Faculty Bibliography

BACKGROUND:The extensive genetic diversity of HIV presents major challenges to treatment and prevention. We aimed to estimate the global and regional distribution of HIV-1 subtypes and recombinants during 1990-2024. METHODS:We conducted a systematic literature review by searching PubMed, Embase, Global Health, and CINAHL for country-specific HIV-1 subtyping data published between Jan 1, 2022, and Jan 22, 2025, and a global survey of the Global HIV Molecular Epidemiology Collaboration for unpublished data collected between 2016 and 2024. We included primary HIV-1 subtyping data with ≥20 samples and known country and years of sample collection during 1990-2024. We excluded publications and survey responses that had no or incomplete subtyping data, were restricted to specific HIV-1 variants, included superinfections, or used secondary data. These data were combined with HIV-1 subtyping data previously collected between 1990 and 2021. Data were aggregated by country for six time periods (1990-99, 2000-04, 2005-09, 2010-14, 2015-19, and 2020-24). Proportions of HIV-1 subtypes, circulating recombinant forms (CRFs), and unique recombinant forms (URFs) were calculated by country and period and were weighted using UNAIDS country estimates of numbers of people living with HIV to estimate regional and global HIV-1 variant proportions. The systematic review is registered with PROSPERO, CRD42017067164. FINDINGS/RESULTS:HIV-1 subtyping data were available for 1 395 222 samples from 154 countries during 1990-2024. In 2020-24, subtype C accounted for 48·7% (95% CI 48·3-49·1) of global HIV-1 infections, followed by subtype A (11·5%; 10·9-12·1), subtype B (10·3%; 10·0-10·5) URFs (5·3%; 4·4-6·3), CRF02_AG (5·1%; 4·5-5·8), CRF01_AE (5·1%; 4·8-5·4), other CRFs (3·9%; 3·3-4·5), subtype G (3·1%; 2·1-4·1), subtype D (3·0%; 2·7-3·3), and CRF07_BC (2·1%; 2·0-2·1). Subtypes F, H, J, K, and L combined accounted for 1·1% of infections and unspecified recombinants for 0·9% (0·7-1·0). HIV-1 variants are differentially distributed across regions, with subtype C dominating in southern Africa; Ethiopia, Eritrea, and Djibouti; and south Asia; subtype A in east Africa and eastern Europe and central Asia; subtype B in North America, Latin America, and western and central Europe; CRF01_AE in southeast Asia; and CRF07_BC in east Asia. Central Africa exhibited the greatest HIV-1 diversity. Global HIV-1 variant distributions were broadly stable during 2000-24, but notable regional changes included increases of HIV-1 recombinants in western and central Europe and of CRF07_BC in east Asia. INTERPRETATION/CONCLUSIONS:Global and regional HIV-1 genetic diversity is complex and evolving, affecting the efficacy of diagnostic and viral load assays, emergence of drug resistance, and vaccine development. Continued surveillance of spatiotemporal trends in HIV-1 genetic diversity is essential. FUNDING/BACKGROUND:Nuffield Department of Population Health, University of Oxford, UK.

BACKGROUND:Exercise links with improved cancer outcomes following a diagnosis of primary breast cancer but experimental evidence and molecular mechanistic interrogation from preclinical studies are limited. The purpose of this study was to evaluate the effects, and dose‒response, of exercise in mouse models of breast cancer, as well as elucidate cancer cell extrinsic and intrinsic responses. METHODS:Independent in vivo modeling was used to investigate the effects of exercise across distinct breast cancer models. Unbiased transcriptomic and metabolomic analyses, alongside cellular and proteomic interrogation, were used to determine tumor microenvironment (TME)- and cancer cell-specific effects. RESULTS:Exercise inhibited breast cancer growth and metastasis across multiple syngeneic mouse models compared to sham control. Tumor growth inhibition was independent of estrogen receptor status, and in the 4T1 model, exercise exerted non-dose-dependent effects. In the Met1 model, exercise decreased TME immune cell content, particularly tumor-associated macrophages, while promoting an activated anticancer innate immune cell gene signature. Concurrent in vivo cancer cell-intrinsic effects were characterized by broad transcriptomic reprogramming including downregulation of metabolic pathways and upregulation of pathways regulating proliferation and apoptosis. Whole tumor metabolomic analyses unveiled broad shifts including decreased nicotinamide adenine dinucleotide (NAD+) and lactate, as well as availability of biosynthetic precursors. Finally, in silico analyses identified TME ligands, such as High Mobility Group Box 2 (HMGB2) and Cardiotrophin-1 (CTF1) as candidate drivers of downstream gene expression changes in cancer cells. CONCLUSION/CONCLUSIONS:Exercise suppresses breast cancer progression, which occurs in conjunction with broad reprogramming of immune TME-cancer processes and their interaction.

