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In light of recent political events in the United States, and with the urging to consider Noddings' care ethics in early childhood education, this conceptual piece considers an often-overlooked question in political discourse: what are the rights of the child, and how might these be centered in discussions of pedagogy, curricula, and legislation? Through an examination of two influential documents, the United Nations' Declaration on the Rights of the Child in 1989 and the Parental Rights in Education Act passed in Florida in 2022, the authors analyze the positioning of children in relation to parents and teachers and discuss the affordances and limitations of this positioning. In sum, authors find an overarching theme of "growth" in the former and a prominent theme of "control" in the latter. Implications for early childhood education are included.

Purpose – Job insecurity is one of the most hazardous work stressors in the twenty-first century, placing employees between employment and unemployment may threaten employees’ health in the workplaces. Using a systematic review, the first aim of this study is to list the mediators and moderators of the link between job insecurity and health-related outcomes, and second, to explain and discuss the mechanisms that could explain the mediating and moderating effects. Design/methodology/approach – We searched four databases (Science Direct, PubMed, Springer Link and Google Scholar) from 2008 to 2018 to detect these mediators and moderators. Also, as the study was conducted during COVID-19 pandemic, we particularly searched and reported the same associations over this period (2019–2022). Findings – The results of the review suggest that job insecurity negatively influences a wide range of both health- and safety-related outcomes in the workplace. The results also showed that the most studied mediator and moderator of the job insecurity-health link over the past 10 years has been workload and employability. During COVID-19, the number of studies on mediators were more than moderators and coping strategies appeared to gain more research attention. Additionally, this review suggests that, to explain the mediation and moderation effects, a combination of cognitive appraisal theory and the conservation of resources theory can be used. Originality/value – Although this review suggests that job insecurity detrimentally influences employee health, the severity of this impact on health-related outcomes may vary by the effects of various moderators.

This study assesses college students' intent to intervene when presented with a hypothetical peer exhibiting depression in one of three scenarios: depression, sadness, and depression in quarantine during COVID-19. Using the Theory of Planned Behavior (TPB), variations in constructs associated with intent were examined by context (external triggers vs. no trigger), knowledge of, and experience with depression. One hundred and sixteen health sciences students read three vignettes and completed an enhanced TPB questionnaire. Intent to intervene was greater when the vignette target was experiencing depression with external stressors. Prior experience with depression and knowing someone with depression were associated with greater intent to connect the hypothetical peer to counseling resources regardless of vignette scenario. Due to increased mental health concerns resulting from the COVID-19 pandemic, efforts promoting awareness of mental illness in peers may benefit from increasing education about stressors and causes of depression that may not be observable.

Famous people can positively influence young people by serving as examples of how to be a good person, but very little is known about which famous people youth look up to and why they do so. We coded and analyzed open-response data from 596 adolescents (M[subscript age] = 14.09 years; 58.5% girls, 57.5% White) in the northeastern United States to understand the types of famous people youth look up to and why they reported nominating them. Youth identified a variety of individuals as their famous character role models (FCRMs), ranging from athletes to politicians to activists and YouTube stars. The results suggest there are various reasons young people look up to FCRMs as examples of how to be a good person, although character attributes appear to be the most frequently cited reasons. Results serve as an important precursor to a more comprehensive investigation of the influence (either positive or negative) of these public figures.

Studies show self-concept highly correlates with mental well-being. Few show self-concept change over time, including the effect of therapeutic interventions and gender differences. Studying how therapy connects with self-concept improvement can lead to improved mental well-being. Over six weeks, 452 college students' self-concept, self-esteem, satisfaction with life, and psychological well-being was measured every two weeks for a total of four times. Self-concept scores were significantly lower for those in therapy than those not. Compared with females, males had a higher self-concept overall but a lower self-concept when in therapy. Those in and out of therapy had an improving self-concept score. Latent class growth modeling identified six trajectory groups for self-concept, where the lower the starting point, the more likely participants were to be in therapy. Future research may investigate the ceiling effect on improvement and extend the study with less frequent testing to better understand long-term self-concept changes in and out of therapy.

Adults are skilled at using language to construct/negotiate identity and to signal affiliation with others, but little is known about how these abilities develop in children. Clearly, children mirror statistical patterns in their local environment (e.g., Canadian children using "zed" instead of "zee"), but do they flexibly adapt their linguistic choices on the fly in response to the choices of different peers? To address this question, we examined the effect of group membership on 7- to 9-year-olds' labeling of objects in a trivia game, exploring whether they were more likely to use a particular label (e.g., "sofa" vs. "couch") if members of their "team" also used that label. In a preregistered study, children (N = 72) were assigned to a team (red or green) and were asked during experimental trials to answer questions--which had multiple possible answers (e.g., "blackboard" or "chalkboard")--after hearing two teammates and two opponents respond to the same question. Results showed that children were significantly more likely to produce labels less commonly used by the community (i.e., dispreferred labels) when their teammates had produced those labels. Crucially, this effect was tied to group membership, and could not be explained by children simply repeating the most recently used label. These findings demonstrate how social processes (i.e., group membership) can guide linguistic variation in children.

Adolescents' civic engagement is related to other aspects of their positive development. Many family and school characteristics can promote adolescents' civic engagement, but they are often studied separately. Furthermore, studies have often used adolescent self-reports and measured only one aspect of the multidimensional construct of civic engagement. Using longitudinal, multi-rater data from 539 adolescents (59.4% girls, 56.8% White) and 356 parents (80% mothers), we examined family and school characteristics that promote adolescents' social responsibility and five civic actions. Structural equation models showed that parents' social responsibility and civic actions predicted adolescents' corresponding civic outcomes six months later. Extracurricular opportunities in school predicted adolescents' community service and helping behaviors. Open classroom climate predicted adolescents' helping behaviors and moderated the association between parents' and adolescents' social responsibility. Parental warmth and classroom discussion of social issues did not predict adolescents' civic engagement. We discuss limitations, implications, and directions for future research.

Abstract Therapeutic hypothermia is the standard treatment for hypoxic-ischemic encephalopathy (HIE), but despite its widespread use, the rates of mortality and neurodevelopmental impairment for moderate to severe HIE remain around 30%. Methylxanthines, such as caffeine and aminophylline, have potential neuroprotective effects in the setting of hypoxic-ischemic injury. However, data on the safety and efficacy of methylxanthines in the setting of therapeutic hypothermia for HIE are limited. This retrospective multicenter study examined in-hospital outcomes in 52 infants with HIE receiving methylxanthines and therapeutic hypothermia. The frequency of mortality and in-hospital morbidities were similar to those of infants enrolled in clinical trials undergoing therapeutic hypothermia without adjunctive therapies. Clinical trials of methylxanthines for neuroprotection in HIE are needed to determine safety and efficacy and should explore optimal dosing and timing of methylxanthine administration.

