Human SARS-CoV-2 challenge uncovers local and systemic response dynamics.

The COVID-19 pandemic is an ongoing global health threat, yet our understanding of the dynamics of early cellular responses to this disease remains limited1. Here in our SARS-CoV-2 human challenge study, we used single-cell multi-omics profiling of nasopharyngeal swabs and blood to temporally resolve abortive, transient and sustained infections in seronegative individuals challenged with pre-Alpha SARS-CoV-2. Our analyses revealed rapid changes in cell-type proportions and dozens of highly dynamic cellular response states in epithelial and immune cells associated with specific time points and infection status. We observed that the interferon response in blood preceded the nasopharyngeal response. Moreover, nasopharyngeal immune infiltration occurred early in samples from individuals with only transient infection and later in samples from individuals with sustained infection. High expression of HLA-DQA2 before inoculation was associated with preventing sustained infection. Ciliated cells showed multiple immune responses and were most permissive for viral replication, whereas nasopharyngeal T cells and macrophages were infected non-productively. We resolved 54 T cell states, including acutely activated T cells that clonally expanded while carrying convergent SARS-CoV-2 motifs. Our new computational pipeline Cell2TCR identifies activated antigen-responding T cells based on a gene expression signature and clusters these into clonotype groups and motifs. Overall, our detailed time series data can serve as a Rosetta stone for epithelial and immune cell responses and reveals early dynamic responses associated with protection against infection.

A preparative small-molecule mimic of liver CYP450 enzymes in the aliphatic C-H oxidation of carbocyclic N-heterocycles.

An emerging trend in small-molecule pharmaceuticals, generally composed of nitrogen heterocycles (N-heterocycles), is the incorporation of aliphatic fragments. Derivatization of the aliphatic fragments to improve drug properties or identify metabolites often requires lengthy de novo syntheses. Cytochrome P450 (CYP450) enzymes are capable of direct site- and chemo-selective oxidation of a broad range of substrates but are not preparative. A chemoinformatic analysis underscored limited structural diversity of N-heterocyclic substrates oxidized using chemical methods relative to pharmaceutical chemical space. Here, we describe a preparative chemical method for direct aliphatic oxidation that tolerates a wide range of nitrogen functionality (chemoselective) and matches the site of oxidation (site-selective) of liver CYP450 enzymes. Commercial small-molecule catalyst Mn(CF3-PDP) selectively effects direct methylene oxidation in compounds bearing 25 distinct heterocycles including 14 out of 27 of the most frequent N-heterocycles found in U.S. Food and Drug Administration (FDA)-approved drugs. Mn(CF3-PDP) oxidations of carbocyclic bioisostere drug candidates (for example, HCV NS5B and COX-2 inhibitors including valdecoxib and celecoxib derivatives) and precursors of antipsychotic drugs blonanserin, buspirone, and tiospirone and the fungicide penconazole are demonstrated to match the major site of aliphatic metabolism obtained with liver microsomes. Oxidations are demonstrated at low Mn(CF3-PDP) loadings (2.5 to 5 mol%) on gram scales of substrate to furnish preparative amounts of oxidized products. A chemoinformatic analysis supports that Mn(CF3-PDP) significantly expands the pharmaceutical chemical space accessible to small-molecule C-H oxidation catalysis.

Elevated ferritin, mediated by IL-18 is associated with systemic inflammation and mortality in acute respiratory distress syndrome (ARDS).

