Tropism for ciliated cells is the dominant driver of influenza viral burst size in the human airway.

Influenza viruses pose a significant burden on global human health. Influenza has a broad cellular tropism in the airway, but how infection of different epithelial cell types impacts replication kinetics and burden in the airways is not fully understood. Using primary human airway cultures, which recapitulate the diverse epithelial cell landscape of the human airways, we investigated the impact of cell type composition on virus tropism and replication kinetics. Cultures were highly diverse across multiple donors and 30 independent differentiation conditions and supported a range of influenza replication. Although many cell types were susceptible to influenza, ciliated and secretory cells were predominantly infected. Despite the strong tropism preference for secretory and ciliated cells, which consistently make up 75% or more of infected cells, only ciliated cells were associated with increased virus production. Surprisingly, infected secretory cells were associated with overall reduced virus output. The disparate response and contribution to influenza virus production could be due to different pro- and antiviral interferon-stimulated gene signatures between ciliated and secretory populations, which were interrogated with single-cell RNA sequencing. These data highlight the heterogeneous outcomes of influenza virus infections in the complex cellular environment of the human airway and the disparate impacts of infected cell identity on multiround burst size, even among preferentially infected cell types.

Functional analysis of ESRP1/2 gene variants and CTNND1 isoforms in orofacial cleft pathogenesis.

Orofacial cleft (OFC) is a common human congenital anomaly. Epithelial-specific RNA splicing regulators ESRP1 and ESRP2 regulate craniofacial morphogenesis and their disruption result in OFC in zebrafish, mouse and humans. Using esrp1/2 mutant zebrafish and murine Py2T cell line models, we functionally tested the pathogenicity of human ESRP1/2 gene variants. We found that many variants predicted by in silico methods to be pathogenic were functionally benign. Esrp1 also regulates the alternative splicing of Ctnnd1 and these genes are co-expressed in the embryonic and oral epithelium. In fact, over-expression of ctnnd1 is sufficient to rescue morphogenesis of epithelial-derived structures in esrp1/2 zebrafish mutants. Additionally, we identified 13 CTNND1 variants from genome sequencing of OFC cohorts, confirming CTNND1 as a key gene in human OFC. This work highlights the importance of functional assessment of human gene variants and demonstrates the critical requirement of Esrp - Ctnnd1 acting in the embryonic epithelium to regulate palatogenesis.

Understanding the potential implementation determinants of Our Plan: a couples-based digital human immunodeficiency virus prevention intervention for same-gender male couples.

Background: There has been a proliferation of digital health interventions (DHIs) focused on addressing human immunodeficiency virus (HIV) prevention and treatment outcomes, including couples-based interventions with same-gender male couples. However, the barriers and facilitators of implementing couples-based HIV and sexually transmitted infection (STI) prevention interventions using digital platforms in community-based organizations remains largely unknown. The goal of this study was to explore the implementation determinants of Our Plan, a couples-based DHI designed for new relationships of same-gender male couples and dyadic, sexual partnerships. Methods: Qualitative interviews were conducted with 40 organization leaders, healthcare providers, and staff at acquired immunodeficiency syndrome (AIDS)-service and community-based organizations in 13 states serving populations in Ending the HIV Epidemic jurisdictions. Interview items and follow-up questions were guided by the Consolidated Framework for Implementation Research (CFIR) to inquire about implementation determinants of Our Plan. Results: Most participants highlighted several relative advantages of Our Plan: increasing capacity to support couples, potential synergy with existing programs, and opportunities to increase patient engagement. Participants also discussed relative disadvantages: misalignment with organizational values in the provision of patient-centered models of care and low interest from some priority populations. Participants emphasized the need for adaptability of Our Plan to fit within their local contexts, which encompassed support for both implementers and end-users, cultural tailoring, and privacy and security features. The desired evidence needed to implement Our Plan focused on data on impact, acceptability, and usability and functionality from communities most heavily impacted by the HIV epidemic. The majority of participants described how Our Plan could be integrated within service delivery and aligned with their organization's aspirational values; however, some noted that their organizational culture valued in-person interactions, particularly among patients experiencing structural vulnerabilities. Finally, participants discussed how the implementation of Our Plan would require additional training and funding for staff to support end-users and a relationship with the developers so that they could demonstrate their investment in the communities that their organizations served. Conclusions: Our Plan was deemed a promising tool among potential implementers. To ensure optimal implementation and organizational fit, Our Plan refinement and evaluation must include implementers and end-users most impacted by the HIV epidemic throughout the entire process.

