Publications by Year: 2025

OBJECTIVE: Antiseizure medications are approved based on clinical trials that demonstrate their efficacy as measured by reductions in seizure frequency (SF). When designing these trials, trialists must select inclusion criteria where SF can be reliably measured to maintain statistical power. Statistical power is based on the magnitude and uncertainty of the difference between active treatment and placebo. To inform choices about how minimum, maximum, and individual participant SF impacts the statistical power of trials, we evaluated how the uncertainty in SF was associated with average SF within multiple clinical trials.

METHODS: Using data from 11 double-blind placebo-controlled trials of antiseizure medications for either focal or generalized onset epilepsy, we used log-log multivariable regression to associate the SD of SF in maintenance with the average SF in baseline and maintenance. We also evaluated whether capturing more seizures in people with high average SF offset the increased uncertainty in SF and asked whether these associations persisted when time to event designs were used.

RESULTS: The uncertainty (SD) of maintenance SF was proportional to baseline average SF (daily diaries: slope of log-log association = .575, 95% confidence interval [CI] = .556-.593; fortnightly diaries: .657, 95% CI = .0642-.0671). Increased uncertainty for high SF was offset by counting more seizures. These relationships were maintained with a time to event design.

SIGNIFICANCE: This study validates the foundational L-relationship between average and SD of SF in which the uncertainty of seizure counts increased proportional to the number of seizures counted. When used for efficacy outcomes of trials, the statistical benefit of counting more seizures in participants with high SF was much greater than the increased challenge from higher uncertainty seizure counts. These results provide quantitative insights for SF-based inclusion criteria and statistical power calculations.

Explosive weapons used in densely populated settings often disproportionately injure craniofacial nerves and lead to otologic trauma. During the Israeli military invasion of Gaza, the collapse of referral pathways and surgical capacity constrained otologic and craniofacial care. The authors aimed to characterize otologic trauma and facial nerve palsy, and to identify predictors of hearing loss severity in this context. The authors conducted a retrospective cohort study of civilians with conflict-related otologic trauma presented to the Nasser Medical Complex in Palestine's Khan Yunis, Gaza Strip, between May 6 and July 6, 2025. Demographic, clinical, audiometric, and radiologic data were abstracted from clinical records. Among 110 patients (median age 30 y; 80% male), blast mechanisms accounted for ∼80% of injuries, and bilateral ear involvement was frequent. Facial palsy was documented in 10.9% of patients. Tympanic membrane (TM) pathology, ranging from small to subtotal perforations and hemotympanum, was common and showed a graded association with both conductive and sensorineural loss in unadjusted and adjusted models. Older age and longer time from injury independently predicted greater sensorineural severity, while facial palsy co-occurred with more severe left-sided losses. No patients underwent nerve exploration or repair.

CD8+ tissue-resident memory T cells (TRM) develop from effectors that seed peripheral tissues where they persist providing defense against subsequent challenges. TRM persistence requires autocrine TGFβ transactivated by integrins expressed on keratinocytes. TRM precursors that encounter antigen in the epidermis during development outcompete bystander TRM for TGFβ resulting in enhanced persistence. ScRNA-seq analysis of epidermal TRM revealed that local antigen experience in the skin resulted in an enhanced differentiation signature in comparison with bystanders. Upon recall, TRM displayed greater proliferation dictated by affinity of antigen experienced during epidermal development. Finally, local antigen experienced TRM differentially expressed TGFβRIII, which increases avidity of the TGFβRI/II receptor complex for TGFβ. Selective ablation of Tgfbr3 reduced local antigen experienced TRM capacity to persist, rendering them phenotypically like bystander TRM. Thus, antigen-driven TCR signaling in the epidermis during TRM differentiation results in a lower TGFβ requirement for persistence and increased proliferative capacity that together enhance epidermal TRM fitness.

There is limited information about long-term outcomes following severe acquired brain injury (ABI). This is due, in part, to the lack of validated longitudinal assessment measures that can be administered remotely. To address this gap, we developed a caregiver-administered telephone interview designed for the remote evaluation of the functional status of patients who are too impaired to provide reliable self-report. The interview comprises items drawn from three existing standardized instruments: the Coma Recovery Scale-Revised (CRS-R), Cognitive Impairment subscale of the Confusion Assessment Protocol (CAP-Cog), and Galveston Orientation and Amnesia Test (GOAT) (subsequently referred to as the CRS-RT, CAP-CogT, and GOAT-T to reflect telephone administration). The CRS-RT items evaluate the level of consciousness, while the CAP-CogT and GOAT-T items assess basic aspects of cognition. We administered the caregiver interview to 48 caregivers of persons with severe acquired disability (i.e., vegetative state to confusional state) and validated caregiver responses by conducting in-person patient examinations using the original versions of the assessment instruments. To establish the concurrent validity of the caregiver interview, we assessed the correlation between the findings from the caregiver interview and the patient examination, using Lin's concordance correlation coefficient (CCC). The mean (standard error) sensitivity, specificity, and accuracy across both sets of interview items were 0.82 (0.03), 0.68 (0.04), and 0.75 (0.03), respectively. Lin's CCC between caregiver responses to the nine interview items addressing the level of consciousness and the corresponding patient examination findings was 0.78 (95% confidence interval [CI]: 0.65, 0.90), with six items exceeding our a priori cut-off of ≥0.70. However, the correlation between caregiver responses to the eight basic cognition items and the patient examination findings was poor (Lin's CCC = 0.37, 95% CI: -0.09, 0.82), with only three items at or above the cut-off. These results indicate that the CRS-RT can be administered remotely to caregivers of persons with severe ABI-related disability to monitor neurobehavioral status longitudinally. The CAP-CogT and GOAT-T items require further study before they can be used for clinical outcome assessment.

