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Rationale: Hyperoxia-induced acute lung injury has been used for many years as a model of oxidative stress mimicking clinical acute lung injury and the acute respiratory distress syndrome. Excess quantities of reactive oxygen species (ROS) are responsible for oxidative stress-induced lung injury. ROS are produced by mitochondrial chain transport, but also by NADPH oxidase (NOX) family members. Although NOX1 and NOX2 are expressed in the lungs, their precise function has not been determined until now.Objectives: To determine whether NOX1 and NOX2 contribute in vivo to hyperoxia-induced acute lung injury.Methods: Wild-type and NOX1- and NOX2-deficient mice, as well as primary lung epithelial and endothelial cells, were exposed to room air or 100% O(2) for 72 hours.Measurements and Main Results: Lung injury was significantly prevented in NOX1-deficient mice, but not in NOX2-deficient mice. Hyperoxia-dependent ROS production was strongly reduced in lung sections, in isolated epithelial type II cells, and lung endothelial cells from NOX1-deficient mice. Concomitantly, lung cell death in situ and in primary cells was markedly decreased in NOX1-deficient mice. In wild-type mice, hyperoxia led to phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), two mitogen-activated protein kinases involved in cell death signaling, and to caspase-3 activation. In NOX1-deficient mice, JNK phosphorylation was blunted, and ERK phosphorylation and caspase-3 activation were decreased.Conclusions: NOX1 is an important contributor to ROS production and cell death of the alveolocapillary barrier during hyperoxia and is an upstream actor in oxidative stress-induced acute lung injury involving JNK and ERK pathways in mice. [ABSTRACT FROM AUTHOR]

Schools are in a unique position to offer opportunities for students to be physically active throughout the school day and promote health and well-being. However, experiences that threaten safety or perceptions of safety might affect students' physical activity behaviors. Using the 2023 national Youth Risk Behavior Survey, six physical activity behaviors and five negative safety and violence experiences were examined from a nationally representative sample of U.S. high school students. This report updates national estimates for physical activity behaviors overall and by sex, grade, race and ethnicity, and sexual identity. In addition, associations between negative experiences and physical activity behaviors were examined, stratified by sex, via unadjusted and adjusted prevalence ratios. Regardless of negative safety and violence experiences, male students had a higher prevalence of meeting aerobic, muscle-strengthening, and both aerobic and muscle-strengthening physical activity guidelines compared with female students. In adjusted models among female students, a positive association was observed between being threatened or injured with a weapon at school and meeting the aerobic guideline, meeting the muscle-strengthening guideline, and playing on ≥1 sports team. Among male students, positive associations were observed between witnessing neighborhood violence and meeting the aerobic guideline and the muscle-strengthening guideline. A negative association was observed between attending physical education classes on all 5 days and witnessing neighborhood violence among female students and being bullied electronically among male students. Physical activity might serve as a mechanism that students employ to cope with negative safety and violence experiences. Understanding current physical activity behaviors among students with these negative experiences will be useful for school leaders, teachers, and public health practitioners who influence physical activity infrastructure and programming in schools and work to support safe, supportive, and inclusive school environments for student health. Although future research is needed to further explore these associations, physical activity continues to be an important behavior to prioritize for adolescent health in the school setting., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Sarah Sliwa reported being a part-time adjunct faculty member at Tufts University Friedman School of Nutrition Science and Policy and being an unpaid advisory board member for Concrete Jungle, a nonprofit organization based in Atlanta, Georgia. No other potential conflicts of interest were disclosed.

Racism is a fundamental determinant of health inequities among racial and ethnic groups and is understudied among adolescents. In 2023, the national Youth Risk Behavior Survey questionnaire included an item assessing experiences of racism in the school setting among students in grades 9-12 in the United States. This report estimates the prevalence of students who reported ever having experienced racism in school and compares prevalence by racial and ethnic groups. For each racial and ethnic group, prevalence differences and prevalence ratios were estimated comparing the prevalence of indicators of poor mental health, suicide risk, and substance use among students who reported that they have ever versus never experienced racism in school. In 2023, approximately one in three high school students (31.5%) said that they had ever experienced racism in school. Reported experiences of racism were most prevalent among Asian (56.9%), multiracial (48.8%), and Black or African American (Black) (45.9%) students and least prevalent among White students (17.3%). Black and Hispanic or Latino (Hispanic) students who reported experiencing racism had a higher prevalence of all health risk behaviors and experiences investigated, including indicators of poor mental health, suicide risk, and substance use compared with students of their racial and ethnic group who reported never experiencing racism. Many of these associations were also found among multiracial and White students. Student reports of racism were associated with indicators of mental health and suicide risk among American Indian or Alaska Native (AI/AN) and Asian students. Among students of color, including AI/AN, Asian, Black, Hispanic, and multiracial students, the prevalence of seriously considering and attempting suicide was more than two times higher among students who ever compared with never experienced racism. These findings demonstrate that racism in the school setting is experienced by high school students attending public and private schools and continues to disproportionately affect students of color. Students who reported experiencing racism had a higher prevalence of indicators of poor mental health, suicide risk, and substance use. Schools can incorporate policies and practices to prevent unfair treatment on the basis of race and ethnicity and offer resources to help students cope with these experiences., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Jonetta Mpofu reported being a board member of the American School Health Association. No other potential conflicts of interest were disclosed.

The Youth Risk Behavior Surveillance System (YRBSS) is a set of surveys that tracks a broad range of behaviors, experiences, and conditions that can lead to poor health among high school students. The system includes a nationally representative Youth Risk Behavior Survey (YRBS) and separate school-based YRBSs conducted by states, tribes, territories, and local school districts. For the 2023 national YRBS, CDC made changes to the sampling method, survey administration mode, and questionnaire. Specifically, the sampling design added an American Indian or Alaska Native (AI/AN) supplemental sample so that separate, precise estimates could be made for AI/AN high school students, in addition to the usual sample designed to provide nationally representative data for the population of students in grades 9-12. To decrease the time needed to collect and process data, CDC changed the survey administration mode from paper-and-pencil scannable booklets to a tablet-based electronic survey. To provide national data on topics of emerging interest, CDC added new questions to the questionnaire. These new questions assessed social media use, experiences of racism at school, adverse childhood experiences, transgender identity, consent for sexual contact, and unfair discipline at school. Public health practitioners and researchers can use YRBSS data to examine the prevalence of youth health behaviors, experiences, and conditions; monitor trends; and guide interventions. This overview report describes 2023 YRBSS survey methodology, including sampling, data collection, data processing, weighting, and data analyses. The 2023 YRBS participation map, survey response rates, and a detailed examination of student demographic characteristics are included in this report. During 2023, in addition to the national YRBS, 68 site-level surveys were administered to high school students in 39 states, three tribal governments, five territories, and 21 local school districts. These site-level surveys use site-specific questionnaires that are similar to the national YRBS questionnaire but are modified to meet sites' needs. This overview and methods report is one of 11 featured in this MMWR supplement, which reports results from the 2023 national YRBS but does not include data from the 68 site-level surveys. Each report is based on data collected using methods presented in this overview report. A full description of YRBSS results and downloadable data are available (https://www.cdc.gov/yrbs/index.html)., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Jonetta Mpofu reported being a board member of the American School Health Association. Lindsay Trujillo reported receiving a grant from Social & Scientific Systems, Inc. No other potential conflicts of interest were disclosed.