Mapping SCA1 regional vulnerabilities reveals neural and skeletal muscle contributions to disease.

Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by an expanded polyglutamine tract in the widely expressed ataxin-1 (ATXN1) protein. To elucidate anatomical regions and cell types that underlie mutant ATXN1-induced disease phenotypes, we developed a floxed conditional knockin mouse (f-ATXN1146Q/2Q) with mouse Atxn1 coding exons replaced by human ATXN1 exons encoding 146 glutamines. f-ATXN1146Q/2Q mice manifested SCA1-like phenotypes including motor and cognitive deficits, wasting, and decreased survival. Central nervous system (CNS) contributions to disease were revealed using f-ATXN1146Q/2Q;Nestin-Cre mice, which showed improved rotarod, open field, and Barnes maze performance by 6-12 weeks of age. In contrast, striatal contributions to motor deficits using f-ATXN1146Q/2Q;Rgs9-Cre mice revealed that mice lacking ATXN1146Q/2Q in striatal medium-spiny neurons showed a trending improvement in rotarod performance at 30 weeks of age. Surprisingly, a prominent role for muscle contributions to disease was revealed in f-ATXN1146Q/2Q;ACTA1-Cre mice based on their recovery from kyphosis and absence of muscle pathology. Collectively, data from the targeted conditional deletion of the expanded allele demonstrated CNS and peripheral contributions to disease and highlighted the need to consider muscle in addition to the brain for optimal SCA1 therapeutics.

Frontotemporal contributions to social and non-social semantic judgements.

Semantic judgements involve the use of general knowledge about the world in specific situations. Such judgements are typically associated with activity in a number of brain regions that include the left inferior frontal gyrus (IFG). However, previous studies showed activity in brain regions associated with mentalizing, including the right temporoparietal junction (TPJ), in semantic judgements that involved social knowledge. The aim of the present study was to investigate if social and non-social semantic judgements are dissociated using a combination of fMRI and repetitive TMS. To study this, we asked participants to estimate the percentage of exemplars in a given category that shared a specified attribute. Categories could be either social (i.e., stereotypes) or non-social (i.e., object categories). As expected, fMRI results (n = 26) showed enhanced activity in the left IFG that was specific to non-social semantic judgements. However, statistical evidence did not support that repetitive TMS stimulation (n = 19) to this brain region specifically disrupted non-social semantic judgements. Also as expected, the right TPJ showed enhanced activity to social semantic judgements. However, statistical evidence did not support that repetitive TMS stimulation to this brain region specifically disrupted social semantic judgements. It is possible that the causal networks involved in social and non-social semantic judgements may be more complex than expected.

Factors Associated with Planned Future Use of PrEP in the Next 3 Months and Likelihood to Use PrEP Among Black Cisgender HIV-negative Women in Texas.

Identifying and then addressing barriers and leveraging facilitators is important to help increase pre-exposure prophylaxis (PrEP) use among Black women vulnerable to HIV acquisition. The present cross-sectional study examined what factors were associated with future plans to use PrEP, and general likelihood to use it among a convenience sample of 152 adult, Black cisgender women from three metropolitan areas in Texas. The final multivariable logistic regression model revealed that relationship status (aOR = 0.20, 95% CI: 0.05-0.73, p < 0.05), PrEP anticipated stigma (aOR = 0.29, 95% CI: 0.10-0.78, p < 0.05), perceived discrimination (aOR = 0.40, 95% CI: 0.21-0.78, p < 0.01) and interest in learning more about PrEP (aOR = 5.32, 95% CI: 2.60-10.9, p < 0.001) were associated with future plans to use PrEP. The final multivariable linear regression model with maximum likelihood estimation identified that perceived discrimination (ß=-0.24, SE: -0.38 - -0.10, p < 0.01), perceived HIV risk (ß = 0.33, SE: 0.18-0.49, p < 0.001), willingness to use PrEP with condoms (ß = 1.26, SE: 0.94-1.60, p < 0.001), and comfort communicating about PrEP with a provider (ß = 0.23, SE: 0.06-0.41, p < 0.01) were associated with general likelihood to use PrEP. Findings reveal key factors that warrant further attention and examination toward improving PrEP use within this population.