BACKGROUND: Inflammatory subphenotypes have been identified in acute respiratory distress syndrome (ARDS). Hyperferritinaemia in sepsis is associated with hyperinflammation, worse clinical outcomes, and may predict benefit with immunomodulation. Our aim was to determine if raised ferritin identified a subphenotype in patients with ARDS. METHODS: Baseline plasma ferritin concentrations were measured in patients with ARDS from two randomised controlled trials of simvastatin (Hydroxymethylglutaryl-CoA Reductase Inhibition with Simvastatin in Acute Lung Injury to Reduce Pulmonary Dysfunction-2 (HARP-2); discovery cohort, UK) and neuromuscular blockade (ROSE; validation cohort, USA). Results were analysed using a logistic regression model with restricted cubic splines, to determine the ferritin threshold associated with 28-day mortality. RESULTS: Ferritin was measured in 511 patients from HARP-2 (95% of patients enrolled) and 847 patients (84% of patients enrolled) from ROSE. Ferritin was consistently associated with 28-day mortality in both studies and following a meta-analysis, a log-fold increase in ferritin was associated with an OR 1.71 (95% CI 1.01 to 2.90) for 28-day mortality. Patients with ferritin >1380 ng/mL (HARP-2 28%, ROSE 24%) had a significantly higher 28-day mortality and fewer ventilator-free days in both studies. Mediation analysis, including confounders (acute physiology and chronic health evaluation-II score and ARDS aetiology) demonstrated a statistically significant contribution of interleukin (IL)-18 as an intermediate pathway between ferritin and mortality. CONCLUSIONS: Ferritin is a clinically useful biomarker in ARDS and is associated with worse patient outcomes. These results provide support for prospective interventional trials of immunomodulatory agents targeting IL-18 in this hyperferritinaemic subgroup of patients with ARDS.

The effectiveness of out-of-hours palliative care telephone advice lines: A rapid systematic review.

BACKGROUND: People with palliative care needs and their carers often rely on out-of-hours services to remain at home. Policymakers have recommended implementing telephone advice lines to ensure 24/7 access to support. However, the impact of these services on patient and carer outcomes, as well as the health care system, remains poorly understood. AIM: To evaluate the clinical- and cost-effectiveness of out-of-hours palliative care telephone advice lines, and to identify service characteristics associated with effectiveness. DESIGN: Rapid systematic review (PROSPERO ID: CRD42023400370) with narrative synthesis. DATA SOURCES: Three databases (Medline, EMBASE and CINAHL) were searched in February 2023 for studies of any design reporting on telephone advice lines with at least partial out-of-hours availability. Study quality was assessed using the Mixed Methods Appraisal Tool, and quantitative and qualitative data were synthesised narratively. RESULTS: Twenty-one studies, published 2000-2022, were included. Most studies were observational, none were experimental. While some evidence suggested that telephone advice lines offer guidance and reassurance, supporting care at home and potentially reducing avoidable emergency care use in the last months of life, variability in reporting and poor methodological quality across studies limit our understanding of patient/carer and health care system outcomes. CONCLUSION: Despite their increasing use, evidence for the clinical- and cost-effectiveness of palliative care telephone advice lines remains limited, primarily due to the lack of robust comparative studies. There is a need for more rigorous evaluations incorporating experimental or quasi-experimental methods and longer follow-up, and standardised reporting of telephone advice line models and outcomes, to guide policy and practice.

Telephone advice lines for adults with advanced illness and their family carers: a qualitative analysis and novel practical framework.

BACKGROUND: Telephone advice lines have been recommended internationally to support around-the-clock care for people living at home with advanced illness. While they undoubtedly support care, there is little evidence about what elements are needed for success. A national picture is needed to understand, improve and standardise service delivery/care. AIM: To explore telephone advice lines for people living at home with advanced illness across the four UK nations, and to construct a practical framework to improve services. DESIGN: A cross-national evaluation of telephone advice lines using structured qualitative interviews. A patient and public involvement workshop was conducted to refine the framework. SETTING/PARTICIPANTS: Professionals with responsibilities for how palliative care services are delivered and/or funded at a local or regional level, were purposively sampled. RESULTS: Seventy-one interviews were conducted, covering 60 geographical areas. Five themes were identified. Availability: Ten advice line models were described. Variation led to confusion about who to call and when. Accessibility, awareness and promotion: It was assumed that patients/carers know who to call out-of-hours, but often they did not. Practicalities: Call handlers skills/expertise varied, which influenced how calls were managed. Possible responses ranged from signposting to organising home visits. Integration/continuity of care: Integration between care providers was limited by electronic medical records access/information sharing. Service structure/commissioning: Sustained funding was often an issue for charitably funded organisations. CONCLUSIONS: Our novel evidence-based practical framework could be transformative for service design/delivery, as it presents key considerations relating to the various elements of advice lines that may impact on the patient/carer experience.

