Citations

Background and Hypothesis Clozapine is an effective yet underutilized treatment for treatment‐resistant schizophrenia spectrum disorders. This study aimed to identify factors affecting clozapine prescribing patterns among patients with treatment‐resistant schizophrenia and schizoaffective disorder at an academic medical center. Study Design This retrospective combined cohort and case‐control study examined demographic, socioeconomic, medical and psychiatric characteristics to determine predictors of clozapine initiation. Eligible patients had a diagnosis of schizophrenia or schizoaffective disorder with at least two prior antipsychotic trials and were admitted to a University of Utah inpatient psychiatric facility (1/2014–3/2021). Patients who did and did not receive clozapine during the index hospitalization were compared in cohort and case‐control study arms. Study Results Twelve percent (59/477) of the cohort received clozapine during the index admission. Among the cohort ( n = 477), Black patients were twice as likely to receive clozapine than White and Hispanic patients (OR 2.18, 95% CI 1.20–3.97, p = 0.008). In the case‐control analysis, patients with a greater number of previous psychiatric admissions (OR 1.14, p = 0.079) and antipsychotic trials (OR 1.40, p = 0.038) had greater odds of receiving clozapine. Homelessness was identified as a predictor against clozapine use (OR 2.77, p = 0.014). Conclusions This is the first study to identify homelessness as a predictor against clozapine use, which raises important clinical and ethical considerations. Our findings also add to the literature on clozapine prescribing discrepancies among ethnic‐minority patients. Overall, clozapine remains underutilized as the gold‐standard treatment for treatment‐resistant schizophrenia‐spectrum disorders, reinforcing a need to improve evidence‐based prescribing.

1604 Background: Diversity in clinical studies is essential to address health disparities, but racial and ethnic minorities are often underrepresented in clinical studies, especially in precision medicine studies using genetic data (1). BASECAMP-1 (NCT04981119) is an ongoing prescreening study to identify patients with unresectable advanced or metastatic solid tumors and tumor-associated HLA-A*02 LOH for the EVEREST-1 and -2 Tmod chimeric antigen receptor T-cell therapy trials. When enrollment began in 2021, eligibility for Part 1 was restricted to patients with germline HLA-A*02:01 based on preclinical data. Additional analysis revealed the blocker in the Tmod construct had activity across HLA-A*02 subtypes (Mock, et al. Mol Ther Oncolytics.2022). Eligibility for Part 1 was then expanded to all HLA-A*02 subtypes, allowing enrollment of more diverse patient populations. HLA-A*02 allele subtypes vary by ethnicity and race; the frequency of HLA-A*02:01 is 96% in non-Hispanic Whites, but ranges from 53% to 73% in other ethnicities and races. The frequency of all other HLA-A*02 allele subtypes (HLA-A*02:XX) is <5% in non-Hispanic Whites but up to 66% in other ethnicities and races (2,3). Methods: Patients eligible for BASECAMP-1 were identified at United States study sites. All patients screened before January 16, 2024, for Part 1 were included for demographic and central lab HLA-A typing. The % increase in eligibility and % of heterozygous HLA-A*02 patients with HLA-A*02:XX were calculated by ethnicity and race. Results: A total of 1124 patients were screened for germline HLA-A*02 typing; 431 patients were HLA-A*02:01 heterozygous, of whom 37 (9%) were Hispanic, 14 (3%) African American (AA), 2 (<1%) American Indian or Alaska Native, 17 (4%) Asian or Pacific Islander (API), and 324 (75%) non-Hispanic White (Table). The eligibility expansion identified 62 patients with HLA-A*02:XX heterozygosity, of whom 6 (10%) were Hispanic, 6 (10%) AA, 19 (31%) API, and 25 (40%) non-Hispanic White. Conclusions: By expanding enrollment to include HLA-A*02:XX, 16% more Hispanic, 43% more AA, and 112% more API patients were identified, improving the diversity in this trial compared with that of initial enrollment. 1. Aldrighetti, et al. JAMA Netw Open 2021. 2. Ellis, et al. Human Immunol. 2000. 3. Gragert, et al. Human Immunol.2013. Clinical trial information: NCT04981119 . [Table: see text]

Abstract Severe mitral annular calcification (MAC) presents a surgical challenge due to the complexity of disease and the risk of valve replacement. There have been a variety of techniques to combat this risk including edge-to-edge repair, collar-enforced prosthesis, and pericardial patch techniques. This report highlights a case in which a novel reproducible surgical technique was used to prevent perivalvular leak with mitral valve replacement. This technique may add to surgeons' repertoire in addressing patients with MAC concentrated on the posterior annulus.

