University of Washington Medical Center

RET fusions appear in 1%-2% of non-small cell lung cancers (NSCLCs). The results from the ARROW study (ClinicalTrials.gov identifier: NCT03037385) supported US Food and Drug Administration approval of pralsetinib, an oral selective RET inhibitor, for metastatic RET-altered NSCLC and RET fusion-positive thyroid cancers. ARROW was a phase I/II open-label study of pralsetinib 400 mg once daily in RET fusion-positive NSCLCs. Coprimary end points were overall response rate (ORR) and safety. Key secondary end points included duration of response, progression-free survival, and overall survival (OS). At data lock (May 20, 2024), 281 patients initiated pralsetinib (median treatment duration, 15.0 months). ORR (measurable disease patients; n = 259) was 78% (95% CI, 69 to 86) for treatment-naïve patients and 63% (95% CI, 54 to 71) for prior platinum-based chemotherapy patients. Median OS was 44.3 months (95% CI, 30.9 to 53.1), 50.1 months (95% CI, 28.3 to not reached) in treatment-naïve patients, and 39.7 months (95% CI, 27.8 to 53.2) in prior platinum patients. Common grade ≥3 treatment-related adverse events were anemia (21%), hypertension (15%), and decreased neutrophils (13%). Three treatment-related deaths occurred (pneumonia, n = 2; interstitial lung disease and rhabdomyolysis, n = 1 each). Safety was consistent with previous ARROW reports; no hypersensitivity was reported in patients receiving prior immunotherapies. Pralsetinib produced robust, durable responses with manageable safety in treatment-naïve and previously treated patients with RET fusion-positive NSCLCs, confirming previous findings with longer follow-up.

Curve progression to surgical range in patients with adolescent idiopathic scoliosis (AIS) is strongly associated with the initial major curve angle and the degree of skeletal maturity as staged by the modified Proximal Humerus Ossification System (PHOS) and other systems. Our purpose was to (1) develop a prognostic model and risk score to estimate the probability of progression to surgical indications in untreated patients using the PHOS and (2) compare its performance to a model using the Risser stage. Patients from the BrAIST study and 2 other institutions were followed to either skeletal maturity (Risser 4+), a major curve angle of ≥45°, or spinal fusion. Candidate variables for the predictive models included age, sex, major curve angle, Scoliosis Research Society (SRS) curve classification, status of triradiate cartilage, Risser stage, and PHOS. Model calibration and discrimination were evaluated. A probability threshold was set, creating low- and high-risk groups to aid in clinical decision-making. Overall, 164 patients (77% female) were included. The mean age at presentation was 12.2±1.4 years (range: 10 to 16 years), and the mean maximum major curve angle was 24±9° (range: 10° to 43°). Fifty-six (34%) patients progressed to a surgical range or had a spinal fusion. The PHOS model included the major curve angle and the presence/absence of a thoracic apex. The model demonstrated strong discrimination (c-statistic = 0.89) and calibration (ICI = 0.02), performing similarly to one developed in this sample using the Risser stage. The sensitivity was 0.91, the specificity was 0.71, the PPV was 0.62, and the NPV was 0.94 at the probability cut-point of 0.22. This study derived a prognostic model estimating the baseline risk of progression to surgical indications in AIS patients using the PHOS. Estimates from this model can inform the shared decision-making process and motivate compliant bracing. Further validation in larger independent samples and exploration of the PHOS to predict bracing outcomes should be performed. Level II.

BackgroundIn silico evaluation (ISE) methods create a digital twin or a computer simulation of actual care pathways, enabling a broader assessment of the potential impact of algorithm-based clinical decision support systems (CDSS) before implementation. A programmatic search of several academic research databases showed at least 886 CDSS development and evaluation studies in the past 3 decades. However, fewer than 3% applied ISE to evaluate the potential impact on broader clinical care pathways.ObjectiveThis study aims to review the scope of proposed ISE methods to evaluate CDSS, with a focus on simulation modeling approaches, care pathway parameters considered, and outcomes evaluated within the ISE methodological domain.MethodsThis review followed the established scoping review methodological guidelines. We conceptualized a tailored search framework and conducted a 2-stage screening process on studies identified through automated searches of selected databases. Relevant information on CDSS study characteristics and the application of care pathway simulation modeling in CDSS evaluation was subsequently extracted.ResultsA small subset of studies on CDSS development conducted ISE. Most ISE studies were published after 2019, reflecting a more recent increase in the application of ISE. These studies frequently emphasized patient, process, and cost-effectiveness outcomes. Notably, the evaluation of outcomes directly related to care providers’ well-being is lacking, highlighting a critical gap in current ISE applications. Among the studies included in this review, various simulation modeling paradigms were used, including dynamic simulations and state-based models. Three themes were found among the different motivations and objectives for using ISE: (1) outcome comparison, (2) outcome comparison with sensitivity analysis, and (3) simulation-based optimization of the proposed CDSS. The first two approaches considered a decoupled CDSS model training followed by simulation-based evaluation of the trained CDSS model. The third approach iteratively improved the CDSS model’s decision-support capabilities through optimization based on care pathway simulations. These approaches can be broadly categorized as decoupled (1 and 2), where CDSS models are evaluated within seperately designed clinical workflow simulations, and integrated (3), where simulation iteratively optimizes CDSS performance.ConclusionsThe growing body of algorithm-based CDSS research underscores the need for evaluation approaches that are resource-efficient and account for systems-level workflow implications. This review highlights both the gaps and the potential of ISE, particularly care pathway simulation-based approaches, as a preimplementation strategy to strengthen evidence before significant resource allocations to pilot or full-scale implementations. ISE presents as a promising intermediary evaluation approach that bridges model-level performance and clinical workflow impact, allowing more contextualized and resource-efficient assessments prior to implementation.