"Our Community Comes First": Investigating Recruitment Ads That Represent and Appeal to Black Women for Online, HIV-Related Research Studies.

BACKGROUND: Black women are underrepresented in health-related research. Consulting Black women in the creation of recruitment materials may help increase their representation in research studies, but few of these recruitment materials have been evaluated. This manuscript reports on the impact of two ads (one featuring older women and one featuring younger women) created through multiple focus group sessions with Black women. The purpose of the ads were to recruit Black women to participate in an online research study about HIV prevention and pre-exposure prophylaxis, PrEP. MATERIALS AND METHODS: Questions about the ads were embedded in the eligibility screener for inclusion in the online parent research study. Respondents were asked which ad they saw, what they liked about it, and what about the ad piqued their interest in the study. RESULTS: In total, 301 Black women completed the eligibility screener for the online study and answered questions pertaining to the two ads. Most participants reported seeing the ad with younger women (260/301, 86.4%). Representation of Black women (n = 70), ad design (n = 64), relevance to Black women and the Black community (n = 60), and comprehensiveness of ad content (n = 38) were the top 4 ad features respondents liked. Relevance to Black women and the Black community (n = 104) as well as ad content (n = 54) (i.e., study purpose, location, duration, images, incentive) were the top two reasons provided about ads that piqued respondent's interest in the online study. CONCLUSION: Findings showcase how recruitment ads informed by Black women could help increase their interest and participation in research.

Tregs with an MHC class II peptide-specific chimeric antigen receptor prevent autoimmune diabetes in mice.

Adoptive immunotherapy with Tregs is a promising approach for preventing or treating type 1 diabetes. Islet antigen-specific Tregs have more potent therapeutic effects than polyclonal cells, but their low frequency is a barrier for clinical application. To generate Tregs that recognize islet antigens, we engineered a chimeric antigen receptor (CAR) derived from a monoclonal antibody with specificity for the insulin B chain 10-23 peptide presented in the context of the IAg7 MHC class II allele present in NOD mice. Peptide specificity of the resulting InsB-g7 CAR was confirmed by tetramer staining and T cell proliferation in response to recombinant or islet-derived peptide. The InsB-g7 CAR redirected NOD Treg specificity such that insulin B 10-23-peptide stimulation enhanced suppressive function, measured via reduction of proliferation and IL-2 production by BDC2.5 T cells and CD80 and CD86 expression on dendritic cells. Cotransfer of InsB-g7 CAR Tregs prevented adoptive transfer diabetes by BDC2.5 T cells in immunodeficient NOD mice. In WT NOD mice, InsB-g7 CAR Tregs prevented spontaneous diabetes. These results show that engineering Treg specificity for islet antigens using a T cell receptor-like CAR is a promising therapeutic approach for the prevention of autoimmune diabetes.

HIV Prevention Intervention-related Research with Adult, Sexual Minority Hispanic Men in the United States: A Systematic Review.

The systematic review describes aims to synthesize the HIV prevention intervention-related research conducted among adult, US sexual minority Hispanic men since 2012. Following PRISMA guidelines, 15 articles representing 14 studies were included in the review: 4 randomized controlled trials, 5 pilots, and 5 formative projects. Two interventions had PrEP-related outcomes whereas 7 focused on behavioral (e.g., condoms, testing) and/or educational outcomes. Few studies used digital health. All but one study was theoretically guided. Community engagement was a common and important thread in the included studies, with community-based participatory research being the most prevalent framework. The inclusion of cultural factors varied widely, as did the availability of Spanish language or bilingual study materials. Future research opportunities are discussed and recommendations to bolster HIV prevention interventions (e.g., tailoring) are presented. These include the need for greater integration of cultural factors (e.g., nuances related to the heterogeneity of Hispanic subgroups) and mitigating critical barriers to help improve uptake of evidence-based strategies in this population.

