primary-cultured monocytes was reduced by treatment with scopolin. Consistently, scopolin treatment increased osteoblast differentiation in the co-culture of monocytes (osteoclasts) and MC3T3-E1 (osteoblast) cells. Scopolin treatment prevented bone mineral density loss in OVX-induced osteoporotic mice. These results suggest that scopolin could be a therapeutic bioactive constituent for the treatment and prevention of osteoporosis.

Purpose: To investigate the antimycotic activity of amphotericin B deoxycholate that has been previously frozen for 28 days before supplementation of Optisol-GS., Methods: Triplicate Optisol-GS samples were inoculated with 10 colony-forming units (CFU) of Candida albicans. Each set of triplicate cultures was supplemented with 2.5 μg/mL of amphotericin B that was either freshly resuspended and never frozen, frozen overnight at -20°C and thawed, or frozen at -20°C for 4 weeks and thawed. The cultures were stored at 4°C, with aliquots taken at 0, 6, 24, and 72 hours for quantification. The efficacy of each preparation of amphotericin B in reducing C. albicans growth was assessed at these time points., Results: Six hours after antifungal supplementation, there was a 1.33 log10 CFU reduction with freshly resuspended amphotericin B, compared with a 1.31 log10 reduction with amphotericin B that was frozen overnight (P = 0.20) and a 1.18 log10 reduction with amphotericin B that was frozen for 4 weeks (P = 0.05). After 72 hours, there was a 2.72 log10 CFU reduction with freshly resuspended amphotericin B, a 2.64 log10 CFU reduction with amphotericin B that was frozen overnight (P = 0.45), and a 2.18 log10 CFU reduction with amphotericin B that was frozen for 4 weeks (P = 0.05)., Conclusions: Previously frozen amphotericin B remains highly effective against C. albicans. Optisol-GS supplemented with 2.5 μg/mL amphotericin B that was frozen for 4 weeks at -20°C resulted in >90% CFU reduction by 6 hours and >99% reduction by 72 hours.

Latent growth models (LGMs) are an application of structural equation modeling and frequently used in developmental and clinical research to analyze change over time in longitudinal outcomes. Maximum likelihood (ML), the most common approach for estimating LGMs, can fail to converge or may produce biased estimates in complex LGMs especially in studies with modest samples. Bayesian estimation is a logical alternative to ML for LGMs, but there is a lack of research providing guidance on when Bayesian estimation may be preferable to ML or vice versa. This study compared the performance of Bayesian versus ML estimators for LGMs by evaluating their accuracy via Monte Carlo (MC) simulations. For the MC study, longitudinal data sets were generated and estimated using LGM via both ML and Bayesian estimation with three different priors, and parameter recovery across the two estimators was evaluated to determine their relative performance. The findings suggest that ML estimation is a reasonable choice for most LGMs, unless it fails to converge, which can occur with limiting data situations (i.e., just a few time points, no covariate or outcome, modest sample sizes). When models do not converge using ML, we recommend Bayesian estimation with one caveat that the influence of the priors on estimation may have to be carefully examined, per recent recommendations on Bayesian modeling for applied researchers.