Complete loss-of-function mutations in the PRKN gene are a major cause of early-onset Parkinson’s disease (PD). PRKN encodes the Parkin protein, an E3 ubiquitin ligase that works in conjunction with the ubiquitin kinase PINK1 in a distinct quality control pathway to tag damaged mitochondria for autophagic clearance, i.e., mitophagy. According to previous structural investigations, Parkin protein is typically kept in an inactive conformation via several intramolecular, auto-inhibitory interactions. Here, we performed molecular dynamics simulations (MDS) to provide insights into conformational changes occurring during the de-repression of Parkin and the gain of catalytic activity. We analyzed four different Parkin-activating mutations that are predicted to disrupt certain aspects of its auto-inhibition. All four variants showed greater conformational motions compared to wild-type protein, as well as differences in distances between domain interfaces and solvent-accessible surface area, which are thought to play critical roles as Parkin gains catalytic activity. Our findings reveal that the studied variants exert a notable influence on Parkin activation as they alter the opening of its closed inactive structure, a finding that is supported by recent structure- and cell-based studies. These findings not only helped further characterize the hyperactive variants but overall improved our understanding of Parkin’s catalytic activity and nominated targets within Parkin’s structure for potential therapeutic designs.

Pleural epithelioid mesothelioma (PEM) is divided into low and high grades based on nuclear atypia, mitoses, and necrosis in the tumor. Assessing mitoses and nuclear atypia tend to be labor-intensive with limited reproducibility. Ki-67 proliferation index was shown to be a prognostic factor in PEM, but its performance has not been directly correlated with tumor grade or mitotic score. This study evaluated the potential of Ki-67 index as a surrogate of tumor grade. We also compared the predictability of mitoses and Ki-67 index for overall survival (OS). Ninety-six PEM samples from 85 patients were identified from the surgical pathology file during 2000-2021 at our institution, and all glass slides were reviewed by 2 pulmonary pathologists to confirm the diagnosis and assign the tumor grade. Digital image analysis (DIA) was done for Ki-67 index. The agreement on tumor grading between 2 reviewers was moderate (kappa value = 0.47). The correlation between mitotic count (average count by 2 reviewers) and Ki-67 index was 0.65. The areas under the curve for predicting tumor grade by mitotic score and Ki-67 index were 0.84 and 0.74 (reviewer 1) and 0.85 and 0.81 (reviewer 2), respectively. High Ki-67 index and mitoses were significantly associated with poor OS (P=0.03 and 0.0005, using 30% and 10/2 mm2 as cutoffs, respectively). In conclusion, Ki-67 index by DIA was associated with tumor grade as well as mitotic count, and its predictability for OS was comparable to that of mitotic score, thus being a potential surrogate for tumor grade.

AbstractBackgroundImmune checkpoint inhibitor (ICI) therapy has led to significant improvement in outcomes for patients with nononcogene‐driven advanced non–small cell lung cancer (NSCLC). The rate of crossover and receipt of postprotocol ICI in frontline trials for advanced NSCLC has not been systematically evaluated.MethodsClinicalTrials.gov was used to identify phase 3 studies evaluating the use of immunotherapy or combination chemoimmunotherapy against chemotherapy alone in the frontline management of advanced NSCLC. Data on outcomes, rate of crossover and/or subsequent post‐protocol receipt of immunotherapy, and the start dates of these clinical trials were then extracted.ResultsTwenty‐three frontline trials in nononcogene‐driven advanced NSCLC were identified. Six trials with ICI monotherapy/dual ICI therapy and 17 trials evaluating chemotherapy/ICI in first‐line advanced NSCLC were included in the analysis. The crossover rate ranged 0% to 54% in ICI monotherapy/dual ICI trials and 0% to 52% in chemotherapy/ICI trials. Nineteen of 23 trials provided information on subsequent postprotocol therapies. Among the trials not allowing crossover, postprotocol ICI was administered to 17% to 45.8% of patients. Information regarding the eventual receipt of ICI therapy was available for 22 of 23 trials. Of 6631 patients, 2507 (37.8%) randomized to the control arm eventually received ICI therapy.ConclusionThe rate of crossover and postprotocol ICI use was low in frontline trials for first‐line NSCLC incorporating ICI. Given the proven improved overall survival of ICI in a broad population, there is a need to ensure availability of this life‐prolonging therapy in future trials, either by crossover treatment or postprotocol administration.