RESUMEN: Esta revisión sistemática describe investigaciones de intervención relacionadas con la prevención de VIH dirigidas a hombres adultos hispánicos, de minorías sexuales conducidas en los Estados Unidos desde el 2012. Siguiendo los lineamientos de PRISMA, 15 artículos que representan 14 estudios fueron incluidos: 4 ensayos controlados aleatorios, 5 estudios pilotos, y 5 trabajos formativos. Dos intervenciones tuvieron resultados relacionados con PrEP y 7 se centraron en resultados conductuales y/o resultados educativos. Pocos de los estudios incluidos incorporaron salud digital. Todos menos unos de los estudios fueron teóricamente guiados. El compromiso de la comunidad fue un hilo en común, como CBPR fue el marco más prevalente. La integración cultural varió ampliamente y también el uso de español o el uso de materiales bilingües. Oportunidades para futura investigaciones se discuten y se ofrecen sugerencias para fortalecer intervenciones para la prevención de VIH (p.ej., adaptar), enfocarse en abordar consideraciones adicionales sobre la cultura (p.ej., matices en diferentes culturas hispanas) y mitigar barreras fundamentales para mejorar el uso de estrategias basadas en evidencia entre esta población.

Insulin B peptide-MHC class II-specific chimeric antigen receptor-Tregs prevent autoimmune diabetes.

Adoptive immunotherapy with Tregs is a promising approach for prevention or treatment of type 1 diabetes. Islet antigen-specific Tregs have more potent therapeutic effects than polyclonal cells, but their low frequency is a barrier for clinical application. To generate Tregs that recognize islet antigens, we engineered a chimeric antigen receptor (CAR) derived from a monoclonal antibody with specificity for the insulin B-chain 10-23 peptide presented in the context of the IA g7 MHC class II allele present in NOD mice. Peptide specificity of the resulting InsB-g7 CAR was confirmed by tetramer staining and T cell proliferation in response to recombinant or islet-derived peptide. The InsB-g7 CAR re-directed NOD Treg specificity such that insulin B 10-23-peptide stimulation enhanced suppressive function, measured via reduction of proliferation and IL-2 production by BDC2.5 T cells and CD80 and CD86 expression on dendritic cells. Co-transfer of InsB-g7 CAR Tregs prevented adoptive transfer diabetes by BDC2.5 T cells in immunodeficient NOD mice. In wild type NOD mice, InsB-g7 CAR Tregs stably expressed Foxp3 and prevented spontaneous diabetes. These results show that engineering Treg specificity for islet antigens using a T cell receptor-like CAR is a promising new therapeutic approach for the prevention of autoimmune diabetes. Brief Summary: Chimeric antigen receptor Tregs specific for an insulin B-chain peptide presented by MHC class II prevent autoimmune diabetes.

Use of Stated Preference Methods in HIV Treatment and Prevention Research in the United States: A Systematic Review.

Stated preference (SP) methods are increasingly being applied to HIV-related research and continuously provide researchers with health utility scores of select healthcare products or services that populations consider important. Following PRISMA guidelines, we sought to understand how SP methods have been applied in HIV-related research. We conducted a systematic review to identify studies meeting the following criteria: SP method is clearly stated, conducted in the United States, was published between 01/01/2012 and 02/12/2022, and included adults aged 18 and over. Study design and SP method application were also examined. We identified six SP methods (e.g., Conjoint Analysis, Discrete Choice Experiment) across 18 studies, which were categorized into one of two groups: HIV prevention and HIV treatment-care. Categories of attributes used in SP methods largely focused on: administration, physical/health effects, financial, location, access, and external influences. SP methods are innovative tools capable of informing researchers on what populations consider most beneficial when deciding on treatment, care, or prevention options for HIV.

Delineating regional vulnerability in the neurodegenerative disease SCA1 using a conditional mutant ATXN1 mouse.

Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by an expanded polyglutamine tract in the widely expressed ATXN1 protein. To elucidate anatomical regions and cell types that underlie mutant ATXN1-induced disease phenotypes, we developed a floxed conditional knockout mouse model ( f-ATXN1 146Q/2Q ) having mouse Atxn1 coding exons replaced by human exons encoding 146 glutamines. F-ATXN1 146Q/2Q mice manifest SCA1-like phenotypes including motor and cognitive deficits, wasting, and decreased survival. CNS contributions to disease were revealed using ATXN1 146Q/2Q ; Nestin-Cre mice, that showed improved rotarod, open field and Barnes maze performances. Striatal contributions to motor deficits were examined using f-ATXN1 146Q/2Q ; Rgs9-Cre mice. Mice lacking striatal ATXN1 146Q/2Q had improved rotarod performance late in disease. Muscle contributions to disease were revealed in f-ATXN1 146Q/2Q ; ACTA1-Cre mice which lacked muscle pathology and kyphosis seen in f-ATXN1 146Q/2Q mice. Kyphosis was not improved in f-ATXN1 146Q/2Q ;Nestin - Cre mice. Thus, optimal SCA1 therapeutics will require targeting mutant ATXN1 toxic actions in multiple brain regions and muscle.