Native Americans (NA) experience interrelated risks of trauma exposure, substance use, and HIV risk behaviors that put them at increased risk for HIV infection. Despite these known risk factors, there are very few published randomized trials testing interventions to reduce trauma-related symptoms and substance misuse among NA., Methods: The Healing Seasons study is a randomized comparsion trial of two counseling strategies, Narrative Exposure Therapy (NET) addressing PTSD or Motivational interviewing with cognitive behavioral therapy skills training (MIST) addressing substance misuse as a means to prevent HIV among NA. Using a community-based participatory research approach, we adapted both evidence-based interventions to be specific to the risk contexts and realities of NA and to include psychoeducational and skill-building components that include cultural-specific stories, virtues, and traditional treatment strategies. Participants, 16 years and older, were recruited from a Pacific Northwest tribal community, screened over the phone, enrolled in person, and randomized in equal numbers to NET or MIST. We stratified by age (16-29 years and 30 or older) and gender (male or female identified) to ensure balance between treatment arms. The primary outcomes were number of sex partners and frequency of sexual acts (with and without condoms), sex under the influence of substances, frequency of substance use, and PTSD severity., Discussion: Behavioral interventions for NA are needed to prevent HIV risk behaviors when faced with trauma symptoms and substance misuse. This study will provide evidence to determine feasibility and efficacy of addressing related risk factors as part of counseling-based HIV prevention intervention to reduce sexual risk among this population., Trial Registration: ClinicalTrials.gov number, NCT03112369, registered April 12, 2017., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Exposure to particulate matter (PM) is a well-known risk factor in the triggering and exacerbation of allergic airway disease. Indoor environments, where people spend most of their time, are of utmost importance. To assess the effects of air purifiers [equipped with high-efficiency particulate air (HEPA) filters] on allergic rhinitis (AR) in adult patients, we performed a multicenter, randomized, double-blind, and placebo-controlled study., Materials and Methods: Patients with house dust mite (HDM)-induced AR were randomly assigned to either active or mockup (placebo) air-purification groups. Two air purifiers (placed in living room and bedroom) were operated for 6 weeks in each home environment. The primary study endpoint was to achieve improvement in AR symptoms and medication scores. Secondary endpoints were to achieve improvement in the quality of life (QoL) and visual analog scale (VAS) scores, as well as in the indoor (bedroom and living room) concentrations of PM 2.5 and PM 10 ., Results: After 6 weeks of air purifier use, medication scores improved significantly in the active (vs. placebo) group, although subjective measures (symptoms, VAS, and QoL scores) did not differ. Bedroom PM 2.5 concentrations initially exceeded living room or outdoor levels, but declined (by up to 51.8%) following active purifier operation. Concentrations of PM 2.5 in living room and PM 10 in bedroom and living room were also significantly reduced through active purification., Conclusion: The use of air purifiers with HEPA filters significantly reduced medication requirements for patients with HDM-induced AR and significantly lowered indoor PM 2.5 concentrations, regardless of room placement. Active intervention to reduce household air pollutants may help improve allergic airway disease (clinicaltrials.gov NCT03313453)., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2020.)

Among many candidates for photoanode materials of photoelectrochemical (PEC) cell, nanostructured tungsten trioxide (WO 3 ) is regarded as one of the most promising materials due to its superior electrical properties and adequate bandgap (∼2.8 eV) and band edge position. WO 3 nanoflakes (WO 3 NFs), which have merits on its high surface area and crystallinity, have been actively studied for this manner but solar-to-hydrogen efficiency of WO 3 NFs based photoanode is still not sufficient both in light absorption and charge separation. Plasmon-induced enhancement using Au nanoparticles is excellent approach for both the efficiency of light absorption and charge separation of WO 3 . However, it still needs optimization on its amount, shape, coverage, and etc. Here, we synthesized WO 3 NFs by solvothermal growth and decorated gold nanoparticles on these nanoflakes by e-beam evaporation and rapid thermal annealing process in a row. By this process, a large-area AuNPs/WO 3 nanocomposite structure with various size, interparticle distance, and coverage of AuNPs were fabricated. These AuNPs/WO 3 NFs type photoanode achieve high light absorption both in UV and visible range and consequently higher photocurrent density. The optimized AuNPs/WO 3 nanocomposite photoanode exhibits 1.01 mA cm -2 of photocurrent density, which is increased to 19.8% compared with bare WO 3 nanoflakes. Field emission-scanning electron microscope, x-ray diffraction, UV-vis spectrometer analysis were measured to analyze the morphology and crystallinity and relationship between structure and PEC performance.

Metalenses have shown a number of promising functionalities that are comparable with conventional refractive lenses. However, current metalenses are still far from commercialization due to the formidable fabrication costs. Here, we demonstrate a low-cost dielectric metalens that works in the visible spectrum. The material of the metalens consists of a matrix-inclusion composite in which a hierarchy satisfies two requirements for the single-step fabrication; a high refractive index and a pattern-transfer capability. We use a UV-curable resin as a matrix to enable direct pattern replication by the composite, and titanium dioxide nanoparticles as inclusions to increase the refractive index of the composite. Therefore, such a dielectric metalens can be fabricated with a single step of UV nanoimprint lithography. An experimental demonstration of the nanoparticle composite-based metalens validates the feasibility of our approach and capability for future applications. Our method allows rapid replication of metalenses repeatedly and thereby provides an advance toward the use of metalenses on a commercial scale.