Relatively little is known about the association between school discipline and student health and well-being. Using CDC's 2023 Youth Risk Behavior Survey, CDC analyzed the prevalence of report of unfair discipline at school and associations with experiences at school, mental health, suicidal thoughts and behaviors, and health risk behaviors among high school students overall and stratified by race and ethnicity. Prevalence estimates, prevalence differences, and prevalence ratios adjusted for race (in overall models), grade, and sex were calculated. Overall, 19.3% of students reported receiving unfair discipline during the previous 12 months; Black or African American students had a higher prevalence (23.1%) compared with Hispanic or Latino students (18.4%) and White students (18.1%). Unfair discipline was reported among a majority of students who describe their sexual identity in some other way (besides gay, heterosexual, lesbian, bisexual, or questioning) for American Indian or Alaska Native (81.7%) and multiracial (57.1%) subgroups. Overall, report of unfair discipline was associated with every health risk behavior and experience examined, including being bullied at school or electronically, skipping school due to feeling unsafe, carrying a weapon at school, prescription opioid misuse, poor mental health, persistent feelings of sadness or hopelessness, seriously considered attempting suicide, and attempted suicide. This pattern of association was similar among most student groups in models stratified by race and ethnicity. This analysis is the first to demonstrate, among a nationally representative sample of high school students, that reports of unfair discipline are associated with various health risk behaviors and experiences. With these findings, public health and education practitioners can create interventions that equitably promote safe, supportive, and inclusive school environments for student health., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Jonetta J. Mpofu reported being a board member of the American School Health Association. No other potential conflicts of interest were disclosed.

Background & Aims: The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing worldwide. Alterations of hepatic microRNA (miRNA) expression/activity significantly contribute to the development and progression of MASLD. Genetic polymorphisms of miR-149 are associated with an increased susceptibility to MASLD development in humans. Aberrant expression of miR-149 was also associated with metabolic alterations in several organs, but the impact of hepatic miR-149-5p deregulation in MASLD remains poorly characterized., Methods: MiR-149-5p was downregulated in the livers of mice by in vivo transduction with hepatotropic adeno-associated virus 8 harboring short-hairpin RNAs (shRNAs) specific for miR-149-5p (shmiR149) or scrambled shRNAs (shCTL). MASLD was then induced with a methionine/choline-deficient (MCD, n = 7 per group) diet or a fructose/palmitate/cholesterol-enriched (FPC, n = 8-12 per group, per protocol) diet. The impact of miR-149-5p modulation on MASLD development was assessed in vivo and in vitro using multi-lineage 3D human liver organoids (HLOs) and Huh7 cells., Results: MiR-149-5p expression was strongly upregulated in mouse livers from different models of MASLD (2-4-fold increase in ob/ob , db/db mice, high-fat and FPC-fed mice). In vivo downregulation of miR-149-5p led to an amelioration of diet-induced hepatic steatosis, inflammation/fibrosis, and to increased whole-body fatty acid consumption. In HLOs, miR-149-5p overexpression promoted lipid accumulation, inflammation and fibrosis. In vitro analyses of human Huh7 cells overexpressing miR-149-5p indicated that glycolysis and intracellular lipid accumulation was promoted, while mitochondrial respiration was impaired. Translatomic analyses highlighted deregulation of multiple potential miR-149-5p targets in hepatocytes involved in MASLD development., Conclusions: MiR-149-5p upregulation contributes to MASLD development by affecting multiple metabolic/inflammatory/fibrotic pathways in hepatocytes. Our results further demonstrate that HLOs are a relevant 3D in vitro model to investigate hepatic steatosis and inflammation/fibrosis development., Impact and Implications: Our research shows compelling evidence that miR-149-5p plays a pivotal role in the development and progression of MASLD. By employing in vivo and innovative in vitro models using multi-lineage human liver organoids, we demonstrate that miR-149-5p upregulation significantly impacts hepatocyte energy metabolism, exacerbating hepatic steatosis and inflammation/fibrosis by modulating a wide network of target genes. These findings not only shed light on the intricate miR-149-5p-dependent molecular mechanisms underlying MASLD, but also underscore the importance of human liver organoids as valuable 3D in vitro models for studying the disease's pathogenesis., (© 2024 The Author(s).)

Purpose: Transgender youth (those whose gender identity differs from their sex assigned at birth) experience stigma and discrimination that can place them at increased risk for poor health outcomes compared with cisgender youth (those whose gender identity aligns with their sex assigned at birth). Limited population-based data exist on disparities among transgender and cisgender youth., Methods: We examined differences in experiences of violence, substance use, mental health, suicide, sexual behavior, unstable housing, parental monitoring, and school connectedness among 98,174 transgender and cisgender high school students using data from 18 states that included an item to assess transgender identity on their 2021 Youth Risk Behavior Survey., Results: Overall, 2.9% of students identified as transgender and 2.6% questioned whether they were transgender. Among transgender students, 71.5% reported that their mental health was not good, 32.3% had attempted suicide, and 29.0% experienced sexual violence. Transgender students were more likely than cisgender students to report experiences of violence, substance use, poor mental health, suicide risk, some sexual risk behaviors, and unstable housing, and were less likely to report feeling connected to others at school., Conclusions: Interventions that can address the causes of these adverse outcomes and promote the health and wellbeing of transgender youths are warranted., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: To explore the prevalence of Multiracial/ethnic identity and its association with mental health among high school students., Methods: The 2021 national Youth Risk Behavior Survey (N=17,232) data were used. Respondents were classified as monoracial/ethnic or Multiracial/ethnic., Results: Overall, 21.5% of students were Multiracial/ethnic. Multiracial/ethnic status was most prevalent among students who identify as American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, and Hispanic or Latino. Logistic regression models showed Multiracial/ethnic classification was associated with persistent feelings of sadness or hopelessness among students identifying as American Indian or Alaska Native, Asian, Black, and White. Multiracial/ethnic Asian students had significantly higher odds of all four indicators of poor mental health compared with monoracial/ethnic Asian students., Conclusion: Multiracial/ethnic students constitute a heterogenous group. This study found important subgroup differences in indicators of mental health that might be missed when Multiracial/ethnic groups are considered in aggregate.

