Faculty Bibliography

Digital spatial profiling (DSP) facilitates RNA sequencing (RNA-seq) of small populations of cells, specifically ~20 pyramidal neurons in postmortem formalin-fixed paraffin-embedded (FFPE) human brain tissue. This approach enables precise expression profiling via RNA-seq data linked to spatially characterized samples utilizing tissue-bound probes. We present a comprehensive protocol for manual slide preparation using the GeoMx DSP system as preliminary steps to spatial characterization of lamina-specific pyramidal neurons in human postmortem Brodmann area 9 (BA9) frontal cortex brain tissue.

BACKGROUND:Oral pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP) provision via online pharmacies (henceforth online PrEP and PEP) offers promise in increasing biomedical HIV prevention coverage. In this study, we aimed to estimate the cost-effectiveness of online PrEP and PEP scale-up in western Kenya. METHODS:We adapted a network-based model, EMOD-HIV, to simulate online PrEP and PEP implementation from 2026 to 2036; costs and use of online PrEP and PEP and client characteristics were informed by the ePrEP Kenya pilot study, which evaluated online PrEP and PEP provision in Nairobi and Mombasa, Kenya. Other parameters were obtained from surveillance data and published literature. Eligible clients were aged 15-49 years reporting condomless sex with non-marital partners. We assumed online PrEP and PEP provision was implemented through public-private partnership, with the Kenya Ministry of Health providing PrEP and PEP drugs and service delivery costs paid by the online pharmacy (and charged to clients). We estimated HIV infections, HIV-related deaths, and disability-adjusted life-years (DALYs) averted compared with the baseline scenario of background oral PrEP only. We calculated incremental cost-effectiveness ratios (ICERs) assessing only costs incurred by the Kenya Ministry of Health over 35 years and used a supply-side threshold of US$500 per DALY averted. We calculated 95% uncertainty intervals (UIs) across 100 parameter sets. FINDINGS/RESULTS:Online PrEP and PEP was projected to reach population coverage of 0·7% (95% UI 0·7-0·8) for PEP and 0·3% (0·2-0·3) for PrEP and avert 13·9% (10·1-17·1) of HIV infections over 10 years. HIV-related deaths were reduced by 4·3% (95% UI 2·0-6·9) over the 35-year time horizon. The intervention was cost-effective from the Kenya Ministry of Health perspective (ICER $212 [95% UI 15-1409] per DALY averted). In a scenario assuming only online PEP availability (to isolate the effect of PEP), 11·6% (95% UI 8·6-15·2) of HIV infections were averted (ICER $210 [95% UI 41-3798] per DALY averted). The intervention remained cost-effective when varying PrEP and PEP effectiveness and assuming HIV testing and treatment disruptions. INTERPRETATION/CONCLUSIONS:Online PrEP and PEP can avert substantial HIV infections, even with low population coverage. PEP was responsible for most intervention health benefits, likely due to high observed demand for PEP compared with PrEP in the pilot study. Leveraging private retailers can be efficient for scaling up HIV prevention in an era of shrinking donor funding. FUNDING/BACKGROUND:Gates Foundation.

Coccidioidomycosis rarely presents as a lung mass, hypereosinophilia, and disseminated pericarditis with pericardial effusion. Even rarer is a case that presents with the constellation of all these findings. We present a case of coccidioidomycosis in an immunocompetent young Jamaican male with all these features, set against an interesting epidemiological context of a likely exposure to coccidioidomycosis spores during an on-foot crossing of the Mexican border into Texas. His treatment course was complicated by declining liver and kidney function due to triazole antifungal therapy, necessitating titration of these doses to tolerable levels. This case highlights the importance of a detailed travel history in unraveling infectious disease diagnoses and underscores the need for high clinical suspicion for coccidioidomycosis, even in patients outside of known endemic regions.

BACKGROUND/UNASSIGNED:Pregnancy requires finely tuned immune changes that support implantation, placental development, maternal-fetal tolerance, and preparation for labor, yet the normative trajectories of circulating inflammatory proteins across gestation remain poorly defined. This cross-sectional study investigates how circulating inflammatory proteins vary with gestational age in pregnancy and examines the impacts of fundamental biological characteristics, such as gravidity and fetal sex. METHODS/UNASSIGNED:Data were drawn from 1154 pregnant individuals from six study sites of the National Institutes of Health Environmental influences on Child Health Outcomes (ECHO) Cohort. We used Olink high-throughput proteomic profiling to map cross-sectional associations between protein expression levels and gestational age at blood draw using linear, spline-based, and generalized additive modeling approaches. RESULTS/UNASSIGNED:Generalized additive models provided the best fit, revealing that immune changes across pregnancy were predominantly nonlinear. Sixty-one proteins showed significant associations with gestational age, with many exhibiting shared inflection points that aligned with major physiological transitions. A small subset of proteins also showed evidence of modification by fetal and maternal characteristics. CD244 displayed different gestational patterns by fetal sex, while CST5 and SIRT2 showed varied gestational associations by maternal gravidity. CONCLUSION/UNASSIGNED:The findings highlight pregnancy as a sequence of coordinated immune transitions rather than a simple linear shift and provide one of the most detailed characterizations to date of circulating inflammatory protein dynamics across human gestation. Establishing these normative trajectories offers a crucial reference for detecting early deviations that may signal risk for pregnancy complications and for identifying biomarkers in maternal and fetal health research.

