Faculty Bibliography

PurposeTo evaluate the diagnostic performance of final-year ophthalmology residents in classifying keratoconus using standard Scheimpflug corneal tomography and to compare their accuracy to that of experienced corneal specialists.DesignProspective, investigator-initiated, multicenter observational study.MethodsFive final-year residents assessed 1,239 anonymized Pentacam HR (Oculus GmbH, Germany) quad-map outputs, categorized as normal, suspect keratoconus, or keratoconus, previously obtained from 620 pediatric patients in a prior population-based imaging study. Two corneal experts independently established the reference standard. Residents rated their diagnostic confidence using Likert scales. Agreement was quantified using Cohen's kappa (κ) and Fleiss's κ.ResultsResident-to-expert agreement ranged from Cohen's κ = 0.031 to 0.324 (slight to fair). Overall inter-rater reliability across all raters was slight, Fleiss's κ = 0.088. Four residents rated their diagnostic skill as neutral; one rated it as poor. Self-assessed competence relative to peers was rated as neutral by three residents and good by two.ConclusionsFinal-year ophthalmology residents showed limited agreement with expert graders when interpreting Scheimpflug images. The alignment between self-assessed confidence and measured diagnostic performance highlights a potential educational gap in image-based diagnosis of ectatic corneal disease. These findings support the need for competency-based curricular enhancements, including image interpretation benchmarks, expert-guided calibration sessions, and simulation-based learning modules, aiming to improve diagnostic accuracy and support earlier detection of keratoconus. Further multicenter studies are needed to validate these results and guide national and international training strategies.

BACKGROUND/UNASSIGNED:Lung cancer remains the leading cause of cancer-related mortality worldwide, with low-dose computed tomography screening demonstrating an approximately 20% reduction in mortality among high-risk individuals. Despite this benefit, screening prevalence remains suboptimal, with often less than 20% of eligible individuals reported to be up to date on screening. Shared decision-making is essential for effective lung cancer screening (LCS) implementation, with decision aids shown to enhance patient knowledge and engagement. OBJECTIVE/UNASSIGNED:The aim of this study is to identify patient preferences, concerns, and design considerations through qualitative evaluation of MyLungHealth, a personalized patient-facing educational tool for LCS integrated with electronic health records, and to describe how these findings informed iterative design modifications. METHODS/UNASSIGNED:We employed qualitative research methods through focus groups (n=34) and individual interviews (n=18) with individuals who met screening eligibility criteria. Participants were recruited from the University of Utah Health and New York University Langone Health between May and December 2023. Feedback was analyzed using Braun and Clarke's thematic analysis principles. RESULTS/UNASSIGNED:Six themes were organized into three overarching domains. Domain A included interpretation and impact of personalized risk information: theme 1, difficulties interpreting risk information, and theme 2, varied impacts of risk information on motivation. Domain B included autonomy, privacy, and user interface preferences: theme 3, desire for autonomy and control over personal health data, and theme 4, preference for straightforward language and multiple information formats. Domain C included integration with clinical workflows and patient portal systems: theme 5, expectations for integration with health care provider workflows, and theme 6, mixed experiences with personal health record systems. These insights led to key design modifications, including simplified risk presentation, multimodal content delivery options (video and text), and implementation of electronic health record alerts for clinicians. CONCLUSIONS/UNASSIGNED:The user-centered design process for MyLungHealth revealed important considerations for developing effective patient education tools for LCS. The findings highlighted the need for simplified risk presentation, personalized information delivery, and integration with clinical workflows. These findings underscore the importance of balancing comprehensive risk communication with user accessibility.

CONTEXT/BACKGROUND:Temozolomide (TMZ) can be an effective medical treatment for aggressive pituitary tumors. In case of disease recurrence following TMZ treatment, however, treatment with the drug generally does not control tumor regrowth. OBJECTIVE:This work aimed to better understand the mechanisms of resistance of corticotroph tumors to TMZ in the context of heterogeneity of methylguanine-DNA methyltransferase (MGMT) expression. METHODS:We performed immunohistochemical analysis of the MGMT expression pattern in 25 corticotroph tumors to evaluate intratumoral heterogeneity. In addition, we created in vitro models of AtT20 corticotroph tumor cells with acquired TMZ-resistance after exposure to high- and low-dose TMZ, the latter representing a clinically achievable TMZ level. RESULTS:MGMT immunostaining in corticotroph tumors showed a considerable heterogeneous intertumoral and intratumoral distribution pattern in 80% of tumors. In the in vitro model, high- and low-dose TMZ challenges induced a 6.3- and 3.4-fold decreased sensitivity to the growth inhibitory effect of TMZ. TMZ-induced changes in cell cycle phases were lower in TMZ-resistant cells than in vehicle-challenged cells. TMZ-resistant cells had higher Mgmt messenger RNA and protein expression and 1.8-fold higher number of Mgmt-positive cells. No difference was observed in the level of Mgmt promoter methylation. CONCLUSION/CONCLUSIONS:Corticotroph pituitary tumors demonstrate a high intertumoral and intratumoral heterogeneity in MGMT expression. In an acquired TMZ-resistant corticotroph pituitary tumor cell model, TMZ resistance was associated with strong increase in MGMT expression and percentage of MGMT-positive cells. We hypothesize that clonal selection of high MGMT-expressing cells is involved in this acquired TMZ resistance.