Introduction: As the chemokine receptor5 (CCR5) may play a role in ischemia, we studied the links between CCR5 deficiency, the sensitivity of neurons to oxidative stress, and the development of dementia., Methods: Logistic regression models with CCR5/apolipoprotein E (ApoE) polymorphisms were applied on a sample of 205 cognitively normal individuals and 189 dementia patients from Geneva. The impact of oxidative stress on Ccr5 expression and cell death was assessed in mice neurons., Results: CCR5-Δ32 allele synergized with ApoEε4 as risk factor for dementia and specifically for dementia with a vascular component. We confirmed these results in an independent cohort from Italy (157 cognitively normal and 620 dementia). Carriers of the ApoEε4/CCR5-Δ32 genotype aged ≥80 years have an 11-fold greater risk of vascular-and-mixed dementia. Oxidative stress-induced cell death in Ccr5 -/- mice neurons., Discussion: We propose the vulnerability of CCR5-deficient neurons in response to oxidative stress as possible mechanisms contributing to dementia., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The tropomyosin receptor kinase B (TrkB) is encoded by the NTRK2 gene. It belongs to the family of transmembrane tyrosine kinases, which have key roles in the development and maintenance of the nervous system. Brain-derived neurotrophic factor (BDNF) and the neurotrophins NT3 and NT4/5 have high affinity for TrkB. Dysregulation of TrkB is associated to a large spectrum of diseases including neurodegeneration, psychiatric diseases and some cancers. The function of TrkB and its role in neural development have mainly been decrypted using transgenic mouse models, pharmacological modulators and human neuronal cell lines overexpressing NTRK2 . In this study, we identified high expression and robust activity of TrkB in ReNcell VM, an immortalized human neural progenitor stem cell line and generated NTRK2 -deficient ( NTRK2 -/- ) ReNcell VM using the CRISPR/Cas9 gene editing technology. Global transcriptomic analysis revealed major changes in expression of specific genes responsible for neurogenesis, neuronal development and glial differentiation. In particular, key neurogenic transcription factors were massively down-regulated in NTRK2 -/- cells, while early glial progenitor markers were enriched in NTRK2 -/- cells compared to NTRK2 +/+ . This indicates a previously undescribed inhibitory role of TrkB on glial differentiation in addition to its well-described pro-neurogenesis role. Altogether, we have generated for the first time a human neural cell line with a loss-of-function mutation of NTRK2 , which represents a reproducible and readily available cell culture system to study the role of TrkB during human neural differentiation, analyze the role of TrkB isoforms as well as validate TrkB antibodies and pharmacological agents targeting the TrkB pathway., 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 © 2023 Roussel-Gervais, Sgroi, Cambet, Lemeille, Seredenina, Krause and Jaquet.)

Background: Research shows associations between bullying victimization and substance use for teens. However, more research about this relationship for younger adolescents and across race/ethnicity is needed., Methods: Prevalence and pooled logistic regression analyses of 2019 Middle School Youth Risk Behavior Survey data from 13 states (N = 74,059 students) examined associations between self-reported bulling victimization (at school, electronically, and both) and having ever tried cigarette smoking, alcohol, or marijuana; used an electronic vapor product; or misused prescription pain medicine. Regression analyses were adjusted by age and sex/race/ethnicity., Results: All 3 measures of bullying victimization were significantly associated (p < .05) with the 5 substance use behaviors examined (adjusted prevalence ratios ranged from 1.29 to 2.32). These associations held across sexes. Significant associations were found within all 7 race/ethnicity categories, with the most associations reported for the non-Hispanic (NH) white, NH black or African American, Hispanic/Latino, and NH Asian groups., Conclusion: The association between bullying and substance use by middle school is a highly relevant issue to consider as students return to classrooms., (Published 2023. This article is a U.S. Government work and is in the public domain in the USA.)

NADPH oxidases are superoxide-producing enzymes that play a role in host defense, biosynthetic pathways, as well as cellular signaling. Humans have 7 NOX isoforms (NOX1-5, DUOX1,2), while mice and rats lack NOX5 and therefore have only 6 NOX isoforms. Whether all human NOX isoforms or their subunits (CYBA, NCF1, 2, 4, NOXO1, NOXA1, DUOXA1, 2) are present and conserved in other mammalian species is unknown. In this study, we have analyzed the conservation of the NOX family during mammalian evolution using an in-silico approach. Complete genomic sequences of 164 mammalian species were available. The possible absence of genes coding for NOX isoforms was investigated using the NCBI orthologs database followed by manual curation. Conservation of a given NOX isoform during mammalian evolution was evaluated by multiple alignment and identification of highly conserved sequences. There was no convincing evidence for the absence of NOX2, 3, 4, and DUOX1, 2 in all the available mammalian genome. However, NOX5 was absent in 27 of 31 rodent, in 2 of 3 lagomorph and in 2 out of 18 bat species. NOX1 was absent in all sequenced Afrotheria and Monotremata species, as well as in 3 of 18 bat species. NOXA1 was absent in all Afrotheria and in 3 out of 4 Eulipotyphla species. We also investigated amino acid sequence conservation among given NOX isoforms. Highly conserved sequences were observed for most isoforms except for NOX5. Interestingly, the highly conserved region of NOX2 sequence was relatively small (11 amino acids), as compared to NOX1, 3, 4. The highly conserved domains are different from one NOX isoform to the other, raising the possibility of distinct evolutionary conserved functional domains. Our results shed a new light on the essentiality of different NOX isoforms. We also identified isoform-defining sequences, i.e., hitherto undescribed conserved domains within specific NOX isoforms., Competing Interests: Declaration of competing interest All authors have no competing interests to declare., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The Wnt signaling pathway within host cells regulates infections by several pathogenic bacteria and viruses. Recent studies suggested that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection depends on β-catenin and can be inhibited by the antileprotic drug clofazimine. Since clofazimine has been identified by us as a specific inhibitor of Wnt/β-catenin signaling, these works could indicate a potential role of the Wnt pathway in SARS-CoV-2 infection. Here, we show that the Wnt pathway is active in pulmonary epithelial cells. However, we find that in multiple assays, SARS-CoV-2 infection is insensitive to Wnt inhibitors, including clofazimine, acting at different levels within the pathway. Our findings assert that endogenous Wnt signaling in the lung is unlikely required or involved in the SARS-CoV-2 infection and that pharmacological inhibition of this pathway with clofazimine or other compounds is not a universal way to develop treatments against the SARS-CoV-2 infection. IMPORTANCE The development of inhibitors of the SARS-CoV-2 infection remains a need of utmost importance. The Wnt signaling pathway in host cells is often implicated in infections by bacteria and viruses. In this work, we show that, despite previous indications, pharmacological modulation of the Wnt pathway does not represent a promising strategy to control SARS-CoV-2 infection in lung epithelia., Competing Interests: The authors declare no conflict of interest.