PURPOSE Outcomes for patients with newly diagnosed multiple myeloma (NDMM) are heterogenous, with overall survival (OS) ranging from months to over 10 years. METHODS To decipher and predict the molecular and clinical heterogeneity of NDMM, we assembled a series of 1,933 patients with available clinical, genomic, and therapeutic data. RESULTS Leveraging a comprehensive catalog of genomic drivers, we identified 12 groups, expanding on previous gene expression–based molecular classifications. To build a model predicting individualized risk in NDMM (IRMMa), we integrated clinical, genomic, and treatment variables. To correct for time-dependent variables, including high-dose melphalan followed by autologous stem-cell transplantation (HDM-ASCT), and maintenance therapy, a multi-state model was designed. The IRMMa model accuracy was significantly higher than all comparator prognostic models, with a c-index for OS of 0.726, compared with International Staging System (ISS; 0.61), revised-ISS (0.572), and R2-ISS (0.625). Integral to model accuracy was 20 genomic features, including 1q21 gain/amp, del 1p, TP53 loss, NSD2 translocations, APOBEC mutational signatures, and copy-number signatures (reflecting the complex structural variant chromothripsis). IRMMa accuracy and superiority compared with other prognostic models were validated on 256 patients enrolled in the GMMG-HD6 (ClinicalTrials.gov identifier: NCT02495922 ) clinical trial. Individualized patient risks were significantly affected across the 12 genomic groups by different treatment strategies (ie, treatment variance), which was used to identify patients for whom HDM-ASCT is particularly effective versus patients for whom the impact is limited. CONCLUSION Integrating clinical, demographic, genomic, and therapeutic data, to our knowledge, we have developed the first individualized risk-prediction model enabling personally tailored therapeutic decisions for patients with NDMM.

Introduction: The impact of COVID-19 was felt across cardiology as resources were redirected to critical care, delaying elective cardiology procedures. Hypothesis: To evaluate differences in outcomes of cardiac implantable electronic device (CIED) procedures in 2020 (height of COVID) vs. 2016-2019 (pre-COVID). Methods: Adults >= 18 years undergoing CIED procedures were identified from National Inpatient Sample Databases (NIS) 2016-2020. Complications and mortality were assessed based on the type of device: Permanent Pacemaker (PPM); Implantable Cardioverter Defibrillator (ICD); Cardiac Resynchronization Therapy with Pacemaker (CRT-P) or defibrillator (CRT-D): Leadless PPM; Generator explant (GE), and Lead extraction (LE). Results: A 13.8% drop in CIED admissions was recorded between 2019 and 2020 (p<0.01). Fewer procedures involving PPM, ICD, CRT-P, CRT-D, LE, and GE were observed between 2019 and 2020. Leadless PPM utilization rose consistently between 2016-2020 (47.6% increase during 2020 vs 2019)(Figure). In 2020, a higher proportion of patients were classified with a Charlson Comorbidity Index score of ≥3 (severe) (47.4% in 2020 vs. 42.9% in 2016-2019, p<0.01). The table shows significantly higher complications during CIED implants with no changes in mortality related to procedures. Conclusions: Patients admitted for CIED implants in 2020 had more severe comorbidities and expressed considerable differences in complications than pre-COVID era (2016-2019), but mortality remained unchanged. Leadless PPM use increased during pandemic, as against a decrease in the use of other CIEDs.