HIV Prevention Research With U.S. Military Service Members: A Systematic Review.

INTRODUCTION: With the goal of maintaining mission readiness, the U.S. Department of Defense monitors a variety of health behaviors among its active duty military service members, including sexual health, HIV, and other sexually transmitted infections. Newer biomedical approaches to HIV prevention and care (e.g., Treatment as Prevention (TasP) via Pre-exposure Prophylaxis (PrEP) and undetectable = untransmissible of antiretroviral therapy (ART/U = U) have evolved over the last few years and are now available. However, the last systematic review on HIV prevention among military populations was published in 2005, calling for the need to provide an update on what HIV prevention research has been conducted with U.S. active duty service members. MATERIALS AND METHODS: PRISMA guidelines were followed to identify articles that met pre-determined eligibility criteria. Several electronic databases were searched, including PubMed. The review focused on HIV prevention research conducted with the U.S. Military (i.e., active duty service members). Inclusion criteria for articles centered on population (U.S. active duty service members aged 17 years and older), language (published in English), study focus (epidemiological, intervention), study design (descriptive, quasi-experimental, and experimental), date of publication, and research focus. Studies with a descriptive focus to understand HIV-related risk behaviors, use of prevention strategies (e.g., condoms, testing, PrEP), and prescribing practices for uptake of prevention strategies among U.S. military service members (i.e., by providers, uptake from nonproviders) were included. Studies that focused on intervening or changing HIV risk (i.e., interventions) among U.S. military service members were also included. RESULTS: The findings in this review were reported based on the PRISMA guidelines. A total of 2,270 articles were identified through electronic databases. Of the 2,270 articles, 809 articles were removed for duplication. Titles and abstracts were reviewed for the remaining 1,461 articles. Of the 1,461 articles, 1,432 were excluded for not meeting the inclusion criteria. In total, 29 studies met the inclusion criteria and were included in this review. Studies were organized into 3 tables based on study focus and target population (e.g., active duty, U.S. Military service members who were providers vs. nonproviders). CONCLUSIONS: The present systematic review describes 29 HIV prevention studies that have been conducted with active duty service members in the U.S. Military since 2000. Overall, most included studies were descriptive, epidemiological studies conducted with active duty service members who were not providers. There were few interventions that reported some success in improving prevention knowledge and condom use. None of the interventions included newer evidence-based strategies of TasP. Although some research had been conducted about PrEP, particularly with providers, there is a clear need for additional studies and interventions to include TasP, given the evidence base of these approaches for reducing acquisition and/or onward transmission of HIV.

Decreasing mutant ATXN1 nuclear localization improves a spectrum of SCA1-like phenotypes and brain region transcriptomic profiles.

Spinocerebellar ataxia type 1 (SCA1) is a dominant trinucleotide repeat neurodegenerative disease characterized by motor dysfunction, cognitive impairment, and premature death. Degeneration of cerebellar Purkinje cells is a frequent and prominent pathological feature of SCA1. We previously showed that transport of ATXN1 to Purkinje cell nuclei is required for pathology, where mutant ATXN1 alters transcription. To examine the role of ATXN1 nuclear localization broadly in SCA1-like disease pathogenesis, CRISPR-Cas9 was used to develop a mouse with an amino acid alteration (K772T) in the nuclear localization sequence of the expanded ATXN1 protein. Characterization of these mice indicates that proper nuclear localization of mutant ATXN1 contributes to many disease-like phenotypes including motor dysfunction, cognitive deficits, and premature lethality. RNA sequencing analysis of genes with expression corrected to WT levels in Atxn1175QK772T/2Q mice indicates that transcriptomic aspects of SCA1 pathogenesis differ between the cerebellum, brainstem, cerebral cortex, hippocampus, and striatum.

Route of self-amplifying mRNA vaccination modulates the establishment of pulmonary resident memory CD8 and CD4 T cells.