The COVID-19 pandemic created an environment of disruption and adversity for many adolescents. We sought to establish the prevalence of non-dating sexual violence, sexual dating violence, and physical dating violence victimization among adolescents during the COVID-19 pandemic and to investigate whether experiences of disruption and adversity placed adolescents at greater risk for these forms of interpersonal violence. We conducted a secondary analysis of data from the Adolescent Behavior and Experiences Survey, collected January to June 2021 from a nationally representative sample of U.S. high school students ( N  = 7,705). Exposures included abuse by a parent; economic, housing, and food and nutrition insecurity; interpersonal connectedness; and personal well-being. Among female students, 8.0% experienced non-dating sexual violence; 12.5% experienced sexual dating violence; and 7.7% experienced physical dating violence. Among male students, 2.2% experienced non-dating sexual violence; 2.4% experienced sexual dating violence; and 4.9% experienced physical dating violence. Among female students, both emotional and physical abuse by a parent was related to non-dating sexual violence, emotional abuse was related to sexual dating violence, and physical abuse was related to physical dating violence. Among males, emotional abuse by a parent was related to physical dating violence and physical abuse by a parent was related to sexual dating violence. Hunger was associated with sexual and physical dating violence among female students and homeless was associated with physical dating violence among male students. Although there were differences by sex, abuse by a parent, hunger, and homelessness created precarity that may have increased the likelihood that adolescents would be exposed to risky peer or dating relationships. Adolescents need support that stops and prevents experiences of non-dating sexual and dating violence connected to interventions that address adversities experienced during the COVID-19 pandemic.

The Youth Risk Behavior Surveillance System (YRBSS) is the largest public health surveillance system in the United States, monitoring a broad range of health-related behaviors among high school students. The system includes a nationally representative Youth Risk Behavior Survey (YRBS) and separate school-based YRBSs conducted by states, tribes, territories, and local school districts. In 2021, these surveys were conducted during the COVID-19 pandemic. The pandemic underscored the importance of data in understanding changes in youth risk behaviors and addressing the multifaceted public health needs of youths. This overview report describes 2021 YRBSS survey methodology, including sampling, data collection procedures, response rates, data processing, weighting, and analyses. The 2021 YRBS participation map, survey response rates, and a detailed examination of student demographic characteristics are included in this report. During 2021, in addition to the national YRBS, a total of 78 surveys were administered to high school students across the United States, representing the national population, 45 states, two tribal governments, three territories, and 28 local school districts. YRBSS data from 2021 provided the first opportunity since the onset of the COVID-19 pandemic to compare youth health behaviors using long-term public health surveillance. Approximately half of all student respondents represented racial and ethnic minority groups, and approximately one in four identified as lesbian, gay, bisexual, questioning, or other (a sexual identity other than heterosexual) (LGBQ+). These findings reflect shifts in youth demographics, with increased percentages of racial and ethnic minority and LGBQ+ youths compared with previous YRBSS cycles. Educators, parents, local decision makers, and other partners use YRBSS data to monitor health behavior trends, guide school health programs, and develop local and state policy. These and future data can be used in developing health equity strategies to address long-term disparities so that all youths can thrive in safe and supportive environments. This overview and methods report is one of 11 featured in this MMWR supplement. Each report is based on data collected using methods presented in this overview. A full description of YRBSS results and downloadable data are available (https://www.cdc.gov/healthyyouth/data/yrbs/index.htm)., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Youths experiencing unstable housing face higher risks for poor physical, mental, and sexual health outcomes and increased risk for suicide compared with their peers experiencing stable housing. In addition, youths of color and sexual minority youths are disproportionately more likely to experience homelessness. For the first time, in 2021, the nationally representative Youth Risk Behavior Survey included an item assessing housing stability, or nighttime residence among students in grades 9-12 in the United States. During 2021, 2.7% of U.S. high school students experienced unstable housing. Among racial and ethnic subgroups, Native Hawaiian or other Pacific Islander youths were most likely to experience unstable housing, followed by American Indian or Alaska Native and Black youths. Sexual minority (lesbian, gay, bisexual, and questioning or other) youths were more likely to experience unstable housing compared with their heterosexual peers. Compared with students who were stably housed, students who were unstably housed were more likely to engage in risky sexual behaviors, substance use, and suicide ideation and attempts, and to experience violence. These findings highlight which adverse health risks and behaviors are elevated among youths experiencing housing insecurity. Focused public health interventions are required to address the disproportionate burden of health risks prevalent among youths who are unstably housed., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Suicide is the third leading cause of death among high school-aged youths aged 14-18 years. The 2021 suicide rate for this age group was 9.0 per 100,000 population. Updating a previous analysis of the Youth Risk Behavior Survey during 2009-2019, this report uses 2019 and 2021 data to examine high school students' reports of suicidal thoughts and behaviors. Prevalence estimates are reported by grade, race and ethnicity, sexual identity, and sex of sexual contacts. Unadjusted logistic regression models were used to calculate prevalence differences comparing 2019 to 2021 and prevalence ratios comparing suicidal behavior between subgroups across demographic characteristics to a referent group. From 2019 to 2021, female students had an increased prevalence of seriously considered attempting suicide (from 24.1% to 30%), an increase in making a suicide plan (from 19.9% to 23.6%), and an increase in suicide attempts (from 11.0% to 13.3%). In addition, from 2019 to 2021, Black or African American (Black), Hispanic or Latino (Hispanic), and White female students had an increased prevalence of seriously considered attempting suicide. In 2021, Black female students had an increased prevalence of suicide attempts and Hispanic female students had an increased prevalence of suicide attempts that required medical treatment compared with White female students. Prevalence of suicidal thoughts and behaviors remained stable overall for male students from 2019 to 2021. A comprehensive approach to suicide prevention with a focus on health equity is needed to address these disparities and reduce prevalence of suicidal thoughts and behaviors for all youths. School and community-based strategies include creating safe and supportive environments, promoting connectedness, teaching coping and problem solving, and gatekeeper training., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

