Publications by Year: 2026

OBJECTIVE: To assess trends in Step 2 CK score by ophthalmology residency match status, and to compare Step 2 CK scores by applicant sex and race and ethnicity.

DESIGN: This is a retrospective cohort study from 2021 to 2023. Applicants were stratified by match status and mean Step 2 CK score was compared between matched and unmatched applicants. Step 2 CK scores were also compared by applicant sex, race/ethnicity, type of medical school, and Alpha Omega Alpha selection. Chi-Squared tests, Kruskal-Wallis tests, and multivariate logistic models were used to assess for association of (1) Step 2 CK score and matching into ophthalmology residency, and (2) applicant characteristics and achieving above the national cohort average (>250) Step 2 CK score.

SETTING: The data is extracted from the San Francisco Match (SF Match).

PARTICIPANTS: Applicants who registered for the SF Match and submitted their application to at least 1 ophthalmology residency program from 2021 through 2023 were included.

RESULTS: Of 2367 total applicants in ophthalmology residency, 64.2% matched successfully. Overall mean Step 2 CK score was 255 for matched and 242 for unmatched applicants (p < 0.001). For each 10-point increase in Step 2 CK score, odds of matching in ophthalmology increased by approximately 63% (p < 0.001). White, Asian, and URiM applicants had mean scores of 252, 251, and 244, respectively (p < 0.001). Identifying as Asian, URiM, and female, and attending an osteopathic school were associated with lower odds of achieving a high Step 2 CK score (OR = 0.70, p = 0.011; OR = 0.32, p < 0.001; OR = 0.78, p = 0.042; OR = 0.31, p < 0.001; respectively).

CONCLUSIONS: Higher Step 2 CK score was associated with higher odds of matching in ophthalmology. Non-White and female students had lower odds of achieving an above average score. Future studies are necessary to determine the barriers that exist which put these applicants at a disadvantage with this standardized exam.

INTRODUCTION: This study investigated if high loop gain (HLG), a specific sleep apnea endotype characterized by unstable respiratory control, is independently associated with adverse cardiac remodeling.

METHODS: Using the Multi-Ethnic Study of Atherosclerosis (MESA) data, a HLG surrogate was quantified using a polysomnographic algorithm measuring respiratory self-similarity (Central Respiratory Event Index [CREI] and respiratory Self-Similarity [SS%]). Cardiac structure was assessed via MRI. Multivariable linear regression analyzed probable HLG associations with the left ventricular mass-to-volume ratio (LVMVR). Propensity score matching compared SS and CREI between participants with and without reduced left ventricular ejection fraction (LVEF).

RESULTS: Severe expressed HLG was defined as the top 2.5 % of CREI values, a criterion that categorized 35 of the 1440 participants, and showed higher LVMVR (1.23 ± 0.31 vs 1.03 ± 0.22, p < 0.001). After central sleep apnea (CSA) adjustment, severe expressed HLG remained an independent predictor for LVMVR (β = 0.110 ± 0.068, p = 0.002) with a significant sex interaction (p for interaction = 0.041), observed in males (β = 0.15 ± 0.09, p < 0.001) but not females. Reduced LVEF participants exhibited elevated SS% (11.41 ± 8.07 vs 8.13 ± 6.26, p = 0.037) and CREI (29.25 ± 19.50 vs 21.49 ± 19.86, p = 0.032). Post-PSM, differences persisted (SS%: 11.53 ± 8.26 vs 7.26 ± 7.07, p = 0 0.032; CREI: 28.96 ± 19.60 vs 18.15 ± 18.46, p = 0.041).

CONCLUSION: Expressed HLG may be an important biomarker for left ventricular modeling/HF progression and allow risk stratification for targeted management.

BACKGROUND: Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are 4-repeat tauopathies (4RT) presenting with overlapping syndromes. Imperfect clinicopathological associations increase sample-size demands in clinical trials. We test whether MRI can enrich trials for PSP/CBD and provide sensitive MRI-based outcome measures.