Respiratory tract resident memory T cells (TRM), typically generated by local vaccination or infection, can accelerate control of pulmonary infections that evade neutralizing antibody. It is unknown whether mRNA vaccination establishes respiratory TRM. We generated a self-amplifying mRNA vaccine encoding the influenza A virus nucleoprotein that is encapsulated in modified dendron-based nanoparticles. Here, we report how routes of immunization in mice, including contralateral versus ipsilateral intramuscular boosts, or intravenous and intranasal routes, influenced influenza-specific cell-mediated and humoral immunity. Parabiotic surgeries revealed that intramuscular immunization was sufficient to establish CD8 TRM in the lung and draining lymph nodes. Contralateral, compared with ipsilateral, intramuscular boosting broadened the distribution of lymph node TRM and T follicular helper cells but slightly diminished resulting levels of serum antibody. Intranasal mRNA delivery established modest circulating CD8 and CD4 T cell memory but augmented distribution to the respiratory mucosa. Combining intramuscular immunizations with an intranasal mRNA boost achieved high levels of both circulating T cell memory and lung TRM. Thus, routes of mRNA vaccination influence humoral and cell-mediated immunity, and intramuscular prime-boosting establishes lung TRM that can be further expanded by an additional intranasal immunization.

Evidence and implication of interventions across various socioecological levels to address HIV testing uptake among men who have sex with men in the United States: A systematic review.

Objectives: Strengthening HIV testing uptake is critical to curtail the HIV epidemics among men who have sex with men in the United States. Despite the implementation of various interventions to promote HIV testing among men who have sex with men, few aggregated evidence is presented to reflect the "lessons learned" and inform future directions. The objective of this systematic review is to comprehensively summarize published studies that described, tested, and evaluated outcomes (e.g. efficacy, effectiveness, acceptability, feasibility and/or qualitative opinions) associated with an HIV testing intervention and identify gaps as well as opportunities to inform the design and implementation of future interventions to enhance HIV testing uptake among men who have sex with men in the United States. Methods: We followed the PRISMA guidelines and conducted a systematic review of articles (published by 23 July 2021) by searching multiple databases (PubMed, MEDLINE, Web of Science and PsycINFO). Results: Among the total number of 3505 articles found through multiple databases, 56 papers were included into the review. Interventional modules that demonstrated acceptability, feasibility and efficacy to improve HIV testing uptake among men who have sex with men include: HIV self-testing, interpersonal-level (e.g. peer-led, couple-based) interventions, personalized interventions and technology-based interventions (e.g. mHealth). Aggregated evidence also reflects the lack of individualized interventions that simultaneously address time-varying needs across multiple socioecological levels (e.g. individual, interpersonal, community, structural and societal). Conclusion: Development of interventions to improve HIV testing rates and frequency of men who have sex with men has proliferated in recent years. Our review presents important implications in sustaining and improving interventions to address HIV testing uptake among men who have sex with men in the United States.

Suboptimal Follow-Up on HIV Test Results among Young Men Who Have Sex with Men: A Community-Based Study in Two U.S. Cities.

Frequent HIV testing and knowledge of HIV serostatus is the premise before timely access to HIV prevention and treatment services, but a portion of young men who have sex with men (YMSM) do not always follow up on their HIV test results after HIV testing, which is detrimental to the implementation of HIV prevention and care among this subgroup. The comprehensive evaluation of factors associated with inconsistent follow-up on HIV test results may inform relevant interventions to address this critical issue among YMSM. To this end, we conducted a cross-sectional study in Nashville, Tennessee and Buffalo, New York from May 2019 to May 2020 to assess demographic, behavioral, and psychosocial correlates of inconsistent follow-up on HIV test results among YMSM. Of the 347 participants, 27.1% (n = 94) reported inconsistent follow-up on their HIV test results. Multivariable logistic regression showed that inconsistent follow-up on HIV test results was positively associated with condomless receptive anal sex, group sex, recreational drug use before or during sex, internalized homophobia, and stress; while negatively associated with housing stability, social support, and general resilience. Future HIV prevention intervention efforts should target these modifiable determinants to enhance the follow-up on HIV test results among YMSM.

Evidence and implication of interventions across various socioecological levels to address pre-exposure prophylaxis uptake and adherence among men who have sex with men in the United States: a systematic review.