Abstract We investigated the putative redundancy of the Dark Tetrad (specifically, Machiavellianism-psychopathy and sadism-psychopathy) through an examination of the differences between correlations with self-reported narrowband personality traits. In addition to measures of the Dark Tetrad, participants in four studies completed measures of various narrowband traits assessing general personality, aggression, impulsivity, Mimicry Deception Theory, and Reinforcement Sensitivity Theory. Results generally supported empirical distinctions between Machiavellianism and psychopathy, and between sadism and psychopathy. Machiavellianism significantly differed from psychopathy across correlations for nine of 10 traits (Study 1), 8 of 25 facets (Study 2), aggression (Study 3), 12 of 25 facets (Study 3), four of five facets (Study 4), impulsivity (Study 4), and five of six facets (Study 4). Sadism significantly differed from psychopathy across correlations with five of 10 traits (Study 1), eight of 25 facets (Study 2), reactive aggression (Study 3), 10 of 25 facets (Study 3), three of six facets (Study 4), impulsivity (Study 4), and three of six facets (Study 4). Our findings challenge the claims that Machiavellianism and psychopathy, as well as sadism and psychopathy, as currently measured, are redundant.

In this study, we used subfossil chironomids to assess temporal changes in lake ecological status over the last ca. 100 years in 30 lakes spread across different ecoregions in Sweden. By comparing Benthic Quality Index values and their temporal trends, we aimed to quantify the cumulative effects of climate change and land use on lakes and unravel how their effects may vary regionally. Results indicate that land use is the overarching driver of ecological changes in impacted lakes, in line with earlier studies showing that local pressures often suppress climate change effects on freshwaters. Furthermore, the known positive co-tolerance of chironomid species to temperature and eutrophication (e.g., cold stenotherm species also being indicators of oligotrophic condition, and conversely) was anticipated to induce antagonistic effects. However, the cumulative effects of climate change and land use differ across the landscape, being synergistic in the boreal forest ecoregion and antagonistic in the mixed forest ecoregion. We suggest that the pre-disturbance conditions (i.e., species composition and pressure sensitivities) play a key role in regulating the interactions between multiple pressures in freshwaters. Overall, this finding is encouraging as it implies that restoration of lakes that focuses on the most impactful pressure (e.g., nutrient loadings from agricultural fields and urban areas) remains a plausible restoration measure despite lake warming. Results also show that the net effect of climate change on the ecological status of the reference lakes varied regionally, being more pronounced in northern lakes due to the predominance of many cold water species which are more prone to disappear in response to small variations in temperature. As reference conditions are seldom revised, it is of fundamental importance to question whether the existing reference conditions are still applicable or need to be revised due to ongoing and future climate change.

Objective: To describe the outcomes of training nephrology clinicians and clinical research participants, to use the Best Case/Worst Case Communication intervention, for discussions about dialysis initiation for patients with life-limiting illness, during a randomized clinical trial to ensure competency, fidelity to the intervention, and adherence to study protocols and the intervention throughout the trial. Methods: We enrolled 68 nephrologists at ten study sites and randomized them to receive training or wait-list control. We collected copies of completed graphic aids (component of the intervention), used with study-enrolled patients, to measure fidelity and adherence. Results: We trained 34 of 36 nephrologists to competence and 27 completed the entire program. We received 60 graphic aids for study-enrolled patients for a 73% return rate in the intervention arm. The intervention fidelity score for the graphic aid reflected completion of all elements throughout the study. Conclusion: We successfully taught the Best Case/Worst Case Communication intervention to clinicians as research participants within a randomized clinical trial. Innovation: Decisions about dialysis are an opportunity to discuss prognosis and uncertainty in relation to consideration of prolonged life supporting therapy. Our study reveals a strategy to evaluate adherence to a communication intervention in real time during a clinical study.

BackgroundBlack cisgender women (hereafter referred to as “women”) experience one of the highest incidences of HIV among all populations in the United States. Pre-exposure prophylaxis (PrEP) is an effective biomedical HIV prevention option, but uptake among women is low. Despite tailored strategies for certain populations, including men who have sex with men and transgender women, Black women are frequently overlooked in HIV prevention efforts. Strategies to increase PrEP awareness and use among Black women are needed at multiple levels (ie, community, system or clinic, provider, and individual or patient). ObjectiveThis study aimed to identify barriers and facilitators to PrEP uptake and persistence among Black cisgender women and to map implementation strategies to identified barriers using the CFIR (Consolidated Framework for Implementation Research)-ERIC (Expert Recommendations for Implementing Change) Implementation Strategy Matching Tool. MethodsWe conducted a secondary analysis of previous qualitative studies completed by a multidisciplinary team of HIV physicians, implementation scientists, and epidemiologists. Studies involved focus groups and interviews with medical providers and women at a federally qualified health center in Chicago, Illinois. Implementation science frameworks such as the CFIR were used to investigate determinants of PrEP use among Black women. In this secondary analysis, data from 45 total transcripts were analyzed. We identified barriers and facilitators to PrEP uptake and persistence among cisgender women across each CFIR domain. The CFIR-ERIC Implementation Strategy Matching Tool was used to map appropriate implementation strategies to address barriers and increase PrEP uptake among Black women. ResultsBarriers to PrEP uptake were identified across the CFIR domains. Barriers included being unaware that PrEP was available (characteristics of individuals), worrying about side effects and impacts on fertility and pregnancy (intervention characteristics), and being unsure about how to pay for PrEP (outer setting). Providers identified lack of training (characteristics of individuals), need for additional clinical support for PrEP protocols (inner setting), and need for practicing discussions about PrEP with women (intervention characteristics). ERIC mapping resulted in 5 distinct implementation strategies to address barriers and improve PrEP uptake: patient education, provider training, PrEP navigation, clinical champions, and electronic medical record optimization. ConclusionsEvidence-based implementation strategies that address individual, provider, and clinic factors are needed to engage women in the PrEP care continuum. Tailoring implementation strategies to address identified barriers increases the probability of successfully improving PrEP uptake. Our results provide an overview of a comprehensive, multilevel implementation strategy (ie, “POWER Up”) to improve PrEP uptake among women. International Registered Report Identifier (IRRID)RR2-10.1371/journal.pone.0285858

Background Immune checkpoint inhibitors (ICIs) are becoming the standard of care for recurrent and metastatic cancer. Opioids, the primary treatment for cancer-related pain, are immunosuppressive raising concerns about their potential to interfere with the efficacy of ICIs. We hypothesize that exogenous opioids given for analgesia suppress antitumor immunity via T cell-mediated mu opioid receptor 1 (OPRM1) signaling.Methods In silico bioinformatics were used to assess OPRM1 receptor expression on tumor-infiltrating immune cells in patients with head and neck squamous cell carcinoma (HNSCC) and across different cancer types. A syngeneic orthotopic mouse model of oral squamous cell carcinoma was used to study the impact of morphine and OPRM1 antagonism on tumor-infiltrating immune cells, tumor growth and antitumor efficacy of anti-Programmed cell death protein 1 (PD-1) monoclonal antibody treatment.Results In patients with HNSCC, OPRM1 expression was most abundant in CD8+ T cells, particularly in patients who had not been prescribed opioids prior to resection and exhibited increased expression of exhaustion markers. Exogenous morphine treatment in tumor-bearing mice reduced CD4+ and CD8+ T-cell infiltration and subsequently anti-PD1 ICI efficacy. Peripherally acting mu opioid receptor antagonism, when administered in the adjunctive setting, was able to block morphine-induced immunosuppression and recover the antitumor efficacy of anti-PD1.Conclusions These findings suggest that morphine acts via a peripheral OPRM1-mediated mechanism to suppress CD8+ T cells, thereby fostering a pro-tumor-impaired immune response. Importantly, peripherally-restricted OPRM1 antagonism can effectively block this morphine-induced immunosuppression while still allowing for centrally-mediated analgesia, indicating a potential therapeutic strategy for mitigating the adverse effects of opioid pain relief in cancer treatment.