METHODS: Longitudinal cohort analysis including participants from the 4 Repeat Tauopathy Neuroimaging Initiative (4RTNI) and phase 2/3 Davunetide trial (DAV). An MRI model trained on autopsy-confirmed cases predicted PSP (MRI-PSP) or CBD (MRI-CBD); corticobasal syndrome (CBS) with positive Alzheimer's biomarkers was reclassified. Clinical scales and MRI-derived thickness/volume were analyzed with linear mixed-effects models. We derived data-driven MRI-signatures (optimal regional combinations) to minimize required trial sample sizes.

RESULTS: 206 participants from 4RTNI (n = 106 with Richardson's syndrome [RS], CBS, or nonfluent/agrammatic primary progressive aphasia [nfvPPA]) and DAV (n = 100 with RS). In 4RTNI, 49 participants were predicted MRI-PSP and 43 MRI-CBD. 76% of MRI-PSP had RS, 24% had CBS/nfvPPA; 66% of MRI-CBD had CBS. PSP and CBD signatures shared midbrain/pontine atrophy but differed in cortical involvement. PSP signature correlated strongly with 12-month change on the PSP Rating Scale (β = -0.59, p < 0.001). MRI-based signatures reduced the estimated sample sizes required to detect 30% reduction in progression over 12-months by 50% for MRI-PSP and 87% for MRI-CBD, compared with clinical outcomes. In DAV, feasibility was replicated.

CONCLUSION: MRI-derived models can identify PSP or CBD with high accuracy, and MRI-based signatures track progression more sensitively than established clinical outcomes. Incorporating these tools into therapeutic trial design could reduce sample sizes and enable more inclusive disease-modifying trials for 4RT.

IMPORTANCE: The prevalence of obesity and cardiovascular-kidney-metabolic (CKM) syndrome continues to rise. Indications for novel CKM therapies, including glucagonlike peptide 1 receptor agonists (GLP-1RAs), sodium-glucose cotransporter-2 inhibitors (SGLT2is), and nonsteroidal mineralocorticoid antagonists (nsMRAs) continue to expand, yet the proportion of adults meeting expanded indications, including for multiple medications remains unclear.

OBJECTIVE: To examine proportion of adults meeting US Food and Drug Administration (FDA)-approved indications for GLP1-RAs, SGLT2is, and nsMRAs across national survey, community-based, and ambulatory health care samples.

DESIGN, SETTING, AND PARTICIPANTS: This study used a representative cross-sectional survey of US adults (National Health and Nutrition Examination Survey [NHANES], weighted 245 million; mean [SD] age, 47 [18] years; 126.8 million [52%] female), 5 pooled community-based cohort studies (the Framingham Heart Study, the Multi-Ethnic Study of Atherosclerosis, the Prevention of Renal and Vascular Endstage Disease Study, the Atherosclerosis Risk in Communities Study, and the Cardiovascular Health Study; n = 30 929; mean [SD] age, 63 [14] years; 16 749 [54%] female), and 2 ambulatory health care samples (the Beth Israel Deaconess Medical Center cohort [BIDMC], n = 84 714; mean [SD] age, 46 [17] years; 51 113 [60%] female] and the Mass General Brigham cohort [MGB], n = 362 485; mean [SD] age, 48 [17] years; 227 206 [61%] female). Data were analyzed from November 2024 to November 2025.

EXPOSURES: FDA-approved indications for GLP-1RAs, SGLT2is, and nsMRAs.

MAIN OUTCOMES AND MEASURES: Medication class eligibility within each study sample.

RESULTS: The proportion of individuals who met current FDA-approved indications for 1 or more CKM medication was 60% in NHANES (representing 148 million US adults), 61% in the pooled cohorts, 42% in the BIDMC ambulatory cohort, and 46% in the MGB ambulatory cohort. Eligibility for GLP-1RA therapy was most common, with 56% (representing 137.1 million US adults) in NHANES, 49% in the pooled cohorts, 41% in the BIDMC cohort, and 46% in the MGB cohort. This was followed by SGLT2i therapy (24% [57.9 million] in NHANES, 33% in the pooled cohorts, 14% for both BIDMC and MGB) and nsMRA (5% [11.7 million] in NHANES, 5% in the pooled cohorts, and 1% to 2% in ambulatory samples). Overlapping eligibility for multiple classes was common, with 12% to 17% for GLP1-RA and SGLT2i therapies and 1% to 5% for all 3 classes (an estimated 11.7 million US adults in NHANES).