Childhood is a period of peak developmental plasticity, involving drastic changes in the maturation of the neural circuitry underlying fear learning. Disruption and atypical development of fear learning are candidate mechanisms underlying child psychopathology. While there is a lack of understanding behind the maturation of fear learning systems in humans, rodent studies in this area delineate the normative development of fear learning systems early in life, and the effects of early threatening and fearful experiences on this developmental trajectory. Here, we review the rodent literature on developmental fear learning, as well as human studies that show translational convergence in typical development and children exposed to early life threat. We identify several gaps in research, including the role that caregivers play in regulating fear learning at different developmental stages and the intergenerational transmission of learned fear. Finally, we provide recommendations on how to address these gaps in a way that would improve our developmental frameworks of fear learning.

INTRODUCTION/BACKGROUND:Although word-finding difficulties (WFD) are prevalent in multiple sclerosis (MS), they remain poorly understood. This cross-sectional study aimed to identify several important practical and theoretical challenges, including key knowledge gaps related to understanding and measuring aspects of language deficit in MS (i.e., WFD). Further investigations of possible correlates of deficits with other symptoms of MS (i.e., such as depression, fatigue and cognitive impairment) were also carried out as part of this study to find out if WFD is a standalone symptom or is a part of a broader and complex symptom of MS. METHODS:In this cohort study, all data from 586 consecutive Persons with MS (PwMS) (137 males and 449 females), with a mean age of 47.1 (SD±10.34) and a median EDSS score of 2.0, were included. A standardized naming task was used as part of a computerized cognitive assessment battery (CAB, NeuroTrax™) with computer-based administration and off-site scoring that has been validated for use in PwMS to determine the associations between cognitive impairment (CI), fatigue, and depression in WFD. RESULTS:A significant correlation (r = 0.327) was noted in this study between cognitive impairment and WFD (p < 0.001). PwMS with CI had a higher rate of WFD (i.e., 43.2%) as compared to individuals with WFD despite not having CI (i.e., 13.9%). Disability (EDSS), disease duration, depression and fatigue, were not correlated with WFD. CONCLUSION/CONCLUSIONS:WFD are most likely part of a larger underlying problem (i.e., CI), but there is a small group of persons with MS and WFD who have isolated WFD. Findings of this study have implications for activities of daily living (ADLs) and therapy for rehabilitation professionals working with PwMS.

PURPOSE/OBJECTIVE:Low back pain (LBP) is a complex, multifactorial condition with numerous contributors across biopsychosocial domains. To advance understanding of this complexity, we synthesized diverse expert knowledge on treatment effectiveness and underlying mechanisms using a systems-based, collaborative modeling approach. METHODS:Twenty-nine experts from diverse disciplines created individual fuzzy cognitive maps (FCMs) to represent their understanding of factors affecting pain, disability, and quality of life (QoL), along with treatment mechanisms. These maps were aggregated into a meta-model comprising 142 Components and 1,161 weighted Connections. Centrality was used to quantify the relative contribution of each domain within the meta-model. Simulations with the meta-model based on expert knowledge (1) estimated the relative effectiveness of treatments on pain, disability, and QoL and (2) identified key Mediators and mediating Domains based on their relative contribution to mediating treatment effects. RESULTS:Psychological, biomechanical, and social/contextual Domains were central to expert conceptualizations of LBP. Simulation indicated cognitive behavioral therapy was considered the most effective among all interventions. Most interventions were mediated by Components across multiple Domains, with psychological factors frequently serving as mediators. The structure of the conceptual meta-model reflected both the multifactorial complexity of LBP and the diversity of expert perspectives regarding factors that influence treatment effectiveness. CONCLUSION/CONCLUSIONS:The developed meta-model provides a novel, systems-based representation of expert knowledge about LBP, enabling quantitative exploration of treatment effects and underlying mechanisms. This conceptual framework also offers a foundation for advancing research on multi-modal, personalized care.

OBJECTIVE:To examine the early experiences influencing research career intentions (RCI) among MD students from racial and ethnic backgrounds underrepresented in medicine (URiM). METHODS:We conducted semi-structured, in-depth interviews with 31 first-year URiM medical students from MD-granting programs across the US to examine student-reported experiences influencing RCI. RESULTS:Participants were first-year medical students (N = 31; mean age 24.8 ± 2.6 years; 64.5% female) identifying as Black (38.7%), Hispanic (32.3%), or Multiracial (29%). Four themes were identified: (1) structured premedical research exposure was described as pivotal to developing early research engagement and interest in research careers; (2) research orientations reflected a commitment to using research as a vehicle for social justice and community impact; (3) high-quality research mentorship was characterized by authentic relational investment, skill development, and the distinct value of racial and ethnic identity-concordant role models; and (4) the research arms race for residency placement was described as amplifying systemic inequities that constrained students' research engagement. Across themes, students described tensions between academic research culture and their personal values, including a desire to advance equity and contribute meaningfully to science. For some, this misalignment made research feel less purposeful or personally aligned. CONCLUSIONS:Medical training programs seeking to support URiM students' RCI should invest in structured premedical research programs and expand access to research mentorship that is both relationally invested and identity concordant. Efforts to cultivate sustained engagement should address publication pressures tied to residency competitiveness, which amplify structural barriers and misalign with students' motivations for pursuing research. Broadening definitions of scholarly contribution and fostering research environments that affirm students' values may be critical to building a robust physician-scientist workforce.