A phosphor substrate converts a moderate amount of blue light to green light to produce white light. In this study, we have successfully demonstrated the enhancement of the light extraction efficiency of YAG:Ce phosphor substrate using a simple imprint process. Spin-on-glass materials were used to fabricate a pattern on the surface of a phosphor substrate, and nano- and micro-scale patterns were formed to test the performance according to the size of pattern. The light extraction efficiency of the phosphor substrate with a micro-cone pattern increased by 33.2% compared with the flat phosphor substrate.

Engagement in HIV care reduces HIV-related health disparities that persist across racial/ethnic and gender lines; yet, African American (AA) women face multiple challenges to remaining engaged in care, including HIV-related stigma. We analyzed longitudinal data from 239 participants in the Unity Health Study to estimate associations between HIV-related stigma and engagement in care among AA women linked to HIV care. In adjusted Poisson regression analyses, engagement in care was not associated with HIV-related stigma but was associated with older age (incidence rate ratio [IRR] = 1.01, 95% confidence interval [CI] = [1.00-1.01], p = .01), higher levels of education (IRR = 1.18, 95% CI = [1.02-1.35], p = .03), and higher levels of social support (IRR = 1.05, 95% CI = [1.01-1.09], p = .04). Our findings suggest the need for targeted interventions to enhance engagement in care and to incorporate social support into health promotion programming for AA women living with HIV.

Vaspin is a protein present in human serum that can cause type-2 diabetes, obesity, and other cardiovascular diseases. We report fluorescent upconverting nanoparticles (UCNPs)-based lateral flow biosensor for ultrasensitive detection of Vaspin. A pair (primary and secondary) of cognate aptamers was used that has duo binding with Vaspin. UCNPs with a diameter of around 100 nm were used as a tag to label a detection probe (secondary aptamer). A primary aptamer (capture probe) was immobilized on the test zone. Sandwich type hybridization reactions among the conjugate probe, target Vaspin, and primary aptamer were performed on the lateral flow biosensor. In the presence of target Vaspin, UCNPs were captured on the test zone of the biosensor and the fluorescent intensity of the captured UCNPs was measured through a colorimetric app under NIR. Fluorescence intensity indicates the quantity of Vaspin present in the sample. A range of Vaspin concentration across 0.1-55 ng ml -1 with a Limit of detection (LOD) 39 pg ml -1 was tested through this UCNPs based LFSA with high sensitivity, reproducibility and repeatability, whereas it's actual range in human blood is from 0.1 to 7 ng ml -1 . Therefore, this research provides a well-suited lateral flow strip with an ultrasensitive and low-cost approach for the early diagnosis of type-2 diabetes and this could be applied to any targets with a duo of aptamers generated., (Copyright © 2019. Published by Elsevier B.V.)

Osteoporosis is characterized by low bone density and quality with high risk of bone fracture. Here, we investigated anti-osteoporotic effects of natural plants ( Lycii Radicis Cortex (LRC) and Achyranthes japonica (AJ)) in osteoblast and osteoclast cells in vitro and ovariectomized mice in vivo. Combined LRC and AJ enhanced osteoblast differentiation and mineralized bone-forming osteoblasts by the up-regulation of bone metabolic markers ( Alpl, Runx2 and Bglap ) in the osteoblastic cell line MC3T3-E1. However, LRC and AJ inhibited osteoclast differentiation of monocytes isolated from mouse bone marrow. In vivo experiments showed that treatment of LRC+AJ extract prevented OVX-induced trabecular bone loss and osteoclastogenesis in an osteoporotic animal model. These results suggest that LRC+AJ extract may be a good therapeutic agent for the treatment and prevention of osteoporotic bone loss.