BACKGROUND: Pre-exposure prophylaxis (PrEP) represents a proven biomedical strategy to prevent HIV transmissions among men who have sex with men (MSM) in the United States (US). Despite the design and implementation of various PrEP-focus interventions in the US, aggregated evidence for enhancing PrEP uptake and adherence is lacking. The objective of this systematic review is to synthesize and evaluate interventions aimed to improve PrEP uptake and adherence among MSM in the US, and identify gaps with opportunities to inform the design and implementation of future PrEP interventions for these priority populations. METHODS: We followed the PRISMA guidelines and conducted a systematic review of articles (published by November 28, 2021) with a focus on PrEP-related interventions by searching multiple databases (PubMed, MEDLINE, Web of Science and PsycINFO). Details of PrEP interventions were characterized based on their socioecological level(s), implementation modalities, and stage(s) of PrEP cascade continuum. RESULTS: Among the 1363 articles retrieved from multiple databases, 42 interventions identified from 47 publications met the inclusion criteria for this review. Most individual-level interventions were delivered via text messages and/or apps and incorporated personalized elements to tailor the intervention content on participants' demographic characteristics or HIV risk behaviors. Interpersonal-level interventions often employed peer mentors or social network strategies to enhance PrEP adoption among MSM of minority race. However, few interventions were implemented at the community-, healthcare/institution- or multiple levels. CONCLUSIONS: Interventions that incorporate multiple socioecological levels hold promise to facilitate PrEP adoption and adherence among MSM in the US given their acceptability, feasibility, efficacy and effectiveness. Future PrEP interventions that simultaneously address PrEP-related barriers/facilitators across multiple socioecological levels should be enhanced with a focus to tackle contextual and structural barriers (e.g., social determinants of health, stigma or medical mistrust) at the community- and healthcare/institution-level to effectively promote PrEP use for MSM of color.

Perspectives on a Couples-Based, e-Health HIV Prevention Toolkit Intervention: A Qualitative Dyadic Study with Black, Heterosexual Couples in New York State.

Web-based technology provides an unparalleled opportunity to increase access and uptake of couples-based HIV prevention interventions. e-Health HIV prevention interventions for US Black heterosexual couples have largely been understudied. To address this gap, we applied the Assessment Phase of the ADAPT-ITT Framework to investigate Black heterosexual couples' perspectives on an existing e-Health, couples-based HIV prevention intervention. Applying a qualitative descriptive approach, joint dyadic interviews were conducted with 28 Black heterosexual couples from three jurisdictions in New York State. Content dyadic analysis revealed three descriptive categories: perspectives of the toolkit intervention (sub-codes: perceived relevance, reactions to core components), recommendations to enhance intervention relevancy (sub-codes: tailoring to relationship type, adding new content), and lasting intervention considerations (sub-codes: toolkit usability and language use). Overall, couples found the toolkit intervention content and usability acceptable and reflected on its potential to build sexual and relationship health. Couples recommended to enhance toolkit adaptability for varied couple's motivation and types re-consider terms like sexual agreements, and include content to facilitate communication regarding sensitive topics (e.g., childhood sexual trauma, co-parenting, family planning) and other issues that may have more relevance to the experience of US Black persons (i.e., wealth building).

Distinct myeloid antigen-presenting cells dictate differential fates of tumor-specific CD8+ T cells in pancreatic cancer.

We investigate how myeloid subsets differentially shape immunity to pancreatic ductal adenocarcinoma (PDA). We show that tumor antigenicity sculpts myeloid cell composition and functionality. Antigenicity promotes accumulation of type 1 dendritic cells (cDC1), which is driven by Xcr1 signaling, and overcomes macrophage-mediated suppression. The therapeutic activity of adoptive T cell therapy or programmed cell death ligand 1 blockade required cDC1s, which sustained splenic Klrg1+ cytotoxic antitumor T cells and functional intratumoral T cells. KLRG1 and cDC1 genes correlated in human tumors, and PDA patients with high intratumoral KLRG1 survived longer than patients with low intratumoral KLRG1. The immunotherapy CD40 agonist also required host cDC1s for maximal therapeutic benefit. However, CD40 agonist exhibited partial therapeutic benefit in cDC1-deficient hosts and resulted in priming of tumor-specific yet atypical CD8+ T cells with a regulatory phenotype and that failed to participate in tumor control. Monocyte/macrophage depletion using clodronate liposomes abrogated T cell priming yet enhanced the antitumor activity of CD40 agonist in cDC1-deficient hosts via engagement of innate immunity. In sum, our study supports that cDC1s are essential for sustaining effective antitumor T cells and supports differential roles for cDC1s and monocytes/macrophages in instructing T cell fate and immunotherapy response.