BACKGROUND/UNASSIGNED:Although technology usage is steadily increasing among older adults, adoption and confidence greatly lag behind their younger counterparts. Sociocultural and health disparities intersect with aging to present distinct structural and psychosocial barriers to the adoption of newer technologies. Digital health literacy interventions can improve task-specific skills, technological self-efficacy, and use frequency, but most do not systematically incorporate older adults' values and goals, which are key drivers of sustained behavior change. OBJECTIVE/UNASSIGNED:The proposed study aims to develop and evaluate the acceptability and feasibility of a person-directed, values-based, in-home digital literacy intervention for older adults, entitled values-informed solutions for technology adoption (VISTA). METHODS/UNASSIGNED:VISTA begins with a values and goals discussion rather than a skills test, mapping "What Matters Most" to individualized, SMART (specific, measurable, achievable, relevant, and time-bound) technology goals. Over 8 to 12 weeks, interventionists co-developed personalized learning plans with participants, delivering up to 6 in-home biweekly visits and interim phone calls. The study provided a tablet and assistance with obtaining home internet when needed. Outcomes included digital literacy (Mobile Device Proficiency Questionnaire), technology and chronic disease self-efficacy, social networks, multimorbidity, and frailty (Fried Frailty Phenotype). Feasibility was assessed via recruitment, retention or completion, data collection rates, survey administration time, withdrawal, intervention fidelity, and per-person cost; acceptability was assessed via a postintervention satisfaction survey (Likert and open-ended items) and willingness to recommend. RESULTS/UNASSIGNED:Funding was secured in November 2023. Institutional review board approval, intervention development, and focus groups were completed throughout 2024. Recruitment and baseline assessments occurred from January 2025 to July 2025, enrolling 21 participants and randomizing 11 to immediate intervention and 10 to waitlist control (waitlist participants received the intervention after a 3-month control period). One consented participant was unable to participate early in the intervention and is not included in analyses. Inclusion criteria included being aged 65 years and older, having English proficiency, and demonstrating a willingness to improve digital literacy. Exclusion criteria involved severe cognitive impairment. At baseline, participants had a mean age of 75.7 (SD 7.74) years and were predominantly female (n=13, 65%) and Black (n=19, 95%); most reported having a low income (10/12, 83%), living alone (12/14, 85.7%), and multimorbidity (mean disease count 3.95, SD 2.46). Follow-up assessments concluded in March 2026; data cleaning and analysis are ongoing, with primary feasibility and acceptability findings anticipated for fall 2026. CONCLUSIONS/UNASSIGNED:This protocol offers a unique model centering on the values and goals of older adults to improve access, use, and understanding of technology. Tapping into the motivators of older adults may provide a more beneficial way to encourage older adult technology use. VISTA could be useful in many general contexts, more specifically for older adults who are homebound or have serious illnesses, or as a preintervention for interventions involving advanced technology understanding.

Pediatric moderate aplastic anemia (MAA) lacks defined diagnostic criteria and a clear standard of care due to limited understanding of its pathophysiology and natural history. To understand current diagnostic and management practices for pediatric patients with MAA, a survey of the North American Pediatric Aplastic Anemia Consortium (NAPAAC) was conducted among 104 providers across 57 institutions. The survey results show that the approach to MAA remains inconsistent. The survey demonstrates broad variability regarding the working definition, diagnostic work-up, and therapeutic management of children with MAA. The diagnostic work-up and treatment options for children with MAA are largely driven by management guidelines for pediatric severe aplastic anemia (SAA). Treatment triggers and preferred therapy types varied widely among respondents. Curated next-generation sequencing panels and whole exome/whole genome sequencing were included by only 55% and 9% of respondents, respectively, suggesting the need to more broadly consider inherited bone marrow failure syndromes in the differential diagnosis of these patients. Based on the most commonly reported practices across NAPAAC institutions, we have included a proposed diagnostic and management algorithm in this manuscript. Effective, risk-adapted treatment for children with MAA requires a better understanding of the biology, natural history, and treatment outcomes in this heterogeneous population.