Accurate clinical documentation is essential for safe, effective patient care. AI tools powered by automatic speech recognition can streamline this process. Variable performance across speakers with diverse accents leads to transcription errors and clinical risk. In testing Whisper and WhisperX on native and non-native English clinical speech, error rates were significantly higher for non-native speakers. Post-processing with GPT-4o restored lost accuracy. This chained approach (WhisperX-GPT) reduced accent-related errors.

Understanding how alcohol-use-disorder (AUD) symptoms unfold in daily life is key to improving assessment and intervention. In this study, we examined the retrospective and prospective validity of repeated daily assessments of AUD symptoms compared with retrospective self-reports. A community sample of young adults ( N = 496) completed daily reports over an 8-week period assessing a subset of AUD symptoms: hazardous use, social/occupational problems, failure to fulfill obligations, craving, tolerance, larger/longer consumption, and time spent obtaining/using alcohol. Retrospective self-reports were collected at baseline and 6-month follow-up. Several symptoms (e.g., hazardous use, social/occupational problems, time spent) showed strong convergence between daily and baseline reports, and others (e.g., craving, tolerance) showed weaker associations. Daily symptom totals predicted 6-month retrospective AUD severity, particularly for symptoms with greater convergence. Daily measures of total AUD symptoms were associated with both baseline and follow-up AUD severity. Findings support the value of daily assessment and underscore discrepancies in retrospective recall.

BackgroundTecovirimat is approved for smallpox treatment under the Food and Drug Administration Animal Rule on the basis of efficacy in nonhuman primate models of mpox (previously known as monkeypox). However, the clinical efficacy of tecovirimat against human clade II mpox is unclear.MethodsIn a phase 3, international, double-blind, randomized, placebo-controlled trial, we evaluated the efficacy of oral tecovirimat in adults with laboratory-confirmed clade II mpox. Participants were randomly assigned in a 2:1 ratio to receive tecovirimat or placebo for 14 days. The primary outcome was clinical resolution, assessed in a time-to-event analysis in participants with active skin or mucosal lesions. Secondary outcomes included reduction in pain, assessed in all participants with laboratory-confirmed mpox and in those with severe pain at baseline (pain score, 7 to 10; scale, 0 [no pain] to 10 [worst pain imaginable]); complete lesion healing (assessed in a time-to-event analysis); viral DNA clearance; and safety.ResultsOf 412 participants who underwent randomization (275 to tecovirimat and 137 to placebo), 344 had laboratory-confirmed mpox, and 336 had active skin or mucosal lesions and were included in the primary analysis. By day 29, the estimated cumulative incidence of clinical resolution was 83% with tecovirimat and 84% with placebo; the competing-risks hazard ratio for clinical resolution was 0.98 (95% confidence interval [CI], 0.74 to 1.31; P=0.89). No substantial between-group differences were seen in pain reduction among participants with severe pain (difference, 0.1 point; 95% CI, −0.8 to 1.0), in complete lesion healing (competing-risks hazard ratio, 0.97; 95% CI, 0.75 to 1.26), or in viral DNA clearance. The incidence of adverse events of grade 3 or higher was similar in the two groups (4% with tecovirimat and 3% with placebo).ConclusionsThis trial showed no evidence that tecovirimat therapy shortened the time to clinical resolution, reduced pain, or increased viral clearance among adults with clade II mpox. (Funded by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health; STOMP/A5418 ClinicalTrials.gov number, NCT05534984.)

Gene editing strategies that do not rely on viral vectors are being explored for their potential to support durable biologics production. While clinical trials have shown that adeno-associated virus encoding broadly neutralizing antibodies can protect against HIV, these interventions often yield limited, short-lived responses. The development of non-viral gene editing approaches in hematopoietic stem and progenitor cells holds promise for long-term antibody production. In this study, we evaluated CRISPR/Cas9 and CRISPR/Cas12a for gene knock-in at the immunoglobulin heavy chain locus in non-human primate (NHP) hematopoietic stem and progenitor cells (HSPCs). Delivering the nuclease as a protein alongside a custom DNA template, we optimized editing with Cas12a and demonstrated higher knock-in efficiency and fewer non-specific edits than Cas9. Transplantation of edited NHP HSPCs into MISTRG mice led to engraftment, B cell differentiation, and transgene expression of a reporter transgene or anti-HIV antibody after gp120 antigen immunization with detectable titers in circulation. These findings demonstrate the feasibility of using non-viral knock-in in HSPCs as a potential strategy for sustained biologics production in the treatment of chronic diseases. Future work will assess the efficacy of this approach in a NHP model of HIV infection.