School connectedness, defined as students' belief that adults and peers in their school care about their learning as well as about them as persons, has been linked to positive educational, behavioral, and health outcomes in adolescence and into adulthood. Data from the 2021 nationally representative Youth Risk Behavior Survey, conducted during the COVID-19 pandemic, were used to estimate prevalence of students' perception of school connectedness and examine associations between school connectedness and seven risk behaviors and experiences: poor mental health, marijuana use, prescription opioid misuse, sexual intercourse, unprotected sex, experiencing forced sex, and missing school because of feeling unsafe. Prevalence estimates were generated and pairwise t-tests were used to detect differences among student subpopulations by sex, grade, race and ethnicity, and sexual identity; Wald chi-square tests were used to detect differences in risk behaviors by level of connectedness within a subpopulation. Logistic regression models were used to estimate prevalence ratios comparing the prevalence of risk behaviors and experiences of students with high connectedness with students with low connectedness, stratified by demographics. During 2021, 61.5% of U.S. high school students reported feeling connected to others at school. In addition, school connectedness was associated with lower prevalence of every risk behavior and experience examined in this study, although certain associations differed by race and ethnicity and sexual identity (e.g., school connectedness was associated with better mental health outcomes for youths with heterosexual, bisexual, and questioning or other sexual identities, but not for youths who identified as lesbian or gay). These findings can guide public health interventions that promote youth well-being by creating school environments where all youths have a sense of belonging and feel they are cared for and supported., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Differentiation of fibroblasts to myofibroblasts is governed by the transforming growth factor beta (TGF-β) through a mechanism involving redox signaling and generation of reactive oxygen species (ROS). Myofibroblasts synthesize proteins of the extracellular matrix (ECM) and display a contractile phenotype. Myofibroblasts are predominant contributors of wound healing and several pathological states, including fibrotic diseases and cancer. Inhibition of the ROS-generating enzyme NADPH oxidase 4 (NOX4) has been proposed to mitigate fibroblast to myofibroblast differentiation and to offer a therapeutic option for the treatment of fibrotic diseases. In this study, we addressed the role of NOX4 in physiological wound healing and in TGF-β-induced myofibroblast differentiation. We explored the phenotypic changes induced by TGF-β in primary skin fibroblasts isolated from Nox4-deficient mice by immunofluorescence, Western blotting and RNA sequencing. Mice deficient for Cyba, the gene coding for p22 phox , a key subunit of NOX4 were used for confirmatory experiments as well as human primary skin fibroblasts. In vivo, the wound healing was similar in wild-type and Nox4-deficient mice. In vitro, despite a strong upregulation following TGF-β treatment, Nox4 did not influence skin myofibroblast differentiation although a putative NOX4 inhibitor GKT137831 and a flavoprotein inhibitor diphenylene iodonium mitigated this mechanism. Transcriptomic analysis revealed upregulation of the mitochondrial protein Ucp2 and the stress-response protein Hddc3 in Nox4-deficient fibroblasts, which had however no impact on fibroblast bioenergetics. Altogether, we provide extensive evidence that NOX4 is dispensable for wound healing and skin fibroblast to myofibroblast differentiation, and suggest that another H 2 O 2 -generating flavoprotein drives this mechanism., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Spheroids and organoids are important novel players in medical and life science research. They are gradually replacing two-dimensional (2D) cell cultures. Indeed, three-dimensional (3D) cultures are closer to the in vivo reality and open promising perspectives for academic research, drug screening, and personalized medicine. A large variety of cells and tissues, including tumor cells, can be the starting material for the generation of 3D cultures, including primary tissues, stem cells, or cell lines. A panoply of methods has been developed to generate 3D structures, including spontaneous or forced cell aggregation, air-liquid interface conditions, low cell attachment supports, magnetic levitation, and scaffold-based technologies. The choice of the most appropriate method depends on (i) the origin of the tissue, (ii) the presence or absence of a disease, and (iii) the intended application. This review summarizes methods and approaches for the generation of cancer spheroids and organoids, including their advantages and limitations. We also highlight some of the challenges and unresolved issues in the field of cancer spheroids and organoids, and discuss possible therapeutic applications.

This study evaluates the influence of a gelatin sponge on adipose-derived stromal cells (ASC). Transcriptomic data revealed that, compared to ASC in a monolayer, a cross-linked porcine gelatin sponge strongly influences the transcriptome of ASC. Wound healing genes were massively regulated, notably with the inflammatory and angiogenic factors. Proteomics on conditioned media showed that gelatin also acted as a concentrator and reservoir of the regenerative ASC secretome. This secretome promoted fibroblast survival and epithelialization, and significantly increased the migration and tubular assembly of endothelial cells within fibronectin. ASC in gelatin on a chick chorioallantoic membrane were more connected to vessels than an empty sponge, confirming an increased angiogenesis in vivo. No tumor formation was observed in immunodeficient nude mice to which an ASC gelatin sponge was transplanted subcutaneously. Finally, ASC in a gelatin sponge prepared from outbred rats accelerated closure and re-vascularization of ischemic wounds in the footpads of rats. In conclusion, we provide here preclinical evidence that a cross-linked porcine gelatin sponge is an optimal carrier to concentrate and increase the regenerative activity of ASC, notably angiogenic. This formulation of ASC represents an optimal, convenient and clinically compliant option for the delivery of ASC on ischemic wounds.