Residual Lung Abnormalities after COVID-19 Hospitalization: Interim Analysis of the UKILD Post-COVID-19 Study.

Rationale: Shared symptoms and genetic architecture between coronavirus disease (COVID-19) and lung fibrosis suggest severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may lead to progressive lung damage. Objectives: The UK Interstitial Lung Disease Consortium (UKILD) post-COVID-19 study interim analysis was planned to estimate the prevalence of residual lung abnormalities in people hospitalized with COVID-19 on the basis of risk strata. Methods: The PHOSP-COVID-19 (Post-Hospitalization COVID-19) study was used to capture routine and research follow-up within 240 days from discharge. Thoracic computed tomography linked by PHOSP-COVID-19 identifiers was scored for the percentage of residual lung abnormalities (ground-glass opacities and reticulations). Risk factors in linked computed tomography were estimated with Bayesian binomial regression, and risk strata were generated. Numbers within strata were used to estimate posthospitalization prevalence using Bayesian binomial distributions. Sensitivity analysis was restricted to participants with protocol-driven research follow-up. Measurements and Main Results: The interim cohort comprised 3,700 people. Of 209 subjects with linked computed tomography (median, 119 d; interquartile range, 83-155), 166 people (79.4%) had more than 10% involvement of residual lung abnormalities. Risk factors included abnormal chest X-ray (risk ratio [RR], 1.21; 95% credible interval [CrI], 1.05-1.40), percent predicted DlCO less than 80% (RR, 1.25; 95% CrI, 1.00-1.56), and severe admission requiring ventilation support (RR, 1.27; 95% CrI, 1.07-1.55). In the remaining 3,491 people, moderate to very high risk of residual lung abnormalities was classified at 7.8%, and posthospitalization prevalence was estimated at 8.5% (95% CrI, 7.6-9.5), rising to 11.7% (95% CrI, 10.3-13.1) in the sensitivity analysis. Conclusions: Residual lung abnormalities were estimated in up to 11% of people discharged after COVID-19-related hospitalization. Health services should monitor at-risk individuals to elucidate long-term functional implications.

Adaptation and multicentre validation of a patient-centred outcome scale for people severely ill with COVID (IPOS-COV).

BACKGROUND: Patient-centred measures to capture symptoms and concerns have rarely been reported in severe COVID. We adapted and tested the measurement properties of the proxy version of the Integrated Palliative care Outcome Scale-IPOS-COV for severe COVID using psychometric approach. METHODS: We consulted experts and followed consensus-based standards for the selection of health status measurement instruments and United States Food and Drug Administration guidance for adaptation and analysis. Exploratory Factor Analysis and clinical perspective informed subscales. We tested the internal consistency reliability, calculated item total correlations, examined re-test reliability in stable patients, and also evaluated inter-rater reproducibility. We examined convergent and divergent validity of IPOS-COV with the Australia-modified Karnofsky Performance Scale and evaluated known-groups validity. Ability to detect change was examined. RESULTS: In the adaptation phase, 6 new items were added, 7 items were removed from the original measure. The recall period was revised to be the last 12-24 h to capture fast deterioration in COVID. General format and response options of the original Integrated Palliative care Outcome Scale were preserved. Data from 572 patients with COVID from across England and Wales seen by palliative care services were included. Four subscales were supported by the 4-factor solution explaining 53.5% of total variance. Breathlessness-Agitation and Gastro-intestinal subscales demonstrated good reliability with high to moderate (a = 0.70 and a = 0.67) internal consistency, and item-total correlations (0.62-0.21). All except the Flu subscale discriminated well between patients with differing disease severity. Inter-rater reliability was fair with ICC of 0.40 (0.3-0.5, 95% CI, n = 324). Correlations between the subscales and AKPS as predicted were weak (r = 0.13-0.26) but significant (p < 0.01). Breathlessness-Agitation and Drowsiness-Delirium subscales demonstrated good divergent validity. Patients with low oxygen saturation had higher mean Breathlessness-Agitation scores (M = 5.3) than those with normal levels (M = 3.4), t = 6.4 (186), p < 0.001. Change in Drowsiness-Delirium subscale correctly classified patients who died. CONCLUSIONS: IPOS-COV is the first patient-centred measure adapted for severe COVID to support timely management. Future studies could further evaluate its responsiveness and clinical utility with clinimetric approaches.