CONCLUSIONS AND RELEVANCE: This study found that up to 61% of adults met FDA-approved indications for at least 1 of 3 novel CKM therapy classes. This represents an estimated 148 million US adults, including 11.7 million US adults with potential FDA indications for triple therapy, highlighting the urgent need to optimize implementation and utilization of CKM syndrome therapies.

IMPORTANCE: Platelet transfusions are critical interventions for neonates and children who are at risk of or who are experiencing bleeding.

OBJECTIVE: To describe the epidemiology of platelet transfusions and associations of blood donor and platelet characteristics with posttransfusion platelet increments, transfusion burden, and clinical outcomes in neonates and children.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study included patients younger than 18 years of age (with birth weights higher than 2500 g) between April 1, 2019, and June 30, 2023, from the Recipient Epidemiology and Donor Evaluation Study-IV-Pediatric Vein-to-Vein multicenter, retrospective, donor-component-recipient-linked database. Neonates were considered individuals less than 28 days of age; otherwise, participants were considered older children.

EXPOSURE: Platelet transfusion.

MAIN OUTCOME AND MEASURES: The main outcomes were posttransfusion platelet increments and subsequent transfusion burden associated with platelet processing and donor characteristics.

RESULTS: Of 249 340 inpatient encounters, platelet transfusion was reported in 8874 (3.6%) patients (4934 of 131 592 encounters [3.7%] male; median [IQR] age 2.5 [0.6-11.2] years). Platelet transfusion was lowest among children younger than 1 year of age (2.6%) and highest among children 1 to less than 6 years of age (4.7%; P < .001). The median (IQR) dose was 14.9 mL/kg for neonates and 9.6 mL/kg for older children. After excluding patients with bleeding, most transfusions in neonates (67.8%) and older children (81.0%) were performed at pretransfusion platelet counts greater than 25 × 103/µL and greater than 10 × 103/µL, respectively. Median (IQR) pretransfusion platelet counts in neonates (34 × 103/µL [20-54 × 103/µL]) were significantly higher than in older children (22 × 103/µL [11-40 × 103/µL]; P < .001). Pathogen reduction (PR) (adjusted odds ratio [AOR], 0.82 [95% CI, 0.73-0.92]), use of platelet additive solution (PAS) (AOR, 0.32 [95% CI, 0.27-0.37]), platelet storage duration longer than 3 days (AORs ranged from 0.67 [95% CI, 0.58-0.76] to 0.82 [95% CI, 0.76-0.88]), male sex (AOR, 0.92 [95% CI, 0.86-0.98]), and donor age 40 years or older (AOR, 0.79 [95% CI, 0.72-0.86]) were associated with lower platelet increments (all P < .001). Use of PR platelets (adjusted rate ratio [ARR], 1.05 [95% CI, 1.02-1.07), use of PAS (ARR, 1.44 [95% CI, 1.40-1.47]), storage duration longer than 3 days (ARR, 1.11 [95% CI, 1.09-1.13] for 4 to <5 days and ARR, 1.28 [95% CI, 1.26-1.30] for ≥5 days), and donor age of 40 years or older (ARR, 1.15 [95% CI, 1.13-1.17] for 40 to <60 years and ARR, 1.10 [95% CI, 1.08-1.12] for ≥60 years) on the first transfusion were associated with a significantly higher rate of receiving a subsequent transfusion. These factors were not associated with hospital length of stay or mortality.

CONCLUSIONS AND RELEVANCE: In this multicenter, donor-product-recipient linked cohort study, after excluding patients with bleeding, most transfusions among neonates and older children were at high pretransfusion platelet counts. Use of PAS, PR, longer storage duration, male donors, and donor age older than 40 years were independently associated with lower posttransfusion platelet increments. Use of PAS, PR, platelet storage longer than 3 days, and donor age 40 years or older were associated with a significantly higher overall platelet transfusion burden but were not associated with hospital length of stay or mortality. These results have important implications for transfusion practices for platelets among neonates and children and need validation in well-designed prospective studies.