BACKGROUND:Global and national initiatives to combat tuberculosis (TB) have expanded over recent years. Despite this, the TB burden remains high in some population groups, with men recognized as having elevated TB risks. Summary measures of sex differences in TB prevalence were last estimated in 2016. Since then, many additional prevalence surveys have been conducted, including in the highest TB burden countries. We conducted a systematic review of sex-stratified TB prevalence survey data published over 1993-2025, to provide updated estimates of male-to-female (M:F) TB prevalence ratios and determine whether sex-related disparities in TB burden have closed over time. METHODS AND FINDINGS/RESULTS:We identified surveys reporting community-representative, sex-stratified estimates of pulmonary TB prevalence in low- and middle-income countries (LMICs), including surveys from an earlier review (covering January 1993-March 2016) and a new systematic review (covering 1st December 2015-13th October 2025). This review was prospectively registered with PROSPERO (CRD42024503853) and included searches of PubMed, Embase, Global Health, the Cochrane Library, Africa Index Medicus, LILACS, and SciELO. We extracted data on bacteriologically confirmed and smear-positive TB prevalence among adults (aged ≥ 15 years), stratified by sex. Risk of bias was evaluated using eight criteria specific to prevalence surveys. We fit multi-level Bayesian regression models with study- and country-level random effects to estimate the M:F ratio of TB prevalence (male prevalence divided by female prevalence), overall and for key subgroups. In meta-regression analyses, we estimated how prevalence ratios varied over time and according to known TB risk factors and TB case definitions. We identified 10,124 publications and extracted data from 100 eligible studies representing 102 unique prevalence surveys and 4,658,310 participants (45.6% male) in 33 LMICs. TB prevalence was higher in men than women in 90/102 of the included surveys, with a pooled M:F prevalence ratio of 2.02 (95% credible interval (CrI): 1.71, 2.34) for bacteriologically confirmed TB and 2.38 (95% CrI: 1.91, 2.90) for smear-positive TB. Time trend analyses showed a 2.0% (95% CrI: -0.2, 4.5%) average annual change in the M:F ratio of bacteriologically confirmed TB over the study period. The M:F prevalence ratio was estimated to be higher for countries with greater excess HIV prevalence among men, and countries with greater gender equity (as measured by the United Nation's Gender Development Index). The estimated M:F prevalence ratio was also higher for surveys that did not restrict testing to individuals reporting TB symptoms. Study limitations include heterogeneity in survey methods and definitions, as well as limited data from the Americas, Eastern Mediterranean, and Europe WHO world regions and post-COVID-19 period. CONCLUSIONS:Men in LMICs consistently experience TB at a higher prevalence than women. Time trend estimates are uncertain, but consistent with widening sex differences in TB prevalence over the last three decades, despite efforts to address the risk factors underlying this excess TB burden.

Patients with metastatic high-grade serous ovarian carcinoma are often unresponsive to immunotherapies; here we identify salt-inducible kinases (SIKs) as key drivers of immunosuppression. Human T cells in the presence of patient ascites express high levels of SIK and the upstream kinase LKB1, whereas SIK inhibition reprograms human T cells and strongly activates antitumor responses. In syngeneic mice with resistant high-grade serous ovarian carcinoma, genetic ablation and pharmaceutical inhibition of SIK consistently demonstrated therapeutic efficacy and survival advantages, and combination of PD-1 blockade with SIK inhibition further extended survival. We identified a major role of T cell-intrinsic SIK2 and -3 signaling in driving immunosuppression in part by TXNIP induction and LYST suppression. Multi-omics analyses on SIK inhibitor therapy revealed reduced disease progression, increased T cell infiltration with enhanced cytotoxicity and effector cytokine IFN-γ, and a shift from immunosuppressive to immunostimulatory cellular niche. We propose SIK inhibitors as a new immunotherapy.