The voltage-gated hydrogen channel Hv1 encoded in humans by the HVCN1 gene is a highly selective proton channel that allows large fluxes of protons across biological membranes. Hv1 form functional dimers of four transmembrane spanning proteins resembling the voltage sensing domain of potassium channels. Each subunit is highly selective for protons and is controlled by changes in the transmembrane voltage and pH gradient. Hv1 is most expressed in phagocytic cells where it sustains NADPH oxidase-dependent bactericidal function and was reported to facilitate antibody production by B cells and to promote the maturation and motility of spermatocytes. Hv1 contributes to neuroinflammation following brain damage and favors cancer progression possibly by extruding protons generated during aerobic glycolysis of cancer cells. Lack of specific Hv1 inhibitors has hampered translation of this knowledge to treat immune, fertility, or malignancy diseases. In this study, we show that the genetic deletion of Hv1 delays tumor development in a mouse model of granulocytic sarcoma and report the discovery and characterization of two novel bioavailable inhibitors of Hv1 channels that we validate by orthogonal assays and electrophysiological recordings., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nicolas Demaurex reports financial support was provided by Innosuisse Swiss Innovation Agency. Antoine El Chemaly, Vincent Jaquet, Yves Cambet and Karl-Heinz Krause holds shares of Hplus Therapeutics, a company developing Hv1 inhibitors., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Low-grade inflammation plays a pivotal role in osteoarthritis (OA) through exposure to reactive oxygen species (ROS). In chondrocytes, NADPH oxidase 4 (NOX4) is one of the major ROS producers. In this study, we evaluated the role of NOX4 on joint homoeostasis after destabilisation of the medial meniscus (DMM) in mice., Methods: Experimental OA was simulated on cartilage explants using interleukin-1β (IL-1β) and induced by DMM in wild-type (WT) and NOX4 knockout (NOX4 -/- ) mice. We evaluated NOX4 expression, inflammation, cartilage metabolism and oxidative stress by immunohistochemistry. Bone phenotype was also determined by micro-CT and histomorphometry., Results: Whole body NOX4 deletion attenuated experimental OA in mice, with a significant reduction of the OARSI score at 8 weeks. DMM increased total subchondral bone plate (SB.Th), epiphysial trabecular thicknesses (Tb.Th) and bone volume fraction (BV/TV) in both NOX4 -/- and wild-type (WT) mice. Interestingly, DDM decreased total connectivity density (Conn.Dens) and increased medial BV/TV and Tb.Th only in WT mice. Ex vivo, NOX4 deficiency increased aggrecan (AGG) expression and decreased matrix metalloproteinase 13 (MMP13) and collagen type I (COL1) expression. IL-1β increased NOX4 and 8-hydroxy-2'-deoxyguanosine (8-OHdG) expression in WT cartilage explants but not in NOX4 -/- . In vivo, absence of NOX4 increased anabolism and decreased catabolism after DMM. Finally, NOX4 deletion decreased synovitis score, 8-OHdG and F4/80 staining following DMM., Conclusion: NOX4 deficiency restores cartilage homoeostasis, inhibits oxidative stress, inflammation and delays OA progression after DMM in mice. These findings suggest that NOX4 represent a potential target to counteract for OA treatment., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Chronic wounds, ie, non-healing ulcers, have a prevalence of ~1% in the general population. Chronic wounds strongly affect the quality of life and generate considerable medical costs. A fraction of chronic wounds will heal within months of appropriate treatment; however, a significant fraction of patients will develop therapy-refractory chronic wounds, leading to chronic pain, infection, and amputation. Given the paucity of therapeutic options for refractory wounds, cell therapy and in particular the use of adipose-derived stromal cells (ASC) has emerged as a promising concept. ASC can be used as autologous or allogeneic cells. They can be delivered in suspension or in 3D cultures within scaffolds. ASC can be used without further processing (stromal vascular fraction of the adipose tissue) or can be expanded in vitro. ASC-derived non-cellular components, such as conditioned media or exosomes, have also been investigated. Many in vitro and preclinical studies in animals have demonstrated the ASC efficacy on wounds. ASC efficiency appears to occurs mainly through their regenerative secretome. Hitherto, the majority of clinical trials focused mainly on safety issues. However more recently, a small number of randomized, well-controlled trials provided first convincing evidences for a clinical efficacy of ASC-based chronic wound therapies in humans. This brief review summarizes the current knowledge on the mechanism of action, delivery and efficacy of ASC in chronic wound therapy. It also discusses the scientific and pharmaceutical challenges to be solved before ASC-based wound therapy enters clinical reality., (© The Author(s) 2022. Published by Oxford University Press.)

Background: Chondrocyte-based cell therapy to repair cartilage has been used for >25 years despite current limitations. This work presents a new treatment option for cartilage lesions., Hypothesis: High-quality hyaline cartilage microtissues called Cartibeads are capable of treating focal chondral lesions once implanted in the defect, by complete fusion of Cartibeads among themselves and their integration with the surrounding native cartilage and subchondral bone., Study Design: Controlled laboratory study., Methods: Cartibeads were first produced from human donors and characterized using histology (safranin O staining of glycosaminoglycan [GAG] and immunohistochemistry of collagen I and II) and GAG dosage. Cartibeads from 6 Göttingen minipigs were engineered and implanted in an autologous condition in the knee (4 or 5 lesions per knee). One group was followed up for 3 months and the other for 6 months. Feasibility and efficacy were measured using histological analysis and macroscopic and microscopic scores., Results: Cartibeads revealed hyaline features with strong staining of GAG and collagen II. High GAG content was obtained: 24.6-µg/mg tissue (wet weight), 15.52-µg/mg tissue (dry weight), and 35 ± 3-µg GAG/bead (mean ± SD). Histological analysis of Göttingen minipigs showed good integration of Cartibeads grafts at 3 and 6 months after implantation. The Bern Score of the histological assay comparing grafted versus empty lesions was significant at 3 months (grafted, n = 10; nongrafted, n = 4; score, 3.3 and 5.3, respectively) and 6 months (grafted, n = 11; nongrafted, n = 3; score, 1.6 and 5.1)., Conclusion: We developed an innovative 3-step method allowing, for the first time, the use of fully dedifferentiated adult chondrocytes with a high number of cell passage (owing to the extensive amplification in culture). Cartibeads engineered from chondrocytes hold potential as an advanced therapy medicinal product for treating cartilage lesions with established efficacy., Clinical Relevance: This successful preclinical study, combined with standardized manufacturing of Cartibeads according to good manufacturing practice guidelines, led to the approval of first-in-human clinical trial by the ethics committee and local medical authority. The generated data highlighted a promising therapy to treat cartilage lesions from a small amount of starting biopsy specimen. With our innovative cell amplification technology, very large lesions can be treated, and older active patients can benefit from it.

The repair of damaged articular cartilage is an unmet medical need. Chondrocyte-based cell therapy has been used to repair cartilage for over 20 years despite current limitations. Chondrocyte dedifferentiation upon expansion in monolayer is well known and is the main obstacle to their use as cell source for cartilage repair. Consequently, current approaches often lead to fibrocartilage, which is biomechanically different from hyaline cartilage and not effective as a long-lasting treatment. Here, we describe an innovative 3-step method to engineer hyaline-like cartilage microtissues, named Cartibeads, from high passage dedifferentiated chondrocytes. We show that WNT5A/5B/7B genes were highly expressed in dedifferentiated chondrocytes and that a decrease of the WNT signaling pathway was instrumental for full re-differentiation of chondrocytes, enabling production of hyaline matrix instead of fibrocartilage matrix. Cartibeads showed hyaline-like characteristics based on GAG quantity and type II collagen expression independently of donor age and cartilage quality. In vivo, Cartibeads were not tumorigenic when transplanted into SCID mice. This simple 3-step method allowed a standardized production of hyaline-like cartilage microtissues from a small cartilage sample, making Cartibeads a promising candidate for the treatment of cartilage lesions., (© The Author(s) 2022. Published by Oxford University Press.)

Hydrogen peroxide (H 2 O 2 ) is a common effector of defense mechanisms against pathogenic infections. However, bacterial factors involved in H 2 O 2 tolerance remain unclear. Here we used transposon-directed insertion-site sequencing (TraDIS), a technique allowing the screening of the whole genome, to identify genes implicated in H 2 O 2 tolerance in Escherichia coli . Our TraDIS analysis identified 10 mutants with fitness defect upon H 2 O 2 exposure, among which previously H 2 O 2 -associated genes ( oxyR , dps , dksA , rpoS , hfq and polA ) and other genes with no known association with H 2 O 2 tolerance in E. coli ( corA , rbsR , nhaA and gpmA ). This is the first description of the impact of gpmA , a gene involved in glycolysis, on the susceptibility of E. coli to H 2 O 2 . Indeed, confirmatory experiments showed that the deletion of gpmA led to a specific hypersensitivity to H 2 O 2 comparable to the deletion of the major H 2 O 2 scavenger gene katG . This hypersensitivity was not due to an alteration of catalase function and was independent of the carbon source or the presence of oxygen. Transcription of gpmA was upregulated under H 2 O 2 exposure, highlighting its role under oxidative stress. In summary, our TraDIS approach identified gpmA as a member of the oxidative stress defense mechanism in E. coli .