Translation and cross-cultural adaptation of the Integrated Palliative Care Outcome Scale in Hindi: Toward capturing palliative needs and concerns in Hindi speaking patients.

BACKGROUND: Culturally relevant patient-centered outcomes tools are needed to identify the needs of patients and to assess their palliative care concerns. AIM: To translate and culturally adapt the Integrated Palliative Care Outcome Scale (IPOS) into Hindi. DESIGN: The study applied a standardized methodology entailing six phases for translation and content validation: equivalence setting through a three-step process; forward translation; blind backward translation; expert review by a panel of the POS team; cognitive de-briefing with patients; and proof-reading of the final tool. All interviews and focus groups were audio-recorded, transcribed and analyzed using content analysis. SETTING/PARTICIPANTS: (1) Healthcare professionals including doctors, nurses, psychologists, counselors, and volunteers working in Indian palliative care settings with expertise in both English and Hindi languages; (2) Hindi speaking patients diagnosed with cancer who were receiving palliative care in community settings. Caregivers, palliative care experts, and language translators contributed to the translation procedure. RESULTS: Phrases like nausea, poor appetite, drowsiness, and depression were difficult to translate into Hindi. Response categories "occasional" and "sometimes" were overlapping. All items, instructions and response categories were simple to understand. A visual thermometer is a unique feature of Hindi IPOS to facilitate responses from less educated patients. CONCLUSION: Hindi IPOS has face and content validity for use in clinical practice and research. The Hindi IPOS has implications beyond Indian palliative care settings. Millions of Hindi speakers can now respond to IPOS, and have a tool for communicating their palliative care needs in their mother tongue to inform patient-centered care.

The circadian clock protein REVERBα inhibits pulmonary fibrosis development.

Pulmonary inflammatory responses lie under circadian control; however, the importance of circadian mechanisms in the underlying fibrotic phenotype is not understood. Here, we identify a striking change to these mechanisms resulting in a gain of amplitude and lack of synchrony within pulmonary fibrotic tissue. These changes result from an infiltration of mesenchymal cells, an important cell type in the pathogenesis of pulmonary fibrosis. Mutation of the core clock protein REVERBα in these cells exacerbated the development of bleomycin-induced fibrosis, whereas mutation of REVERBα in club or myeloid cells had no effect on the bleomycin phenotype. Knockdown of REVERBα revealed regulation of the little-understood transcription factor TBPL1. Both REVERBα and TBPL1 altered integrinß1 focal-adhesion formation, resulting in increased myofibroblast activation. The translational importance of our findings was established through analysis of 2 human cohorts. In the UK Biobank, circadian strain markers (sleep length, chronotype, and shift work) are associated with pulmonary fibrosis, making them risk factors. In a separate cohort, REVERBα expression was increased in human idiopathic pulmonary fibrosis (IPF) lung tissue. Pharmacological targeting of REVERBα inhibited myofibroblast activation in IPF fibroblasts and collagen secretion in organotypic cultures from IPF patients, thus suggesting that targeting of REVERBα could be a viable therapeutic approach.