IMPORTANCE: Reliable early response biomarkers for overall survival (OS) are lacking for patients receiving immune checkpoint inhibitor (ICI) therapy for advanced non-small cell lung cancer (NSCLC). Existing imaging-based measures, such as Response Evaluation Criteria in Solid Tumors (RECIST) and tumor volume change (TVC), have limited predictive value for long-term outcomes, and advanced imaging-based biomarkers may enhance decision-making in clinical practice and clinical trials.

OBJECTIVE: To develop and validate a fully automated deep-learning imaging-based biomarker using pretherapy and 12-week follow-up computed tomography (CT) scans.

DESIGN, SETTING, AND PARTICIPANTS: This prognostic study used retrospectively collected HER data from routine clinical practice (RCP) and clinical trial data from 2013 to 2023. A model using serial CT scans, Serial CT response score (Serial CTRS) was developed using a RCP discovery dataset, validated with 10 US and European institution RCP test datasets, and independently validated on a multinational clinical phase 1 trial of dostarlimab (GARNET). Participants were adults with advanced NSCLC starting ICIs in the period from 2013 to 2021 (RCP discovery), from 2013 to 2022 (RCP test), or from 2017 to 2018 (GARNET).

INTERVENTIONS: ICI monotherapy or combination therapy in the first-line or later-line setting.

MAIN OUTCOMES AND MEASURES: Cox proportional hazards regression and receiver operating characteristic-area under the curve modeled associations between Serial CTRS and OS.

RESULTS: The study included 1830 patients (RCP discovery, 1171 patients; RCP test, 605 patients; GARNET, 54 patients) with a median (IQR) age of 67 (19-95) years; 1000 participants were male (55%), and 830 were female (45%). Serial CTRS was associated with OS in multivariable analysis controlling for age, sex, programmed death-ligand 1 expression, histologic profile, and tumor volume (hazard ratio [HR] for 10%-point higher probability of 12-month OS, 0.74 [95% CI, 0.70-0.79] for RCP test; 0.45 [95% CI, 0.32-0.65] for GARNET). Serial CTRS outperformed RECIST and TVC in OS risk discrimination, with higher HRs distinguishing low-survival and high-survival groups in RCP test (HR, 6.19; 95% CI, 4.12-9.28) and GARNET (HR, 18.00; 95% CI, 5.40-59.97). Predictive value persisted across programmed death-ligand 1 and RECIST subgroups, including stable disease.

CONCLUSIONS AND RELEVANCE: In this prognostic study of patients with advanced NSCLC receiving ICI treatment, the fully automated biomarker Serial CTRS predicted OS more effectively than resource-intensive RECIST and TVC measurements using the same scans.

IMPORTANCE: The associations of adverse childhood experiences (ACEs) and adverse adulthood experiences (AAEs) with incident dementia and stroke in the Chinese population are not well understood.

OBJECTIVES: To investigate the associations of ACEs and AAEs with dementia and stroke incidence, and to examine whether depression mediates these associations.

DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study utilized data from the China Health and Retirement Longitudinal Study (June 2015 to December 2020). Participants aged 45 years and older with complete adverse experience data were included and were followed up for a mean (SD) of 4.89 (0.48) years for dementia and 4.84 (0.57) years for stroke. Statistical analysis was performed from August 20, 2025, to November 23, 2025.

EXPOSURES: ACEs and AAEs were assessed through a structured questionnaire, with cumulative scores calculated for both categories.

MAIN OUTCOMES AND MEASURES: Dementia was identified using a standardized cognitive battery and activities of daily living scale, while stroke was determined through self-reported physician diagnosis. Depression was evaluated using the 10-item Centre for Epidemiologic Studies Depression Scale. Cox proportional hazards regression analysis was used to explore the association of ACEs and AAEs with the risk of new-onset dementia and stroke, with results presented as hazard ratios (HRs) with 95% CIs.