Social and educational disruptions during the COVID-19 pandemic have exacerbated concerns about adolescents' mental health and suicidal behavior. Data from the 2021 Adolescent Behaviors and Experiences Survey (ABES) indicate that 37.1% of U.S. high school students reported poor mental health during the COVID-19 pandemic, with 19.9% considering and 9.0% attempting suicide in the preceding year (1). Adverse childhood experiences (ACEs)* are associated with poor mental health and suicidal behaviors (2,3), and high prevalence of some ACEs have been documented during the pandemic (4). ACEs are preventable, potentially traumatic events that occur in childhood (ages 0-17 years) such as neglect, experiencing or witnessing violence, or having a family member attempt or die by suicide. Also included are aspects of a child's environment that can undermine their sense of safety, stability, and bonding. Associations between ACEs occurring during the pandemic and mental health or suicidal behaviors among U.S. high school students were examined using ABES data. Experience of one to two ACEs was associated with poorer mental health and increased suicidal behaviors, and these deleterious outcomes increased with additional ACE exposure. After adjusting for demographic characteristics, adolescents who reported four or more ACEs during the pandemic had a prevalence of poor current mental health four times as high as, and a prevalence of past-year suicide attempts 25 times as high as, those without ACEs during the pandemic. Experience of specific ACE types (e.g., emotional abuse) was associated with higher prevalences of poor mental health and suicidal behaviors. Prevention and intervention strategies (5), including early identification and trauma-informed mental health service and support provision, for ACEs and their acute and long-term impacts could help address the U.S. child and adolescent mental health and suicide crisis. † ., Competing Interests: All authors have completed the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

An increasing number of elderly people retain their natural teeth into old age and further, the prevalence of endosseous implants for supporting oral prosthesis is ever increasing. These teeth and implants now present a considerable challenge in terms of maintenance, especially when patients become dependent on care. Periodontal and peri-implant diseases are more prevalent in elderly than in younger age cohorts. There are distinct differences related to the inflammatory response between periodontal and peri-implant tissues, both in young and old age. The age-related reasons for the increase in periodontal infections may be related to poor oral hygiene because of a loss of dexterity or vision, but also to immunosenescence. This term describes the aging of the immune system and the decline of its effectiveness with age. Low-grade infections, like chronic periodontitis, may cause low-grade inflammation and subsequently increase the likelihood of developing chronic diseases. In return, treatment of periodontitis may improve general health, as demonstrated for diabetes. A second mechanism illustrating how poor oral health translates into systemic disease is the risk of developing aspiration pneumonia. The treatment options in old age should be evaluated with regard to the issues of general health and maintenance. Systematic periodontal maintenance therapy, as performed in younger age cohorts, may be difficult to implement in elderly people experiencing institutional or hospital confinement because of logistics, barriers related to patients and caregivers, or cost. The scale of periodontal disease in old age represents a public health issue., (© 2022 The Authors. Periodontology 2000 published by John Wiley & Sons Ltd.)

Not all antibodies against SARS-CoV-2 inhibit viral entry, and hence, infection. Neutralizing antibodies are more likely to reflect real immunity; however, certain tests investigate protein/protein interaction rather than the fusion event. Viral and pseudoviral entry assays detect functionally active antibodies but are limited by biosafety and standardization issues. We have developed a Spike/ACE2-dependent fusion assay, based on a split luciferase. Hela cells stably transduced with Spike and a large fragment of luciferase were co-cultured with Hela cells transduced with ACE2 and the complementary small fragment of luciferase. Cell fusion occurred rapidly allowing the measurement of luminescence. Light emission was abolished in the absence of Spike and reduced in the presence of proteases. Sera from COVID-19-negative, non-vaccinated individuals or from patients at the moment of first symptoms did not lead to a significant reduction of fusion. Sera from COVID-19-positive patients as well as from vaccinated individuals reduced the fusion. This assay was more correlated to pseudotyped-based entry assay rather than serology or competitive ELISA. In conclusion, we report a new method measuring fusion-inhibitory antibodies in serum, combining the advantage of a complete Spike/ACE2 interaction active on entry with a high degree of standardization, easily allowing automation in a standard bio-safety environment.

The reactive oxygen species (ROS)-generating enzyme NOX3 has recently been implicated in the pathophysiology of several acquired forms of sensorineural hearing loss, including cisplatin-, noise- and age-related hearing loss. NOX3 is highly and specifically expressed in the inner ear and therefore represents an attractive target for specific intervention aiming at otoprotection. Despite the strong rationale to inhibit NOX3, there is currently no specific pharmacological inhibitor available. Molecular therapy may represent a powerful alternative. In this study, we developed and tested a collection of small interfering (si) RNA constructs to establish a proof of concept of NOX3 inhibition through local delivery in the mouse inner ear. The inhibitory potential of 10 different siRNA constructs was first assessed in three different cells lines expressing the NOX3 complex. Efficacy of the most promising siRNA construct to knock-down NOX3 was then further assessed in vivo , comparing middle ear delivery and direct intracochlear delivery through the posterior semi-circular canal. While hearing was completely preserved through the intervention, a significant downregulation of NOX3 expression in the mouse inner ear and particularly in the spiral ganglion area at clinically relevant levels (>60%) was observed 48 h after treatment. In contrast to successful intracochlear delivery, middle ear administration of siRNA failed to significantly inhibit Nox3 mRNA expression. In conclusion, intracochlear delivery of NOX3-siRNAs induces a robust temporal NOX3 downregulation, which could be of relevance to prevent predictable acute insults such as cisplatin chemotherapy-mediated ototoxicity and other forms of acquired hearing loss, including post-prevention of noise-induced hearing loss immediately after trauma. Successful translation of our concept into an eventual clinical use in humans will depend on the development of atraumatic and efficient delivery routes into the cochlea without a risk to induce hearing loss through the intervention., Competing Interests: The authors declare that this study received funding from Decibel Therapeutics. The funder was involved in the study design. However, the funder had no role in the data collection, analysis, interpretation, the writing of this article or the decision to submit it for publication., (Copyright © 2022 Nacher-Soler, Marteyn, Barenzung, Sgroi, Krause, Senn and Rousset.)