Implementation Fidelity and Theory-Informed Dose Effects of a Teen Pregnancy Prevention Program for Native American Youth.

In 2019, Native youth had the highest rate of teen pregnancy of all racial/ethnic groups. "Respecting the Circle of Life" (RCL) is one of the first evidence-based teen pregnancy prevention programs for Native teens and there is interest in replicating the program across tribal communities. To inform replication, it is important to consider process data including quality, fidelity, and dosage as these may all moderate impact of the program. Participants were Native youth aged 11-19 and a trusted adult. This study includes participants randomized to the RCL program only (N = 266). Data sources include independent observations, facilitator self-assessments, attendance logs, and self-report assessments completed by enrolled youth at baseline and 3 months post assessment. Data was compiled and summed by cohort. Dosage was number of minutes participating in activities separated by theoretical constructs. Linear regression models were utilized to assess moderation of the effects of the intervention dosage on outcomes of interest. Eighteen facilitators delivered RCL. One hundred eighteen independent observations and 320 facilitator self-assessments were collected and entered. Findings indicate RCL was implemented with high fidelity and quality (4.40 to 4.82 out of a 5-point Likert scale; 96.6% of planned activities completed). Dosage was high with an average completion of 7 out of 9 lessons. There was no association between theoretical construct dosage and outcomes of interest. Overall, this study indicates RCL was delivered with high fidelity, quality, and dosage in this trial. This paper informs future replication of RCL and provides support for hiring paraprofessionals from the local community as facilitators, delivering the RCL to peer groups of the same age and sex, delivering the RCL with short duration and high frequency, and encouraging youth to attend all RCL lessons, but continue to serve youth who have missed one or more lessons.

Assessing the Effectiveness of the Respecting the Circle of Life Project on Condom and Contraception Self-efficacy Among American Indian Youth.

Respecting the Circle of Life (RCL) is a teen pregnancy prevention program that was evaluated for effectiveness on sexual health risk behaviors through a two-arm randomized control trial (RCT) with American Indian (AI) youth ages 11-19. The objective of this study is to investigate the effects of RCL compared to a control group on items of condom and contraception self-efficacy. Linear regression analysis was used to compare differences in each item that included condom and contraception self-efficacy scales among the intervention and control participants at baseline, 3 and 9 months post intervention. Youth enrolled in the intervention reported higher levels of condom and contraception self-efficacy across almost all individual items. Exceptions include items related to partner negotiation of condom self-efficacy at 3 months (p = 0.227) and 9 months (p = 0.074) post intervention. Findings indicate RCL is effective at improving overall condom and contraception self-efficacy but did not impact the specific component of partner negotiation for either condom or contraception self-efficacy. This inquiry provides rationale to further explore components of RCL related to partner negotiation.

Measuring the effects of the COVID-19 pandemic on Diné and White Mountain Apache school personnel, families, and students: protocol for a prospective longitudinal cohort study.

BACKGROUND: This paper describes the protocol for a longitudinal cohort study, "Project SafeSchools" (PSS), which focuses on measuring the effects of COVID-19 and the return to in-person learning on Diné (Navajo) and White Mountain Apache (Apache) youth, parents, and educators. The early surges of the COVID-19 pandemic led to the closure of most reservation and border town schools serving Diné and Apache communities. This study aims to: (1) understand the barriers and facilitators to school re-opening and in-person school attendance from the perspective of multiple stakeholders in Diné and Apache communities; and (2) evaluate the educational, social, emotional, physical, and mental health impacts of returning to in-person learning for caregivers and youth ages 4-16 who reside or work on the Diné Nation and the White Mountain Apache Tribal lands. METHODS: We aim to recruit up to N = 200 primary caregivers of Diné and Apache youth ages 4-16 and up to N = 120 school personnel. In addition, up to n = 120 of these primary caregivers and their children, ages 11-16, will be selected to participate in qualitative interviews to learn more about the effects of the pandemic on their health and wellbeing. Data from caregiver and school personnel participants will be collected in three waves via self-report surveys that measure COVID-19 related behaviors and attitudes, mental health, educational attitudes, and cultural practices and beliefs for both themselves and their child (caregiver participants only). We hypothesize that an individual's engagement with a variety of cultural activities during school closures and as school re-opened will have a protective effect on adult and youth mental health as they return to in-person learning. DISCUSSION: The results of this study will inform the development or implementation of preventative interventions that may help Diné and Apache youth and their families recover from the negative impact of the COVID-19 pandemic, and positively impact their health and wellness.