Enzyme replacement therapy (ERT) is the only approved disease-modifying treatment modality for Pompe disease, a rare, inherited metabolic disorder caused by a deficiency in the acid α-glucosidase (GAA) enzyme that catabolizes lysosomal glycogen. First-generation recombinant human GAA (rhGAA) ERT (alglucosidase alfa) can slow the progressive muscle degeneration characteristic of the disease. Still, most patients experience diminished efficacy over time, possibly because of poor uptake into target tissues. Next-generation ERTs aim to address this problem by increasing bis-phosphorylated high mannose (bis-M6P) N-glycans on rhGAA as these moieties have sufficiently high receptor binding affinity at the resultant low interstitial enzyme concentrations after dosing to drive uptake by the cation-independent mannose 6-phosphate receptor on target cells. However, some approaches introduce bis-M6P onto rhGAA via non-natural linkages that cannot be hydrolyzed by natural human enzymes and thus inhibit the endolysosomal glycan trimming necessary for complete enzyme activation after cell uptake. Furthermore, all rhGAA ERTs face potential inactivation during intravenous delivery (and subsequent non-productive clearance) as GAA is an acid hydrolase that is rapidly denatured in the near-neutral pH of the blood. One new therapy, cipaglucosidase alfa plus miglustat, is hypothesized to address these challenges by combining an enzyme enriched with naturally occurring bis-M6P N-glycans with a small-molecule stabilizer. Here, we investigate this hypothesis by analyzing published and new data related to the mechanism of action of the enzyme and stabilizer molecule. Based on an extensive collection of in vitro, preclinical, and clinical data, we conclude that cipaglucosidase alfa plus miglustat successfully addresses each of these challenges to offer meaningful advantages in terms of pharmacokinetic exposure, target-cell uptake, endolysosomal processing, and clinical benefit.

BackgroundPeople living with HIV experience HIV stigma alongside a spectrum of aging-related health conditions that accelerate their vulnerability to the ill effects of loneliness and social isolation. Group-singing interventions are efficacious in improving psychosocial well-being among older people in the general population; however, the social curative effects of group singing have not been explored in relation to HIV stigma. By promoting group identification, bonding, and pride, group singing may reduce loneliness, social isolation, and other negative impacts of HIV stigma among older people living with HIV. Access to group-singing programs may be enhanced by technology. ObjectiveWhile group singing has been extensively studied in older adults, group-singing interventions have not been adapted for older people living with HIV to target loneliness and social isolation in the context of HIV stigma. The objective of this study was to describe the systematic development of a group-singing intervention to reduce loneliness and social isolation among older people living with HIV. MethodsIn the San Francisco Bay Area between February 2019 and October 2019, we engaged older people living with HIV in a rigorous, 8-stage, community-engaged intervention adaptation process using the Assessment, Decision, Adaptation, Production, Topical Experts, Integration, Training, and Testing (ADAPT-ITT) framework. On the basis of a formative assessment of the needs and preferences of older people living with HIV, we selected an evidence-based group-singing intervention for older adults and systematically adapted the intervention components by administering them to a community advisory council (n=13). ResultsThe result was United Voices, a 12-week hybrid (web-based and in-person) group-singing intervention for older people living with HIV. United Voices comprises 12 web-based (ie, via Zoom [Zoom Video Communications]) rehearsals, web-based and in-person drop-in helpdesk sessions, and a professionally produced final concert recording. ConclusionsThrough an iterative process and in consultation with stakeholders and topic experts, we refined and manualized United Voices and finalized the design of a pilot randomized controlled trial to evaluate the feasibility and acceptability of the intervention protocol and procedures. The findings provide insights into the barriers and facilitators involved in culturally tailoring interventions for older people living with HIV, implementing intervention adaptations within web-based environments, and the promise of developing hybrid music-based interventions for older adults with HIV.

Abstract Importance Atopic dermatitis (AD) is associated with psychosocial symptoms, resulting in significant mental health burden and reduced quality of life. Objective To understand mental health support received by patients from their primary eczema provider. Design We administered a cross‐sectional survey (N = 954) to US caregivers and adult patients with AD. Setting The National Eczema Association (United States) conducted an online survey in October 2022 among self‐selected patients and caregivers. Outcome Patients and caregivers of AD patients reported on mental health conversations and types of mental health support received by their/their child's provider. Results Many patients did not discuss (41.9%) or were not asked (50.5%) about their mental health by their eczema provider, and 64% reported not receiving a mental health referral. Patients were more likely to receive mental health support if they were male (2.00 [1.08–3.69]), low or middle education level (4.89 [2.10–11.36], 2.71 [1.36–5.40]), or had purchased insurance policies (4.43 [1.79–10.98]). Providers were most likely to refer patients to counseling services (22.5%), followed by alternative mental health therapy (14.9%), cognitive behavioural therapy (13.3%) and peer/social support groups (12.2%). Conclusion Despite the strong association between AD and mental health conditions, there is a significant proportion of patients that report not receiving mental health support from their/their child's primary eczema provider. Screening with validated measures may improve the identification of patients requiring additional support. Future research should evaluate the efficacy of mental health resources and barriers to accessing and referring patients for mental health care.

Background: : Biobehavioral interventions including relaxation, distraction, and mindfulness meditation exercises have been shown to decrease perioperative stress, anxiety, and pain. Our aims were to 1) quantify pediatric surgical patient-reported pre-operative exposure to and post-operative use of biobehavioral interventions; 2) understand barriers and facilitators to incorporation of biobehavioral interventions into clinical practice; and 3) evaluate associated patient-reported outcomes. Methods: : We conducted an embedded mixed-methods study with a quantitative focus. Data were collected as part of the 18-hospital ENhanced Recovery In CHildren Undergoing Surgery (ENRICH-US) clinical trial for children, ages 10–18 years, undergoing elective gastrointestinal surgery. Patients/caregivers were surveyed about preoperative exposure to and postoperative use of biobehavioral interventions. Four semi-structured group interviews with 20 pediatric surgery providers were conducted. Outcomes included pain-related functional disability, health-related quality of life (HRQoL), and perioperative nervousness. Results: : 41 % (n = 67) of 164 enrolled patients/caregivers reported preoperative exposure to and 71 % (n = 117) reported postoperative use of a biobehavioral intervention(s). Barriers to incorporation of biobehavioral interventions included lack of standardized workflows, clinician knowledge, and resources. Potential facilitators included media and peer-counseling. After adjusting for individual and hospital characteristics, those who reported using a biobehavioral intervention(s) were 70 % less likely to report worsened postoperative nervousness (95 % CI 0.10–0.91; p = 0.03). Reported use of a biobehavioral intervention(s) was not found to be associated with pain-related functional disability or HRQoL. Conclusions: : Use of a biobehavioral intervention(s) may stabilize postoperative nervousness of children undergoing surgery. There is a need for redesign of clinical workflows and clinician training to facilitate integration of biobehavioral interventions.

The acquisition of variation is a fundamental -- but poorly understood -- part of child language acquisition. We fully endorse Shin and Miller's call for us to recognize the importance of this core issue, and argue that our understanding could be further enriched by greater reliance on convergent methods. As such, we implore researchers to consider perception as well as production data, and to consider acquisition across different domains and different populations of children.