Purpose: Surveillance data are used for public health action, but the practice of analyzing data by single demographic characteristics may produce findings that reflect abstract categories rather than a person's lived experience. Intersectionality is a theoretical framework that advocates for individuals to be recognized as the whole of their identity and within context of power structures. Using the national Youth Risk Behavior Survey 2015-2019, we examined 5-year trends in experiencing violence, poor mental health, and suicidal risk behavior among US high school students using intersections of race/ethnicity and sex., Methods: We used SUDAAN to calculate prevalence estimates and logistic regression models to assess for linear trends while accounting for the weighting and complex survey design., Results: Among all students in aggregate, experiencing dating violence decreased while being threatened with a weapon at school and feeling persistently sad or hopeless increased over time; however, these trends did not apply to most students when stratified by identity. The one near-universal experience was that students in aggregate and almost all identities had an increased trend of skipping school because they felt unsafe there., Discussion: By focusing on identities defined by two main drivers of health disparities-race/ethnicity and sex-we found that changes in risk behaviors did not occur equally among students and that prevalence estimates were highest among Black males, Black females, and Hispanic females. We outlined the power structures that frame the current educational environment. Patterns of health disparities can be highlighted by analyzing surveillance data through an intersectional lens., (Published by Elsevier Inc.)

Background: The SARS-CoV-2 pandemic was particularly devastating for elderly people, and the underlying mechanisms of the disease are still poorly understood. In this study, we investigated fusion inhibitory antibodies (fiAbs) in elderly and younger COVID-19 patients and analyzed predictive factors for their occurrence. Methods: Data and samples were collected in two cohorts of hospitalized patients. A fusion assay of SARS-CoV-2 spike-expressing cells with ACE2-expressing cells was used to quantify fiAbs in the serum of patients. Results: A total of 108 patients (52 elderly (mean age 85 ± 7 years); 56 young (mean age 52 ± 10 years)) were studied. The concentrations of fiAbs were lower in geriatric patients, as evidenced at high serum dilutions (1/512). The association between fiAbs and anti-Spike Ig levels was weak (correlation coefficient < 0.3), but statistically significant. Variables associated with fusion were the delay between the onset of symptoms and testing (HR = −2.69; p < 0.001), clinical frailty scale (HR = 4.71; p = 0.035), and WHO severity score (HR = −6.01, p = 0.048). Conclusions: Elderly patients had lower fiAbs levels after COVID-19 infection. The decreased fiAbs levels were associated with frailty.

Charcot-Marie-Tooth disease type 1 (CMT1A) is a hereditary peripheral neuropathy for which there is no available therapy. Alpha-1 antitrypsin (AAT) is an abundant serine protease inhibitor with anti-inflammatory and immunomodulating properties. Here, we tested whether treatment with human AAT (hAAT) would have a therapeutic effect on CMT1A in a PMP22 transgenic mouse model. Our results show that hAAT significantly improved compound muscle action potential and histopathological features and decreased circulating IL-6 in CMT1A mice. We also investigated some of the possible underlying mechanisms in vitro. We confirmed that hAAT inhibits ADAM-17, a protease that has been implicated in blocking myelination. Furthermore, both hAAT and recombinant human AAT (rhAAT) were able to attenuate the activation of a macrophage/microglia cell line, markedly decreasing the activation of the MHC class II promoter and the expression of pro-inflammatory genes such as IL-1β and the endoplasmic reticulum (ER) stress marker ATF3 . Taken together, our results demonstrate for the first time that hAAT is able to reduce the progression of CMT1A, possibly by dampening inflammation and by regulating ADAM-17. Given the already well-established safety profile of hAAT, specifically in AAT deficiency disease (AATD), we suggest that the findings of our study should be promptly investigated in CMT1A patients.

Youths have experienced disruptions to school and home life since the COVID-19 pandemic began in March 2020. During January-June 2021, CDC conducted the Adolescent Behaviors and Experiences Survey (ABES), an online survey of a probability-based, nationally representative sample of U.S. public- and private-school students in grades 9-12 (N = 7,705). ABES data were used to estimate the prevalence of disruptions and adverse experiences during the pandemic, including parental and personal job loss, homelessness, hunger, emotional or physical abuse by a parent or other adult at home, receipt of telemedicine, and difficulty completing schoolwork. Prevalence estimates are presented for all students and by sex, race and ethnicity, grade, sexual identity, and difficulty completing schoolwork. Since the beginning of the pandemic, more than half of students found it more difficult to complete their schoolwork (66%) and experienced emotional abuse by a parent or other adult in their home (55%). Prevalence of emotional and physical abuse by a parent or other adult in the home was highest among students who identified as gay, lesbian, or bisexual (74% emotional abuse and 20% physical abuse) and those who identified as other or questioning (76% and 13%) compared with students who identified as heterosexual (50% and 10%). Overall, students experienced insecurity via parental job loss (29%), personal job loss (22%), and hunger (24%). Disparities by sex and by race and ethnicity also were noted. Understanding health disparities and student disruptions and adverse experiences as interconnected problems can inform school and community initiatives that promote adolescent health and well-being. With community support to provide coordinated, cross-sector programming, schools can facilitate linkages to services that help students address the adverse experiences that they faced during the ongoing COVID-19 pandemic. Public health and health care professionals, communities, schools, families, and adolescents can use these findings to better understand how students' lives have been affected during the pandemic and what challenges need to be addressed to promote adolescent health and well-being during and after the pandemic., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Hydrogen peroxide (H 2 O 2 ) is a key defense component of host-microbe interaction. However, H 2 O 2 concentrations generated by immune cells or epithelia are usually insufficient for bacterial killing and rather modulate bacterial responses. Here, we investigated the impact of sublethal H 2 O 2 concentration on gene expression of E. coli BW25113 after 10 and 60 min of exposure. RNA-seq analysis revealed that approximately 12% of bacterial genes were strongly dysregulated 10 min following exposure to 2.5 mM H 2 O 2 . H 2 O 2 exposure led to the activation of a specific antioxidant response and a general stress response. The latter was characterized by a transient down-regulation of genes involved in general metabolism, such as nucleic acid biosynthesis and translation, with a striking and coordinated down-regulation of genes involved in ribosome formation, and a sustained up-regulation of the SOS response. We confirmed the rapid transient and specific response mediated by the transcription factor OxyR leading to up-regulation of antioxidant systems, including the catalase-encoding gene ( katG ), that rapidly degrade extracellular H 2 O 2 and promote bacterial survival. We documented a strong and transient up-regulation of genes involved in sulfur metabolism and cysteine biosynthesis, which are under the control of the transcription factor CysB. This strong specific transcriptional response to H 2 O 2 exposure had no apparent impact on bacterial survival, but possibly replenishes the stores of oxidized cysteine and glutathione. In summary, our results demonstrate that different stress response mechanisms are activated by H 2 O 2 exposure and highlight the cysteine synthesis as an antioxidant response in E. coli .