Improving communication between American Indian youth and caregivers to prevent teenage pregnancy.

American Indian (AI) youth are at increased risk for poor reproductive health outcomes. Parental communication and monitoring are established predictors of sexual risk-taking among adolescents. No program evaluations of sexual risk avoidance programs have focused exclusively on AI youth and parents. This study assesses the impact of the Respecting the Circle of Life (RCL) Teenage Pregnancy Prevention program on parent-youth communication and parental monitoring through a randomized controlled trial with AI youth ages 11-19 and their trusted adults (parents/caregivers) (N = 518). RCL consists of 8-peer group and one parent-youth session. Trusted adult participants completed the Parental Monitoring Scale and the Parent Adolescent Communication Scale at baseline and 3 and 9 months post-intervention via self-report. Intervention impact was evaluated using linear regression models, which included an indicator for study group. At 3 months post, trusted adults in the intervention reported significantly higher levels of sexual health communication (P = 0.042) and spoke to their child more often about how to get condoms (P = 0.001), get birth control (P = 0.014) and protect themselves from human immunodeficiency virus (P = 0.005) compared with trusted adults in the control condition. Program impact varied by age and sex. This study adds to literature and extends findings on RCL impact.

'Empowering our people' to address depression, violence, and sexual risk among Native Americans with recent binge alcohol use.

Background: This study was launched in response to an American Indian (AI) community's concern regarding the comorbid occurrence of substance use, poor mental health, and other risk factors on sexual health. The purpose of this manuscript was to assess the relationship between alcohol use, violence, depression and STI/HIV risk behaviors on the frequency of unprotected sex acts and number of sexual partners among AI adults.Methods: Specifically, this analysis examines sociodemographic characteristics, experience of sexual and physical violence, binge drinking, depression, and sexual risk taking among n = 281 AI adults ages 18-55. Regression models examine associations between the aforementioned risk factors, number of sex partners and number of unprotected sex acts, by depression status and sex, among participants.Results: Frequent binge drinking predicted frequency of unprotected sex for both males and females; ever experiencing physical violence was a powerful predictor of unprotected sex for females, but not males. Ever experiencing physical violence strongly predicted having multiple sexual partners for females but was related to decreased number of sexual partners for males. Females ever experiencing sexual violence had more sexual partners; this was not observed for males. Binge drinking predicted frequency of unprotected sex acts, regardless of depression status.Discussion: Interventions for AI adults seeking to reduce sexual health risk should reflect past violence victimization in sexual decision making, primarily among women. The significant role of binge alcohol use for modifying sexual decisions should be of prime focus and interventions should be personalized to address individuals' own alcohol use patterns. Additional research should explore how binge alcohol use moderates the relationship between depression and sexual risk.

Charitably funded hospices and the challenges associated with the COVID-19 pandemic: a mixed-methods study (CovPall).