Subcutaneous injection of unfractionated heparin (UH) or low molecular weight heparin (LMWH) is frequently utilized for venous thromboembolism chemoprophylaxis. We previously discovered that nurses believe patients experience more pain with UH compared to the LMWH enoxaparin; however, no published studies that are appropriately powered exist comparing pain associated with subcutaneous chemoprophylaxis. Our objective was to assess if differences exist in pain associated with subcutaneous administration of UH and enoxaparin. We conducted an observational study of patients who underwent major abdominal surgery between 11/2017–4/2019. All patients received one of three prophylactic regimens: (1) UH only, (2) Initial dose of UH followed by enoxaparin, or (3) enoxaparin only. Of the 74 patients observed, 40 patients received UH followed by enoxaparin, 17 received UH only, and 17 received enoxaparin only. There was a significant difference in patients' mean perceived pain between subcutaneous UH and enoxaparin injections (mean post-injection pain after UH 3.3 vs. enoxaparin 1.5; p

Abstract Introduction Despite advances in atopic dermatitis (AD) treatments, many patients face challenges obtaining medications. This study aimed to determine the frequency and causes of insurance coverage delays and denials for AD prescriptions and characterize the associated wait times and extent to which patients understand what to do when faced with a coverage issue. Methods This was a cross-sectional, observational study in which adult U.S. residents (aged 18+ years) with AD or caregivers of pediatric U.S. patients with AD (aged 0–17 years) completed an online survey (3 June–16 July 2021). Results Respondents (N = 978) were primarily adults with AD (81.8%), female (67.7%), and white (70.2%). There were 645 insurance delays or denials for AD prescriptions, with 48.1% (470/978) of respondents experiencing at least one delay/denial in the past year. Most delays/denials were for topical steroids (39.2%, 253/645), the most highly used prescription treatment class (83.9%, 821/978). However, the highest rate of delay/denials was for biologics, of which 43.6% (109/250) of all prescriptions faced a delay or denial. Denials were caused primarily by step therapy (27.6%) and delays by prior authorization (55.1%). Only 56.0% of respondents said they would know what to do if they faced an issue with AD prescription coverage. Conclusions Patients with AD frequently experience insurance-related barriers to obtaining recommended therapies, and many do not know how to respond when these barriers arise. Strategies to improve timely therapeutic access are needed.

Abstract Freshwater macroinvertebrates are a diverse group and play key ecological roles, including accelerating nutrient cycling, filtering water, controlling primary producers, and providing food for predators. Their differences in tolerances and short generation times manifest in rapid community responses to change. Macroinvertebrate community composition is an indicator of water quality. In Europe, efforts to improve water quality following environmental legislation, primarily starting in the 1980s, may have driven a recovery of macroinvertebrate communities. Towards understanding temporal and spatial variation of these organisms, we compiled the TREAM dataset (Time seRies of European freshwAter Macroinvertebrates), consisting of macroinvertebrate community time series from 1,816 river and stream sites (mean length of 19.2 years and 14.9 sampling years) of 22 European countries sampled between 1968 and 2020. In total, the data include >93 million sampled individuals of 2,648 taxa from 959 genera and 212 families. These data can be used to test questions ranging from identifying drivers of the population dynamics of specific taxa to assessing the success of legislative and management restoration efforts.

Abstract Asthma has striking disparities across ancestral groups, but the molecular underpinning of these differences is poorly understood and minimally studied. A goal of the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) is to understand multi-omic signatures of asthma focusing on populations of African ancestry. RNASeq and DNA methylation data are generated from nasal epithelium including cases (current asthma, N = 253) and controls (never-asthma, N = 283) from 7 different geographic sites to identify differentially expressed genes (DEGs) and gene networks. We identify 389 DEGs; the top DEG, FN1, was downregulated in cases (q = 3.26 × 10−9) and encodes fibronectin which plays a role in wound healing. The top three gene expression modules implicate networks related to immune response (CEACAM5; p = 9.62 × 10−16 and CPA3; p = 2.39 × 10−14) and wound healing (FN1; p = 7.63 × 10−9). Multi-omic analysis identifies FKBP5, a co-chaperone of glucocorticoid receptor signaling known to be involved in drug response in asthma, where the association between nasal epithelium gene expression is likely regulated by methylation and is associated with increased use of inhaled corticosteroids. This work reveals molecular dysregulation on three axes – increased Th2 inflammation, decreased capacity for wound healing, and impaired drug response – that may play a critical role in asthma within the African Diaspora.

Abstract Background Islet autoantibodies form the foundation for type 1 diabetes (T1D) diagnosis and staging, but heterogeneity exists in T1D development and presentation. We hypothesized that autoantibodies can identify heterogeneity before, at, and after T1D diagnosis, and in response to disease-modifying therapies. Methods We systematically reviewed PubMed and EMBASE databases (6/14/2022) assessing 10 years of original research examining relationships between autoantibodies and heterogeneity before, at, after diagnosis, and in response to disease-modifying therapies in individuals at-risk or within 1 year of T1D diagnosis. A critical appraisal checklist tool for cohort studies was modified and used for risk of bias assessment. Results Here we show that 152 studies that met extraction criteria most commonly characterized heterogeneity before diagnosis (91/152). Autoantibody type/target was most frequently examined, followed by autoantibody number. Recurring themes included correlations of autoantibody number, type, and titers with progression, differing phenotypes based on order of autoantibody seroconversion, and interactions with age and genetics. Only 44% specifically described autoantibody assay standardization program participation. Conclusions Current evidence most strongly supports the application of autoantibody features to more precisely define T1D before diagnosis. Our findings support continued use of pre-clinical staging paradigms based on autoantibody number and suggest that additional autoantibody features, particularly in relation to age and genetic risk, could offer more precise stratification. To improve reproducibility and applicability of autoantibody-based precision medicine in T1D, we propose a methods checklist for islet autoantibody-based manuscripts which includes use of precision medicine MeSH terms and participation in autoantibody standardization workshops.

Background: Awareness and uptake of human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) remains low among Black/African American cisgender women, partly due to low self-reported PrEP knowledge and comfort among primary care providers. Ensuring providers are trained on PrEP is crucial, as increased PrEP knowledge is associated with higher rates of PrEP prescription. Objective: We aimed to develop a PrEP training for providers to improve their self-efficacy in discussing and prescribing PrEP for Black women, with the ultimate goal of increasing PrEP awareness and utilization among Black women. Design: In this qualitative study, we conducted focus groups with medical providers at three federally qualified health centers in the Southern and Midwestern United States to identify themes informing the development of a provider PrEP training. Methods: Providers were asked for input on content/design of PrEP training. Transcripts underwent rapid qualitative analysis using the Stanford Lightning Report Method. Themes were identified and presented under the domains of the Consolidated Framework for Implementation Research. Results: Ten providers completed four focus groups. Themes included the individual characteristics of providers (low comfort initiating PrEP discussions, particularly among White providers) and the outer setting of client attitudes (perceptions of potential provider bias/racism, varying levels of concern about HIV acquisition). Opportunities were identified to maximize the benefit of training design (e.g., developing case scenarios to enhance providers’ cultural competency with Black women and PrEP knowledge). Conclusion: This comprehensive PrEP training features both didactic material and interactive role-plays to equip providers with the clinical knowledge for prescribing PrEP while building their competency discussing PrEP with Black women. This training is particularly important for providers who have racial or gender discordance with Black women and express lower comfort discussing PrEP with these clients. Provider training could lead to minimizing racial- and gender-based inequities in PrEP use.