Although the largest completely symmetric closed assembly that can be built from a single building block is the 60-subunit icosahedron¹, viruses can form capsid assemblies with hundreds to thousands of identical subunits through quasisymmetry-using the same subunit in symmetrically non-equivalent locations in the assembly^2-5. Quasisymmetric one-component assemblies could have considerable advantages for delivery of biologics because of the large internal volume achieved using only a single building block, but the design of these structures is challenging because of the inherent complexity of designing chemically identical subunits to both adopt different conformations and make different interactions in the distinct symmetrically non-equivalent locations. Here we conjectured that quasisymmetry could arise from spontaneous symmetry breaking in a system of strongly interacting building blocks with programmed curvatures and show that this principle, coupled with a design approach combining a parametric representation of cage architecture with RoseTTAFold diffusion generative modelling, can generate a rich array of quasisymmetric assemblies. Electron microscopy confirmed the structures of designed 3 ≤ T ≤ 36 cages with 180-2,160 subunits and diameters from 68 nm to 220 nm, and designed 1 < T < 3 non-icosahedral clathrin-like assemblies. Cryogenic electron microscopy structure determination showed how the global symmetry breaking associated with the formation of both hexons and pentons in the T = 3 architecture arises from symmetry breaking in the designed subunit interface. Our results indicate how the detailed architecture of complex systems can be controlled by designing overall system properties, and our approach provides a roadmap for designing large quasisymmetric assemblies for biologics delivery and other applications.

MAIN PURPOSE/OBJECTIVE:Endoscopic management offers acceptable oncologic control in select patients with upper tract urothelial carcinoma (UTUC) while preserving renal function. Adjuvant intracavitary treatment with chemotherapy or Bacillus Calmette-Guérin (BCG) has been proposed to reduce recurrence risk. We aimed to evaluate the impact of adjuvant intracavitary treatment on ipsilateral UTUC recurrence following endoscopic management. MATERIALS AND METHODS/METHODS:We queried a multi-institutional cohort of patients who underwent endoscopic management for UTUC. Treatment groups were defined as no instillation, single post-operative instillation, or multiple instillations. Ipsilateral UTUC recurrence-free survival (RFS) was estimated using Kaplan-Meier curves and Cox proportional hazards models evaluated factors associated with recurrence. RESULTS:A total of 599 renal units, of which 43 received single instillation and 86 multiple instillations, in 334 patients treated endoscopically for UTUC were analyzed. The median follow-up time for patients without recurrence was 12 months (IQR 4-33). Multiple adjuvant instillations of any intracavitary treatment were associated with a significantly improved RFS (HR 0.52, 95% CI 0.34-0.79), whereas a single instillation was not associated with a significant reduction in recurrence (HR 0.64, 95% CI 0.37-1.13). This association between multiple instillations and improved RFS remained significant after adjustment for clinical risk factors, including tumor grade (adjusted HR 0.36, 95% CI 0.16-0.81), and was confirmed in sensitivity analyses limited to patients with primary UTUC (HR 0.46, 95% CI 0.26-0.85). CONCLUSION/CONCLUSIONS:Multiple intracavitary instillations of BCG or chemotherapy after endoscopic management of UTUC were associated with longer ipsilateral RFS. These findings suggest a potential benefit of repeated instillations and warrant prospective validation.

BACKGROUND:Current guidelines recommend screening donor hearts for hypertrophy using solely left ventricular (LV) wall thickness measurements, but this does not capture the type of LV geometric remodeling. Remodeling patterns have been shown to be predictive of clinical outcomes in many cardiovascular diseases but have not been evaluated in donor heart assessment. OBJECTIVES/OBJECTIVE:The purpose of this study was to describe the prevalence and clinical impact of geometric remodeling patterns in brain-dead donor heart acceptance and recipient survival. METHODS:The DHS (Donor Heart Study) collected echocardiograms from brain-dead donors across the United States from February 2015 to May 2020. Donor hearts were classified by LV geometric remodeling patterns using ASE (American Society of Echocardiography) guidelines and were compared with LV wall thickness measurements of >1.3 cm for the association with transplant acceptance and 3-year recipient mortality, using multivariable modeling. RESULTS:Concentric remodeling (58.5%) was the most common geometric remodeling pattern in 3,647 brain dead donors. Donor hearts with increased LV wall thickness (>1.3 cm) were more likely reclassified as concentric remodeling (52.1%) than concentric hypertrophy (43.8%). Donors with nonacceptance surveys (n = 1,874) commonly (20.3%) had LV hypertrophy listed as a reason for rejection, but most of those hearts had normal geometry (10.8%) or concentric remodeling (60.0%). Neither increased LV wall thickness (adjusted HR [aHR]: 0.94; 95% CI: 0.73-1.21), concentric remodeling (aHR: 1.13; 95% CI: 0.86-1.47), nor concentric hypertrophy (aHR: 0.64; 95% CI: 0.35-1.15) correlated with 3-year recipient survival. CONCLUSIONS:Classifying donor hearts using LV geometric remodeling patterns may reduce the number turned down for "hypertrophy" without compromising recipient survival.