BACKGROUND: Independent charitably funded hospices have been an important element of the UK healthcare response to the COVID-19 pandemic. Hospices usually have different funding streams, procurement processes, and governance arrangements compared to NHS provision, which may affect their experiences during the COVID-19 pandemic. The aim of this study is to understand the challenges faced by charitably funded hospices during the COVID-19 pandemic. METHODS: Eligible Organisations providing specialist palliative or hospice care completed the online CovPall survey (2020) which explored their response to the COVID-19 pandemic. Eligible organisations were then purposively selected to participate in interviews as part of qualitative case studies (2020-21) to understand challenges in more depth. Free-text responses from the survey were analysed using content analysis and were categorised accordingly. These categorisations were used a priori for a reflexive thematic analysis of interview data. RESULTS: 143 UK independent charitably funded hospices completed the online CovPall survey. Five hospices subsequently participated in qualitative case studies (n = 24 staff interviews). Key themes include: vulnerabilities of funding; infection control during patient care; and bereavement support provision. Interviewees discussed the fragility of income due to fundraising events stopping; the difficulties of providing care to COVID-19 and non-COVID-19 patients within relatively small organisations; and challenges with maintaining the quality of bereavement services. CONCLUSION: Some unique care and provision challenges during the COVID-19 pandemic were highlighted by charitably funded hospices. Funding core services charitably and independently may affect their ability to respond to pandemics, or scenarios where resources are unexpectedly insufficient.

Development of "CULTURE FORWARD: A strengths and culture-based tool to protect our native youth from suicide".

OBJECTIVE: Indigenous knowledge and practices promote American Indian/Alaska Native (AI/AN; Native) communities' health and well-being. Historical losses and continued oppression have resulted in disproportionately higher AI/AN youth suicide rates. This article describes the development of a new national resource guide titled "CULTURE FORWARD" for tribal leaders and stakeholders to support youth suicide prevention efforts through cultural strengths. METHOD: The CULTURE FORWARD guide was developed over 6 months through a community-engaged process. We conducted nine roundtables and eight interviews with a wide variety of community members, leaders, and providers representing 36 diverse tribal communities and geographic regions. Participants discussed AI/AN youth risk and protective factors, successful community efforts to prevent suicide, and content and dissemination ideas. A comprehensive literature review complemented qualitative findings. A diverse and representative National Advisory Editorial Board guided content and design throughout development. RESULTS: Qualitative data were analyzed iteratively and thematically. Across all listening sessions, culture was identified as a key protective factor against AI/AN youth suicide. Five themes related to cultural strengths informed guide chapters. Each chapter includes an introduction; how that theme helps prevent Native youth suicide; a review of academic literature, community stories and programs; action steps; and additional resources. CONCLUSIONS: CULTURE FORWARD honors and empowers communities by weaving strands of knowledge, stories, and practical resources highlighting Native communities' strengths to protect against Native youth suicide. The guide is free online and print copies are being distributed nationally. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Transcriptome analysis of IPF fibroblastic foci identifies key pathways involved in fibrogenesis.

INTRODUCTION: Fibroblastic foci represent the cardinal pathogenic lesion in idiopathic pulmonary fibrosis (IPF) and comprise activated fibroblasts and myofibroblasts, the key effector cells responsible for dysregulated extracellular matrix deposition in multiple fibrotic conditions. The aim of this study was to define the major transcriptional programmes involved in fibrogenesis in IPF by profiling unmanipulated myofibroblasts within fibrotic foci in situ by laser capture microdissection. METHODS: The challenges associated with deriving gene calls from low amounts of RNA and the absence of a meaningful comparator cell type were overcome by adopting novel data mining strategies and by using weighted gene co-expression network analysis (WGCNA), as well as an eigengene-based approach to identify transcriptional signatures, which correlate with fibrillar collagen gene expression. RESULTS: WGCNA identified prominent clusters of genes associated with cell cycle, inflammation/differentiation, translation and cytoskeleton/cell adhesion. Collagen eigengene analysis revealed that transforming growth factor ß1 (TGF-ß1), RhoA kinase and the TSC2/RHEB axis formed major signalling clusters associated with collagen gene expression. Functional studies using CRISPR-Cas9 gene-edited cells demonstrated a key role for the TSC2/RHEB axis in regulating TGF-ß1-induced mechanistic target of rapamycin complex 1 activation and collagen I deposition in mesenchymal cells reflecting IPF and other disease settings, including cancer-associated fibroblasts. CONCLUSION: These data provide strong support for the human tissue-based and bioinformatics approaches adopted to identify critical transcriptional nodes associated with the key pathogenic cell responsible for fibrogenesis in situ and further identify the TSC2/RHEB axis as a potential novel target for interfering with excessive matrix deposition in IPF and other fibrotic conditions.