Nutrition and resilience are linked, though it is not yet clear how diet confers stress resistance or the breadth of stressors that it can protect against. We have previously shown that transiently restricting an essential amino acid can protect Drosophila melanogaster against nicotine poisoning. Here, we sought to characterize the nature of this dietary-mediated protection and determine whether it was sex, amino acid and/or nicotine specific. When we compared between sexes, we found that isoleucine deprivation increases female, but not male, nicotine resistance. Surprisingly, we found that this protection afforded to females was not replicated by dietary protein restriction and was instead specific to individual amino acid restriction. To understand whether these beneficial effects of diet were specific to nicotine or were generalizable across stressors, we pre-treated flies with amino acid restriction diets and exposed them to other types of stress. We found that some of the diets that protected against nicotine also protected against oxidative and starvation stress, and improved survival following cold shock. Interestingly, we found that a diet lacking isoleucine was the only diet to protect against all these stressors. These data point to isoleucine as a critical determinant of robustness in the face of environmental challenges.

BackgroundIndividuals with Parkinson disease (PD) can improve their overall mobility and participation in daily activities as they engage in frequent exercise. Despite the need for individually tailored exercises, persons with PD often face barriers to accessing physical rehabilitation professionals who can provide them. Telerehabilitation (TR) may facilitate access to necessary and individually tailored rehabilitation for individuals with PD. ObjectiveThe purpose of this study was to assess the feasibility of TR for individuals with PD and explore clinical outcomes compared to in-person care. MethodsThis was a pilot randomized controlled trial conducted at 2 outpatient neurorehabilitation clinics with 3 study groups: clinic+TR, TR-only, and usual care (UC). TR was administered using a web-based application with a mobile app option. One-hour interventions were performed weekly for 4 weeks, in-person for the clinic+TR and UC groups and virtually for the TR-only group. Home exercises were provided on paper for the UC group and via the web-based platform for the clinic+TR and TR-only groups. Feasibility was assessed by recruitment and retention success and patient and therapist satisfaction, as rated in surveys. Clinical outcomes were explored using performance and patient-reported measures in between- and within-group analyses. ResultsOf 389 patients screened, 68 (17.5%) met eligibility criteria, and 20 (29.4% of those eligible) were enrolled (clinic+TR, n=6; TR-only, n=6; and UC, n=8). One patient (TR-only) was withdrawn due to a non–study-related injurious fall. Regardless of group allocation, both patients and therapists generally rated the mode of care delivery as “good” or “very good” across all constructs assessed, including overall satisfaction and safety. In the analysis of all groups, there were no differences in clinical outcomes at the discharge visit. Within-group differences (from baseline to discharge) were also generally not significant except in the UC group (faster 5-time sit-to-stand time and higher mini balance evaluation systems test balance score) and clinic+TR group (higher mini balance evaluation systems test balance score). ConclusionsHigh satisfaction amongst patients and clinicians regardless of group, combined with nonsignificant between-group differences in clinical outcomes, suggest that TR is feasible for individuals with PD in early-moderate stages. Future trials with a larger sample are necessary to test clinical effectiveness. As larger trials enroll patients with diverse characteristics (eg, in terms of age, disease progression, caregiver support, technology access and capacity, etc), they could begin to identify opportunities for matching patients to the optimal utilization of TR as part of the therapy episode. Trial RegistrationClinicalTrials.gov NCT06246747; https://clinicaltrials.gov/study/NCT06246747

OBJECTIVES:. Interhospital transfer of patients with acute respiratory failure (ARF) is relevant in the current landscape of critical care delivery. However, current transfer practices for patients with ARF are highly variable, poorly formalized, and lack evidence. We aim to synthesize the existing evidence, identify knowledge gaps, and highlight persisting questions related to interhospital transfer of patients with ARF. DATA SOURCES:. Ovid Medline, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Embase, CINAHL Plus, and American Psychological Association. STUDY SELECTION:. We included studies that evaluated or described hospital transfers of adult (age > 18) patients with ARF between January 2020 and 2024 conducted in the United States. Using predetermined search terms and strategies, a total of 3369 articles were found across all databases. After deduplication, 1748 abstracts were screened by authors with 45 articles that advanced to full-text review. This yielded 16 studies that fit our inclusion criteria. DATA EXTRACTION:. The studies were reviewed in accordance to Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews by three authors. DATA SYNTHESIS:. Included studies were mostly retrospective analyses of heterogeneous patients with various etiologies and severity of ARF. Overall, transferred patients were younger, had high severity of illness, and were more likely to have commercial insurance compared with nontransferred cohorts. There is a paucity of data examining why patients get transferred. Studies that retrospectively evaluated outcomes between transferred and nontransferred cohorts found no differences in mortality, although transferred patients have a longer length of stay. There is limited evidence to suggest that patients transferred early in their course have improved outcomes. CONCLUSIONS:. Our scoping review highlights the sparse evidence and the urgent need for further research into understanding the complexity behind ARF transfers. Future studies should focus on defining best practices to inform clinical decision-making and improve downstream outcomes.

Background N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a biomarker of cardiac ventricular wall stress that is incorporated into pulmonary hypertension (PH) risk stratification models. Sendaway sampling may enable patients to perform NT-proBNP tests remotely. This UK-wide study aimed to assess the agreement of sendaway NT-proBNP with standard venous NT-proBNP and to assess the effect of delayed processing.Methods Reference venous NT-proBNP was collected from PH patients. Samples for capillary and venous sendaway tests were collected contemporaneously, mailed to a reference laboratory and processed at 3 and 7 days using a Roche Cobas e411 device. Differences in paired measurements were analysed with Passing-Bablok regression, percentage difference plots and the % difference in risk strata.Results 113 patients were included in the study. 13% of day 3 capillary samples were insufficient. Day 3 capillary samples were not equivalent to reference samples (Passing Bablok analysis slope of 0.91 (95% CI 0.88 to 0.93) and intercept of 6.0 (95% CI 0.2 to 15.9)). The relative median difference was −7% and there were acceptable limits of agreement. Day 3 capillary NT-proBNP accurately risk stratified patients in 93.5% of cases. By comparison, day 3 venous results accurately risk stratified patients in 90.1% of cases and were equivalent by Passing-Bablok regression. Delayed sampling of sendaway tests led to an unacceptable level of agreement and systematically underestimated NT-proBNP.Conclusions Sendaway NT-proBNP sampling may provide an objective measure of right ventricular strain for virtual PH clinics. Results must be interpreted with caution in cases of delayed sampling.

Abstract Drosophila melanogaster is unique among animal models because it has a fully defined synthetic diet available to study nutrient-gene interactions. However, use of this diet is limited to adult studies due to impaired larval development and survival. Here, we provide an adjusted formula that reduces the developmental period, restores fat levels, enhances body mass, and fully rescues survivorship without compromise to adult lifespan. To demonstrate an application of this formula, we explored pre-adult diet compositions of therapeutic potential in a model of an inherited metabolic disorder affecting the metabolism of branched-chain amino acids. We reveal rapid, specific, and predictable nutrient effects on the disease state consistent with observations from mouse and patient studies. Together, our diet provides a powerful means with which to examine the interplay between diet and metabolism across all life stages in an animal model.