IMPORTANCE: The treatment landscape for hepatocellular carcinoma (HCC) is rapidly evolving, with the approval of multiple systemic therapies for patients with advanced disease since 2017. However, ideal treatment sequencing approaches remain unknown, and data on clinical practice patterns are limited.

OBJECTIVE: To evaluate current treatment patterns, sequencing, and survival outcomes among patients receiving systemic therapy for HCC.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study used data from a nationwide electronic health record (EHR)-derived database of more than 280 oncology practices at more than 800 US cancer clinics to assess adult patients who were treated with systemic therapy for HCC from January 1, 2011, to December 31, 2023.

EXPOSURE: First-line systemic therapy type.

MAIN OUTCOMES AND MEASURES: Overall survival (OS) was defined as the time from first-line systemic therapy initiation to death, last clinical activity, or the censor date of December 31, 2023. Progression-free survival (PFS) was defined as the time from first-line systemic therapy initiation to the earliest of EHR-documented disease progression, death, last clinical encounter, or the censor date.

RESULTS: Among 4198 patients (median [IQR] age, 67 [61-74] years; 3353 [79.9%] male), sorafenib was the most common first-line systemic therapy until it was overtaken by atezolizumab-bevacizumab in 2020; durvalumab-tremelimumab also became a common first-line therapy in 2023. Of the full study cohort, 871 (20.7%) received second-line therapy. Median OS was 8.1 months (95% CI, 7.7-8.6 months) but was not significantly associated with first-line systemic therapy type. Median PFS was 3.9 months (95% CI, 3.7-4.0 months); first-line atezolizumab-bevacizumab (hazard ratio, 0.84; 95% CI, 0.71-0.99) was associated with improved PFS compared with sorafenib.

CONCLUSIONS AND RELEVANCE: In this cohort study of patients treated with systemic therapy for HCC between 2011 and 2023, atezolizumab-bevacizumab and durvalumab-tremelimumab emerged as the most common first-line systemic therapies administered for HCC, but relatively few patients received second-line therapy. Additional research is needed to determine optimal treatment sequencing and increase the likelihood that patients may benefit from second-line systemic therapy options.

BACKGROUND: Efforts to advance health equity are essential in providing high-quality healthcare. The outpatient setting is where the majority of health equity work has been supported with longitudinal relationships, established metrics, and existing dashboards; similar work in the inpatient setting is lacking.

OBJECTIVES: To understand the perspectives of frontline hospitalists regarding how health equity is approached and measured in the inpatient setting.

METHODS: We conducted an embedded mixed-methods study using semistructured focus groups and surveys. Participants were members of a national collaborative of hospital medicine groups partnering to improve healthcare delivery. Rapid qualitative methods including templated summaries and matrix analysis were used to identify key themes and subthemes using a mixed inductive and deductive approach.

RESULTS: Twenty-two participants engaged in five focus groups. Three key themes were identified: (1) there is no consensus on how to define and scope health equity in the inpatient setting, (2) organizational support and resources for addressing health equity in inpatient settings are variable, and (3) there is an emotional toll on hospitalists working in the face of health inequities.

CONCLUSIONS: Advancing health equity in the inpatient setting is needed and will benefit from embracing clear definitions and scope, broad organizational support, and recognition of its impact on hospitalists.

Genetic interactions play a crucial role in elucidating the susceptibility and etiology of complex multifactorial diseases. Despite significant efforts to identify disease-associated nonlinear effects in genome-wide association studies, efficient methods for detecting the epistatic impact of rare variants remain lacking. In this study, we proposed iRUNNER, a novel and powerful mutation burden test focused on analyzing the interaction effects of rare variants on a binary trait. Different from conventional association tests comparing cases with controls, iRUNNER evaluates the relative enrichment of rare variant interaction burden of pairwise genes in patients against its baseline, estimated by a recursive truncated negative-binomial regression model that leverages multiple genomic features from public databases. Extensive simulations demonstrated that iRUNNER outperforms existing epistasis tests in statistical power and maintains reasonable type I error rates even when population stratification exists in control samples. Applied to real datasets of five complex diseases, iRUNNER yielded substantial gains in gene-gene interaction detections. Notably, the majority of these signals were missed by alternative methods, especially in small to medium-sized samples. Furthermore, we found that these identified gene pairs of each trait can form interconnected networks, which may provide valuable insights into the underlying molecular mechanisms. We have implemented iRUNNER as a module in our integrative platform KGGSeq (http://pmglab.top/kggseq/) that enables rapid testing of pairwise interactions among all possible non-synonymous rare coding variants within hours.