Achalasia is an uncommon primary esophageal motility disorder characterized by impaired lower esophageal sphincter relaxation and absent esophageal peristalsis. These changes result in progressive esophageal dilation and functional obstruction. Although classically associated with dysphagia and regurgitation, respiratory manifestations may predominate due to chronic aspiration of retained esophageal contents, which can obscure the underlying diagnosis and delay appropriate management. We report the case of a 20-year-old male with a history of asthma, gastroesophageal reflux disease, and gastroparesis who presented with one day of shortness of breath and productive cough, initially treated as an asthma exacerbation. Imaging performed to evaluate new-onset respiratory symptoms for one day prior to admission revealed a markedly dilated, fluid-filled esophagus and radiographic findings consistent with aspiration pneumonia. He was initially treated with one dose of 2 mg IV cefepime, then modified to Unasyn 3 mg and doxycycline 100 mg. Subsequent endoscopic evaluation confirmed severe esophageal dilation with retained food contents, supporting the diagnosis of advanced achalasia. This case highlights how achalasia may present primarily with pulmonary complications in young patients, particularly when coexisting respiratory disease is present. Delayed recognition can result in significant morbidity, including recurrent aspiration, malnutrition, and progressive esophageal dysfunction. Early consideration of esophageal motility disorders in patients with refractory respiratory symptoms and GI history is essential to prevent complications and guide timely therapeutic intervention.

IMPORTANCE/UNASSIGNED:Parent/caregiver-infant early relational health (ERH) is known to play a critical role in the promotion of socio-emotional functioning and wellbeing across the life course. The negative impact of the COVID-19 pandemic on maternal mental health and secondarily on ERH and child socio-emotional functioning is clear. However, the direct impact of maternal viral exposure during pregnancy on ERH has not been investigated. OBJECTIVE/UNASSIGNED:The goal of this study was to determine the impact of prenatal SARS-CoV-2 exposure on ERH and infant socio-emotional functioning in the first 6 months of life. DESIGN/UNASSIGNED:Mothers with and without SARS-CoV-2 exposure during pregnancy who gave birth from 02/2020 to 09/2021 were enrolled from 05/2020 to 09/2021 in one of two parallel prospective studies (the COVID-19 Mother Baby Outcomes [COMBO] Initiative or the Respiratory Syndrome Coronavirus 2 in Pregnancy and Infancy [ESPI] COMBO sub-study). Mothers reported on their health and the socio-emotional functioning of their infant via online surveys (REDCap) at enrollment, 1, 2, 4, and 6 months. At 4 to 6 months, dyads were invited to participate in a video-based, remote assessment of ERH. PARTICIPANTS/UNASSIGNED:884 mother-infant dyads from three U.S. States (Alabama, New York, and Utah). EXPOSURE/UNASSIGNED:Prenatal SARS-CoV-2. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Edition (ASQ:SE-2). RESULTS/UNASSIGNED:316 (36%) mothers had a positive prenatal SARS-CoV-2 exposure. Prenatal SARS-CoV-2 exposure was associated with an adjusted estimate of ~5% reduction (incidence rate ratio=0.95, 95% confidence interval [0.90, 1.00], p=0.03) in observed maternal caregiving quality, after accounting for postnatal maternal mental health and sociodemographic factors. We found no evidence of effect on other ERH constructs or infant socio-emotional functioning. CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this large prospective cohort study, prenatal SARS-CoV-2 was associated with a small decrement in caregiving quality, but not other ERH constructs or infant socio-emotional functioning. These findings should be interpreted as hypothesis generating and will require replication in independent studies.

BACKGROUND:Systematic social observation (SSO) quantifies changes in the social and built environment and can be useful for evaluating the neighborhood effects of substance use programs. METHODS:We developed, implemented, and validated an SSO instrument in the Bronx, New York City, and Providence, Rhode Island. Research assistants assessed neighborhoods in the Bronx (4/19/2023-6/22/2023) and Providence (11/4/2024-12/20/2024) following a randomization schedule to minimize temporal biases. We used exploratory factor analysis (EFA) and Bayesian multi-level item response theory (IRT) models to derive social and built environment indices and externally validated the measures against arrest data. RESULTS:EFA for the Bronx (n = 564) and Providence (n = 463) identified three factors assessed with the instrument: drug litter, people, and built environment. IRT-based social and built environment indices exhibited positive spatial autocorrelation (the Bronx Moran's I = 0.393, P < 0.001; Providence Moran's I = 0.068, P < 0.001). In the Bronx, item severity and discrimination were highest for the drug litter factor; item parameters were relatively uniform in Providence. The Bronx index was associated with total (incidence rate ratio [IRR] = 1.42, 95% confidence interval [CI] = 1.04-1.95) and drug-related (IRR = 1.60, 95% CI = 1.10-2.32) arrests. The Providence index was not associated with arrests. CONCLUSIONS:Our SSO protocol can be replicated in diverse settings to evaluate the neighborhood effects of substance use programs and broader effects of neighborhood conditions on substance use. The social and built environment indices for the Bronx and Providence may be useful outcomes in future studies. External validation suggests the Bronx index captured drug-related environmental variation; the Providence index may capture variation unrelated to policing patterns.