Abstract Background Surgical opioid overprescribing can result in long-term use or misuse. Between July 2018 and March 2019, the multicomponent intervention, Minimizing Opioid Prescribing in Surgery (MOPiS) was implemented in the general surgery clinics of five hospitals and successfully reduced opioid prescribing. To date, various studies have shown a positive outcome of similar reduction initiatives. However, in addition to evaluating the impact on clinical outcomes, it is important to understand the implementation process of an intervention to extend sustainability of interventions and allow for dissemination of the intervention into other contexts. This study aims to evaluate the contextual factors impacting intervention implementation. Methods We conducted a qualitative study with semi-structured interviews held with providers and patients of the general surgery clinics of five hospitals of a single health system between March and November of 2019. Interview questions focused on how contextual factors affected implementation of the intervention. We coded interview transcripts deductively, using the Consolidated Framework for Implementation Research (CFIR) to identify the relevant contextual factors. Content analyses were conducted using a constant comparative approach to identify overarching themes. Results We interviewed 15 clinicians (e.g., surgeons, nurses), 1 quality representative, 1 scheduler, and 28 adult patients and identified 3 key themes. First, we found high variability in the responses of clinicians and patients to the intervention. There was a strong need for intervention components to be locally adaptable, particularly for the format and content of the patient and clinician education materials. Second, surgical pain management should be recognized as a team effort. We identified specific gaps in the engagement of team members, including nurses. We also found that the hierarchical relationships between surgical residents and attendings impacted implementation. Finally, we found that established patient and clinician views on opioid prescribing were an important facilitator to effective implementation. Conclusion Successful implementation of a complex set of opioid reduction interventions in surgery requires locally adaptable elements of the intervention, a team-centric approach, and an understanding of patient and clinician views regarding changes being proposed.

Abstract Background Sex workers, those who trade sex for monetary or nonmonetary items, experience high rates of HIV transmission but have not been adequately included in HIV prevention and Pre-Exposure Prophylaxis (PrEP) adherence program development research. Community-empowered (C.E.) approaches have been the most successful at reducing HIV transmission among sex workers. Centering Healthcare (Centering) is a C.E. model proven to improve health outcomes and reduce health disparities in other populations, such as pregnant women, people with diabetes, and sickle cell disease. However, no research exists to determine if Centering can be adapted to meet the unique HIV prevention needs of sex workers. Objective We aim to explain the process by which we collaboratively and iteratively adapted Centering to meet the HIV prevention and PrEP retention needs of sex workers. Methods We utilized the Assessment, Decision, Adaptation, Production, Topical Experts, Integration, Training, Testing (ADAPT-ITT) framework, a model for adapting evidence-based interventions. We applied phases one through six of the ADAPT-ITT framework (Assessment, Decision, Adaptation, Production, Topical Experts, Integration) to the design to address the distinct HIV prevention needs of sex workers in Chicago. Study outcomes corresponded to each phase of the ADAPT-ITT framework. Data used for adaptation emerged from collaborative stakeholder meetings, individual interviews (n = 36) and focus groups (n = 8) with current and former sex workers, and individual interviews with care providers (n = 8). In collaboration with our community advisory board, we used a collaborative and iterative analytical process to co-produce a culturally adapted 3-session facilitator's guide for the Centering Pre-exposure Prophylaxis (C-PrEP +) group healthcare model. Results The ADAPT-ITT framework offered structure and facilitated this community-empowered innovative adaptation of Centering Healthcare. This process culminated with a facilitator's guide and associated materials ready for pilot testing. Conclusions In direct alignment with community empowerment, we followed the ADAPT-ITT framework, phases 1–6, to iteratively adapt Centering Healthcare to suit the stated HIV Prevention and PrEP care needs of sex workers in Chicago. The study represents the first time Centering has been adapted to suit the HIV prevention and PrEP care needs of sex workers. Addressing a gap in HIV prevention care for sex workers, Centering PrEP harnesses the power of community as it is an iteratively adapted model that can be piloted and replicated regionally, nationally, and internationally.

Replication is generally considered a keystone of the scientific enterprise. Unfortunately, in communication science, there is a lack of clarity on what a replication actually entails, and to what extent replicators may deviate from original studies. In order to support researchers in conducting, evaluating, and justifying the setup of replications of communication science experiments, we provide a taxonomy of replication types. We argue that researchers almost always need to adapt some elements of an original communication study to meaningfully replicate it. The extent to which deviations—ranging from mere updates to deliberate deviations and additions—are permissible, however, depends on the motivation behind conducting a replication study. We distinguish three basic motivations: verification of an original study’s findings, testing the generalizability of an original study (which we further differentiate into the generalizability of study outcomes vs. theoretical claims), and extending an original study beyond the original goals. We argue that these motivations dictate what types of deviations are permissible and thereby determine the type of replication (i.e., direct, modified, and conceptual). We end with concrete recommendations for replicators: to specify the motivation to conduct a replication study and clearly label and justify any deviations from the original study for all study elements.

BackgroundType 1 diabetes (T1D) is preceded by a heterogenous pre-clinical phase, islet autoimmunity (IA). We aimed to identify pre vs. post-IA seroconversion (SV) changes in DNAm that differed across three IA progression phenotypes, those who lose autoantibodies (reverters), progress to clinical T1D (progressors), or maintain autoantibody levels (maintainers).MethodsThis epigenome-wide association study (EWAS) included longitudinal DNAm measurements in blood (Illumina 450K and EPIC) from participants in Diabetes Autoimmunity Study in the Young (DAISY) who developed IA, one or more islet autoantibodies on at least two consecutive visits. We compared reverters - individuals who sero-reverted, negative for all autoantibodies on at least two consecutive visits and did not develop T1D (n=41); maintainers - continued to test positive for autoantibodies but did not develop T1D (n=60); progressors - developed clinical T1D (n=42). DNAm data were measured before (pre-SV visit) and after IA (post-SV visit). Linear mixed models were used to test for differences in pre- vs post-SV changes in DNAm across the three groups. Linear mixed models were also used to test for group differences in average DNAm. Cell proportions, age, and sex were adjusted for in all models. Median follow-up across all participants was 15.5 yrs. (interquartile range (IQR): 10.8-18.7).ResultsThe median age at the pre-SV visit was 2.2 yrs. (IQR: 0.8-5.3) in progressors, compared to 6.0 yrs. (IQR: 1.3-8.4) in reverters, and 5.7 yrs. (IQR: 1.4-9.7) in maintainers. Median time between the visits was similar in reverters 1.4 yrs. (IQR: 1-1.9), maintainers 1.3 yrs. (IQR: 1.0-2.0), and progressors 1.8 yrs. (IQR: 1.0-2.0). Changes in DNAm, pre- vs post-SV, differed across the groups at one site (cg16066195) and 11 regions. Average DNAm (mean of pre- and post-SV) differed across 22 regions.ConclusionDifferentially changing DNAm regions were located in genomic areas related to beta cell function, immune cell differentiation, and immune cell function.