RESULTS: Among 11 601 participants (mean [SD] age, 59.18 [9.41] years; 5569 male [48.0%]), 9145 (78.8%) were exposed to at least 1 ACE indicator, 4241 (36.6%) to at least 1 AAE indicator, and 3531 (30.4%) to both ACE and AAE markers. Both ACEs (HR, 1.11; 95% CI, 1.05-1.18) and AAEs (HR, 1.23; 95% CI, 1.14-1.33) were significantly associated with higher hazards of dementia during follow-up, whereas only AAEs were associated with higher hazards of stroke (HR, 1.19; 95% CI, 1.12-1.26). Latent class analysis identified a high-risk ACEs subgroup associated with incident stroke (HR, 1.33; 95% CI, 1.08-1.65). In the joint effects analyses, participants in the high-risk groups for both ACEs and AAEs exhibited higher hazards of dementia (HR, 3.28; 95% CI, 1.54-7.02) and stroke (HR, 2.50; 95% CI, 1.24-5.30). Depression mediated 34.3% of the association of ACEs with dementia (β = 0.10; 95% CI, 0.04-0.17), 20.9% of the association of AAEs with dementia (β = 0.22; 95% CI, 0.13-0.30), and 17.5% of the association of AAEs with stroke (β = 0.18; 95% CI, 0.11-0.24).

CONCLUSIONS AND RELEVANCE: In this cohort study, exposure to adverse experiences throughout life was associated with increased risks of dementia and stroke, with depression mediating these associations. These findings highlight the importance of implementing life-course interventions that address both psychological trauma and mental health to reduce the burden of neurovascular diseases.

BACKGROUND: Individuals with an evening chronotype often experience circadian misalignment, which may disrupt health behaviors and cardiometabolic functions.

METHODS: We conducted a prospective study in 322 777 UK Biobank participants aged 39 to 74 years free of known cardiovascular disease (CVD). Chronotype was self-reported using a single representative question. The Life's Essential 8 (LE8) score was calculated from 8 CVD risk factors and ranged from 0 to 100 with higher scores indicating better cardiovascular health. Incident CVD was defined as first myocardial infarction or stroke. Cox proportional hazards models estimated the association between chronotype and CVD risk, adjusted for sociodemographics, shift work, and family history of CVD. We evaluated the role of LE8 in the chronotype-CVD association by decomposing the total effect into natural direct effect (independent of LE8) and natural indirect effect (mediated by LE8).

RESULTS: Participants with a "definite evening" chronotype were associated with 79% higher prevalence of an overall poor LE8 score (<50 points) compared with "intermediate" type (95% CI, 1.72-1.85). Over a median 13.8 years of follow-up, there were 17 584 incident CVD events (11 091 myocardial infarction; 7214 stroke). The hazard ratio (HR) for total CVD was 1.03 (95% CI, 0.998-1.07) for the "definite morning" and 1.16 (95% CI, 1.10-1.22) for "definite evening" compared with "intermediate" chronotype (P-trend: 0.10). LE8 explained 75% of the association between evening chronotype and CVD (natural indirect effect comparing "definite evening" with "intermediate": HR, 1.11 [95% CI, 1.09-1.13]).

CONCLUSIONS: Our findings suggest that individuals with an evening chronotype may particularly benefit from interventions targeting CVD risk factors.

Objective: To examine regional differences in cannabis use and probable cannabis use disorder (CUD) in US veterans. Methods: Participants (N = 2,441) were drawn from a nationally representative sample of US veterans who participated in the 2022 National Health and Resilience in Veterans Study, conducted from August 11 to September 12, 2022. Weighted estimates indicated that 85.5% reported no cannabis use, 11.6% reported cannabis use, and 2.9% screened positive for probable CUD. Chi-square tests were conducted to assess differences in cannabis use and probable CUD across 9 US Census Bureau-defined regions: New England, Middle Atlantic, East and West North Central, South Atlantic, East and West South Central, Mountain, and Pacific. Results: Significant regional differences were observed in cannabis use and CUD across the 9 regions (χ216 = 73.33, P < .001). Veterans in the Pacific region exhibited the highest rates of cannabis use (18.6%) compared to all other regions except New England (8.2%-13.4%, Ps < .05). The Pacific region also had significantly higher rates of probable CUD (8.8%) relative to all other regions (0.7%-3.5%, Ps < .05). Conclusion: These findings demonstrate substantial regional differences in cannabis use and probable CUD among US veterans and underscore the importance of routine screening for cannabis-related problems in health care settings serving veterans, particularly in higher-prevalence regions of the United States.