"Empowering Our People": Impact of a Culturally Adapted Evidence-Based Intervention on Sexually Transmitted Infection Risks Among Native Americans With Binge Substance Use.

BACKGROUND: The objective of this study was to evaluate a culturally adapted evidence-based intervention called EMPWR (Educate, Motivate, Protect, Wellness and Respect) for impacts on sexually transmitted infection (STI) screening and sexual health risk behaviors. METHODS: We enrolled Native American adults with recent binge substance use from a rural, reservation community in the Southwest into a 1:1 randomized controlled trial conducted on July 2015 to June 2019. All participants were offered non-clinic-based self-administered STI screening. Data were collected via self-report at baseline, 3 months, and 6 months after the intervention. Baseline and end line data are presented. RESULTS: Three hundred one participants were enrolled and had a mean age of 33.8 years; 46.5% of the sample were female, and 9.1% were employed at baseline. EMPWR participants were more likely to complete STI self-screening than control participants (38.2% vs. 23.8%, P = 0.0275). EMPWR participants reported fewer unprotected sex acts in the past 3 months (9.3 vs. 16.0, P = 0.001) and were more likely to refuse sex if their partner was not tested (23.6% vs. 12.4%, P = 0.049). The between-group difference in STI positivity 1 year after study completion was nearing statistical significance (intervention: 39.5% vs. control: 59.6%, P = 0.0575). CONCLUSIONS: The culturally adapted evidence-based intervention, EMPWR, increased uptake of STI screening and refusal of sex if partner was not STI tested and decreased the frequency of unprotected sex acts among Native American adults with recent binge substance use living on a rural reservation. Future research is needed to examine EMPWR impacts among other Native American subgroups and its potential for advancing sexual health equity in this high-priority population.

Prevention of Sexually Transmitted Diseases and Pregnancy Prevention Among Native American Youths: A Randomized Controlled Trial, 2016-2018.

Objectives. To evaluate the efficacy of the Respecting the Circle of Life program (RCL) among Native American youths 11 to 19 years of age residing in a rural reservation community in the southwestern United States. Methods. Between 2016 and 2018, we conducted a randomized controlled trial of the RCL program with 534 Native youths. Participants completed assessments at baseline and 9 and 12 months after the intervention. We conducted intention-to-treat analyses based on study group randomization. Results. At 9 months, intervention participants had significantly better condom use self-efficacy (P < .001), higher intentions to use condoms (P = .024) and abstain from sex (P = .008), and better contraceptive use self-efficacy (P < .001) than control participants, as well as better condom use (P = .032) and contraceptive use (P = .002) negotiation skills. At 12 months, intervention participants had significantly better sexual and reproductive health knowledge (P = .021), condom use self-efficacy (P < .001), contraceptive use self-efficacy (P < .001), and contraceptive use negotiation skills (P = .004) than control participants. Intervention participants reported significantly more communication with their parents about sexual and reproductive health than control participants at both 9 and 12 months (P = .042 and P = .001, respectively). Conclusions. The RCL program has a significant impact on key factors associated with pregnancy prevention among Native youths and should be used as an adolescent pregnancy prevention strategy. Trial Registration.  Clinical Trials.gov identifier: NCT02904629. (Am J Public Health. 2021;111(10): 1874-1884. https://doi.org/10.2105/AJPH.2021.306447).