By definition, ill and injured animals are on the negative valence of animal welfare. For beef cattle kept in feedlot settings, advances in cattle health management have resulted in a greater understanding and prevention of illness and injury. However, the management of cattle once they become ill and injured is an understudied area, and there are gaps in knowledge that could inform evidence-based decision-making and strengthen welfare for this population. The aim of this review is to provide a comprehensive overview of the acquired knowledge regarding ill and injured feedlot cattle welfare, focusing on existing knowledge gaps and implications for hospital and chronic pen management and welfare assurance. Ill and injured feedlot cattle consist of acutely impaired animals with short-term health conditions that resolve with treatment and chronically impaired animals with long-term health conditions that may be difficult to treat. A literature search identified 110 articles that mentioned welfare and ill and injured feedlot cattle, but the population of interest in most of these articles was healthy cattle, not ill and injured cattle. Articles about managing ill and injured cattle in specialized hospital (n = 12) or chronic (n = 2) pens were even more sparse. Results from this literature search will be used to outline the understanding of acutely and chronically ill and injured feedlot cattle, including common dispositions and welfare considerations, behavior during convalescence, and strategies for identifying and managing ill and injured cattle. Finally, by working through specific ailments common in commercial feedlot environments, we illustrate how the Five Domains Model can be used to explore feelings and experiences and subsequent welfare state of individual ill or injured feedlot cattle. Using this approach and our knowledge of current industry practices, we identify relevant animal-based outcomes and critical research questions to strengthen knowledge in this area. A better understanding of this overlooked topic will inform future research and the development of evidence-based guidelines to help producers care for this vulnerable population.

BackgroundThe COVID-19 pandemic affected older adults worldwide. Sedentary older adults experienced more severe adverse health effects due to their shelter-in-place. Physical activity was strongly recommended during periods of social distancing. The present study evaluated the impact of a virtually supervised exercise program on the physical fitness and mental health of Mexican older adults during the pandemic’s lockdown.MethodsParticipants were 44 older adults who were assigned to one of four physical fitness groups: a healthy control group (Ctrl-H, n = 15), a comorbidity control group (Ctrl-COM, n = 9), an exercise group without comorbidities (Exe-H, n = 11), and an exercise group with comorbidities (Exe-COM, n = 9). The participants engaged in a 60-min, virtually-supervised concurrent exercise session three times/week for 12 weeks. Fitness was measured using the online Senior Fitness Tests and the 4-m Gait Speed Test. Mental health was evaluated through virtual interviews using the Hamilton Depression Rating Scale, the Geriatric Depression Scale, and the Connor-Davidson Resilience Scale. Within-subject pre vs. post-intervention comparisons tested for significant differences, between-groups and over time.ResultsSignificant interactions were found in the scores of the Geriatric Depression Scale (p ≤ 0.0001; ηp2 = 0.35), the Hamilton Depression Scale (p ≤ 0.0001; ηp2 = 0.35), resilience scores (p ≤ 0.0001; ηp2 = 0.46), lower-body strength (p ≤ 0.0001; ηp2 = 0.32), timed up-and-go test (p = 0.018; ηp2 = 0.18), the 6MWT distance scores (p ≤ 0.0001; ηp2 = 0.39), and the 4-m gait speed test scores (p = 0.011; ηp2 = 0.20).ConclusionA long-term virtually-supervised exercise program conducted during the COVID-19 lockdown period led to marked improvements in both the fitness and mental health of older Mexican adults. Comorbidities did not diminish these benefits. These findings provide empirical support for online exercise programs in the daily routines of older adults to make clinically meaningful improvements in both physical and mental well-being.

Hematopoietic cell transplant (HCT) is a curative treatment for multiple malignant and non-malignant disorders. While morbidity and mortality have decreased significantly over the years, some patients still require management in the pediatric intensive care unit (PICU) during their HCT course for additional respiratory, cardiovascular, and/or renal support. We retrospectively reviewed pediatric patients (0–18 years) who underwent HCT from January 2015–December 2020 at our institution to determine risk factors for PICU care and evaluate PICU utilization and outcomes. We also assessed pulmonary function testing (PFT) data to determine if differences were noted between PICU and non-PICU patients as well as potential evolution of pulmonary dysfunction over time. Risk factors of needing PICU care were lower age, lower weight, having an underlying inborn error of metabolism, and receiving busulfan-based conditioning. Nearly half of PICU encounters involved use of each of respiratory support types including high-flow nasal cannula, non-invasive positive pressure ventilation, and mechanical ventilation. Approximately one-fifth of PICU encounters involved renal replacement therapy. Pulmonary function test results largely did not differ between PICU and non-PICU patients at any timepoint aside from individuals who required PICU care having lower DLCO scores at one-year post-HCT. Future directions include consideration of combining our data with other centers for a multi-center retrospective analysis with the goal of gathering and reporting additional multi-center data to work toward continuing to decrease morbidity and mortality for patients undergoing HCT.

ABSTRACTFoot-and-mouth disease (FMD) is one of the most devastating diseases of livestock which can cause significant economic losses, especially when introduced to FMD-free countries. FMD virus (FMDV) belongs to the family Picornaviridae and is antigenically heterogeneous with seven established serotypes. The prevailing preventive and control strategies are limited to restriction of animal movement and elimination of infected or exposed animals, which can be potentially combined with vaccination. However, FMD vaccination has limitations including delayed protection and lack of cross-protection against different serotypes. Recently, antiviral drug use for FMD outbreaks has increasingly been recognized as a potential tool to augment the existing early response strategies, but limited research has been reported on potential antiviral compounds for FMDV. FMDV 3C protease (3Cpro) cleaves the viral-encoded polyprotein into mature and functional proteins during viral replication. The essential role of viral 3Cpro in viral replication and the high conservation of 3Cpro among different FMDV serotypes make it an excellent target for antiviral drug development. We have previously reported multiple series of inhibitors against picornavirus 3Cpro or 3C-like proteases (3CLpros) encoded by coronaviruses or caliciviruses. In this study, we conducted structure-activity relationship studies for our in-house focused compound library containing 3Cpro or 3CLpro inhibitors against FMDV 3Cpro using enzyme and cell-based assays. Herein, we report the discovery of aldehyde and α-ketoamide inhibitors of FMDV 3Cpro with high potency. These data inform future preclinical studies that are related to the advancement of these compounds further along the drug development pathway.IMPORTANCEFood-and-mouth disease (FMD) virus (FMDV) causes devastating disease in cloven-hoofed animals with a significant economic impact. Emergency response to FMD outbreaks to limit FMD spread is critical, and the use of antivirals may overcome the limitations of existing control measures by providing immediate protection for susceptible animals. FMDV encodes 3C protease (3Cpro), which is essential for virus replication and an attractive target for antiviral drug discovery. Here, we report a structure-activity relationship study on multiple series of protease inhibitors and identified potent inhibitors of FMDV 3Cpro. Our results suggest that these compounds have the potential for further development as FMD antivirals.