The microbiome has been described as the last human "organ" and is currently the topic of great research interest worldwide. The application of culture-independent methods, like 16S ribosomal next-generation sequencing, has offered researchers the opportunity to identify bacterial populations that were impossible to detect previously using conventional culture methods. Further standardization of these new approaches to characterizing the microbiome is desirable. The present review discusses the mounting evidence suggesting that alterations in the microbiome and microbial metabolites, such as short-chain fatty acids in the gut, mouth, and ocular surface, may play a key role in the pathogenesis of ocular pathologies such as ocular surface disease, glaucoma, uveitis, age-related macular degeneration, and diabetic retinopathy. Clarifying the probable role of the microbiome in ocular diseases would not only offer valuable insights into pathogenesis but could also enable the development of novel therapeutic approaches. As yet, microbial-based therapeutic applications in ophthalmology are limited. Nevertheless, recently emerging strategies utilizing probiotics and prebiotics, or even fecal transplantation to regulate microbiome composition, offer promising research avenues for developing future innovative therapies for ocular diseases. Further studies employing standardized methodological protocols are needed to ensure the reproducibility of results and to eventually unlock the precise links between the microbiome and the eye.

BACKGROUND:Persons with HIV have an increased risk of cardiovascular and metabolic diseases compared to HIV serostatus-negative individuals. OBJECTIVE:We conducted a pilot wait-list control randomized trial to assess the feasibility and acceptability of a virtual environment for CVD and metabolic disease prevention education in men living with HIV. METHODS:In phase one, we conducted interviews and virtual environment beta testing with (n=25) individuals. In phase two, reported here, we conducted a wait-list control trial with permuted block randomization. Participants were allocated to the virtual environment intervention (n = 40) or a wait-list control arm (n = 38). The primary outcomes were feasibility (defined by recruitment and retention metrics) and acceptability (defined by levels of engagement) with virtual environment. We also examined preliminary effect sizes across several cardiovascular health-related indicators. RESULTS:Participants had a mean age of 41.8 years (SD=10.4) and had been living with HIV for an average of 15.9 years (SD=9.7). Participants were 62.5% Black and 26.7% Hispanic. A total of 45.0% of the intervention arm engaged with the virtual environment, with an average session duration of 110 minutes. The most engaged content modules were nutrition (146 engagements), oral health (138 engagements), fitness tips and videos (82 engagements), and relaxation techniques (75 engagements). Retention was 61.5% at final assessment, which to our knowledge, is notably higher than the typical retention rates seen in remote digital health research and all behavioral intervention research. Preliminary efficacy analyses across 3- and 6-month changes revealed medium effect sizes favoring the intervention for key nutritional outcomes (vegetable consumption: d=0.59-0.66; whole grain intake: d=0.41-0.46); and vigorous physical activity (d=0.38-0.57). Small-to-medium effect sizes were observed for fast food reduction (d=0.37 at 6-months), total physical activity (d=0.37 at 6-months), and depressive symptoms (d=0.22 at 3-months), as well as HIV illness perceptions, including timeline acute/chronic (d=0.44 at 3-months), illness coherence (d=0.33 at 3-months), and emotional representations (d=0.23-0.33). CONCLUSIONS:The LEARN Study demonstrated the feasibility and acceptability of a virtual environment designed for cardiovascular and metabolic disease prevention education in persons with HIV. The high engagement rates with specific educational content and strong retention highlight the promise of this innovative approach. Preliminary effect sizes suggested positive trends in cardiovascular health indicators and mental well-being, indicating further potential benefits of the intervention. These findings support progression to a fully powered randomized controlled trial. Subsequent funding has been awarded, based on this work, to expand the research in LEARN2. We will integrate lessons learned and focus on HIV- related conditions with shared risk factors to enhance the study's impact. By addressing HIV conditions with interrelated risk factors, we aim to provide a more comprehensive intervention to improve the overall health and well-being of individuals living with HIV. CLINICALTRIAL/BACKGROUND:ClinicalTrials.gov NCT05242952. INTERNATIONAL REGISTERED REPORT/UNASSIGNED:RR2-10.2196/38348.