Abstract Background Ciswomen constitute a disproportionately low percentage of pre-exposure prophylaxis for HIV prevention (PrEP) users compared to men. Despite PrEP’s effectiveness, women are 5.25 times less likely to take PrEP than men. Identifying women who have increased reasons for HIV prevention and educating and offering PrEP to these women is crucial to reducing HIV transmission and overall health equity. However, the best method of identifying women at highest risk of acquiring HIV remains unknown. This study aimed to identify common HIV risk factors and data sources for identifying these common factors (e.g., electronic medical record data, open source neighborhood data), as well as potential intervention points and missed opportunities for PrEP linkage. Methods We conducted an evaluation of multiple data sources: semi-structured qualitative interviews, electronic medical record (EMR) chart abstraction, and open source data abstraction. We accessed EMRs for enrolled participants and all participants signed a standard release of medical information (ROI) form for all institutions at which they had received medical care for the five-year period preceding their HIV diagnosis. Data were abstracted using a standardized procedure. Both structured and unstructured fields (i.e., narrative text of free notes) within the EMR were examined and included for analysis. Finally, open data sources (e.g., STI cases, HIV prevalence) were examined by community area of Chicago. Open data sources were used to examine several factors contributing to the overall Economic Hardship Index (EHI) score. We used these calculated scores to assess the economic hardship within participants’ neighborhoods. Results A total of 18 cisgender women with HIV participated in our study. Participants were mostly Black/African American (55.6%) and young (median age of 34). Our analysis identified two main themes influencing HIV risk among participants: contextual factors and relationship factors. Further, potential pre-diagnosis intervention points and missed opportunities were identified during reproductive health/prenatal visits, behavioral/mental health visits, and routine STI testing. Our evaluation of multiple data sources included investigating the presence or absence of information in the EMR (STI history, HIV testing, substance use, etc.) as well as whether pertinent information could be gathered from open access sources. Conclusion Ciswomen recently diagnosed with HIV identified many shared experiences, including syndemic conditions like mental illness and substance abuse, sex with men who have sex with men, and frequent moving in areas with high HIV incidence prior to their diagnosis. It is imperative that providers ask patients about social history, information about partners, and other key variables, in addition to the standardized questions. Findings can be used to better recognize ciswomen most vulnerable to HIV and offer PrEP to them, reducing HIV transmission.

Abstract Background Since 2005, highly pathogenic avian influenza A H5N1 viruses have spread from Asia worldwide, infecting poultry, humans and wild birds. Subsequently, global interest in avian influenza (AI) surveillance increased. Objectives Mongolia presents an opportunity to study viruses in wild birds because the country has very low densities of domestic poultry and supports large concentrations of migratory water birds. Methods We conducted AI surveillance in Mongolia over two time periods, 2009–2013 and 2016–2018, utilizing environmental fecal sampling. Fresh fecal samples were collected from water bird congregation sites. Hemagglutinin (HA) and neuraminidase (NA) subtypes of positive samples were identified through viral isolation or molecular assays, with pathogenicity determined by HA subtype or sequencing the HA cleavage site. Results A total of 10,222 samples were collected. Of these, 7,025 fecal samples were collected from 2009 to 2013, and 3,197 fecal samples were collected from 2016 to 2018. Testing revealed 175 (1.7%) positive samples for low‐pathogenicity influenza A, including 118 samples from 2009 to 2013 (1.7%) and 57 samples from 2016 to 2018 (1.8%). HA and NA subtyping of all positives identified 11 subtypes of HA and nine subtypes of NA in 29 different combinations. Within periods, viruses were detected more frequently during the fall season than in the early summer. Conclusion Mongolia's critical wild bird habitat is positioned as a crossroad of multiple migratory flyways. Our work demonstrates the feasibility of using an affordable environmental fecal sampling approach for AI surveillance and contributes to understanding the prevalence and ecology of low‐pathogenicity avian influenza viruses in this important location, where birds from multiple flyways mix.

Abstract Background HIV seroprevalence in Nigeria is increasing among men who have sex with men (MSM) from 14% to 2007 to 23% in 2014, threatening progress towards ending the epidemic in the country. Expanding access to HIV testing and linkage to care for key populations, like young MSM (YMSM), is critical to end the HIV epidemic in Nigeria. The Intensive Combination Approach to Roll Back the Epidemic in Nigerian Adolescents (iCARE Nigeria) pilot intervention successfully implemented a combination of evidence-based interventions utilizing peer navigators and popular social media apps and platforms to reach young men at risk for HIV exposure, including YMSM. We conducted sequential mixed methods explanatory implementation research to expand on the previously reported effectiveness and implementation outcomes and to explore the determinants and strategies which contributed to primary study results. Methods We conducted key informant interviews and focus group discussions with 2 peer navigators and 3 study staff at the end of the pilot. We used directed content analysis to understand the quantitative results from the pilot. Using the Implementation Research Logic Model, we were able to identify and map strategies through mechanisms of action from barriers addressed to the reported implementation outcomes including feasibility, acceptability fidelity and adoption. Results We found that iCARE Nigeria’s pilot intervention implementers reported high feasibility, acceptability fidelity and adoption were associated with implementation of strategies which addressed many challenging contextual factors, including social stigma, online social networking, legal barriers surrounding MSM behavior, and the COVID-19 pandemic. These strategies included integration of stakeholders’ interests, selection of experienced peer navigators including from the targeted population, training and supportive supervision using an implementation guide, ensuring safety (COVID and legal) and identification of clinics serving the targeted population. Conclusion Mixed methods using implementation research frameworks provided insights into the strategies and barriers and facilitators they addressed which may explain the success of the pilot. These results can inform strategies needed to scale-up the intervention to youth including YMSM in other areas in Nigeria and the region. Trial registration ISRCTN: ISRCTN94590823, https://doi.org/10.1186/ISRCTN94590823

Abstract Neuroligins are transmembrane cell adhesion proteins well-known for their genetic links to autism spectrum disorders. Neuroligins can function by regulating the actin cytoskeleton, however the factors and mechanisms involved are still largely unknown. Here, using the Drosophila neuromuscular junction as a model, we reveal that F-Actin assembly at the Drosophila NMJ is controlled through Cofilin signaling mediated by an interaction between DNlg2 and RACK1, factors not previously known to work together. The deletion of DNlg2 displays disrupted RACK1-Cofilin signaling pathway with diminished actin cytoskeleton proteo-stasis at the terminal of the NMJ, aberrant NMJ structure, reduced synaptic transmission, and abnormal locomotion at the third-instar larval stage. Overexpression of wildtype and activated Cofilin in muscles are sufficient to rescue the morphological and physiological defects in dnlg2 mutants, while inactivated Cofilin is not. Since the DNlg2 paralog DNlg1 is known to regulate F-actin assembly mainly via a specific interaction with WAVE complex, our present work suggests that the orchestration of F-actin by Neuroligins is a diverse and complex process critical for neural connectivity.

Abstract Background Type 1 diabetes (T1D) results from immune-mediated destruction of insulin-producing beta cells. Prevention efforts have focused on immune modulation and supporting beta cell health before or around diagnosis; however, heterogeneity in disease progression and therapy response has limited translation to clinical practice, highlighting the need for precision medicine approaches to T1D disease modification. Methods To understand the state of knowledge in this area, we performed a systematic review of randomized-controlled trials with $$\ge$$ ≥ 50 participants cataloged in PubMed or Embase from the past 25 years testing T1D disease-modifying therapies and/or identifying features linked to treatment response, analyzing bias using a Cochrane-risk-of-bias instrument. Results We identify and summarize 75 manuscripts, 15 describing 11 prevention trials for individuals with increased risk for T1D, and 60 describing treatments aimed at preventing beta cell loss at disease onset. Seventeen interventions, mostly immunotherapies, show benefit compared to placebo (only two prior to T1D onset). Fifty-seven studies employ precision analyses to assess features linked to treatment response. Age, beta cell function measures, and immune phenotypes are most frequently tested. However, analyses are typically not prespecified, with inconsistent methods of reporting, and tend to report positive findings. Conclusions While the quality of prevention and intervention trials is overall high, the low quality of precision analyses makes it difficult to draw meaningful conclusions that inform clinical practice. To facilitate precision medicine approaches to T1D prevention, considerations for future precision studies include the incorporation of uniform outcome measures, reproducible biomarkers, and prespecified, fully powered precision analyses into future trial design.