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OBJECTIVES Early warning scores detecting clinical deterioration in pediatric inpatients have wide-ranging performance and use a limited number of clinical features. This study developed a machine learning model leveraging multiple static and dynamic clinical features from the electronic health record to predict the composite outcome of unplanned transfer to the ICU within 24 hours and inpatient mortality within 48 hours in hospitalized children. METHODS Using a retrospective development cohort of 17 630 encounters across 10 388 patients, 2 machine learning models (light gradient boosting machine [LGBM] and random forest) were trained on 542 features and compared with our institutional Pediatric Early Warning Score (I-PEWS). RESULTS The LGBM model significantly outperformed I-PEWS based on receiver operating characteristic curve (AUROC) for the composite outcome of ICU transfer or mortality for both internal validation and temporal validation cohorts (AUROC 0.785 95% confidence interval [0.780–0.791] vs 0.708 [0.701–0.715] for temporal validation) as well as lead-time before deterioration events (median 11 hours vs 3 hours; P = .004). However, LGBM performance as evaluated by precision recall curve was lesser in the temporal validation cohort with associated decreased positive predictive value (6% vs 29%) and increased number needed to evaluate (17 vs 3) compared with I-PEWS. CONCLUSIONS Our electronic health record based machine learning model demonstrated improved AUROC and lead-time in predicting clinical deterioration in pediatric inpatients 24 to 48 hours in advance compared with I-PEWS. Further work is needed to optimize model positive predictive value to allow for integration into clinical practice.

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening, stem cell disorder that renders red blood cells vulnerable to complement-mediated hemolysis. This study describes the health-related quality of life (HRQoL) and symptom-specific functional impairment of patients with PNH in a real-world setting. Methods: US-based adults with PNH treated with a parenterally administered complement inhibitor (PACI) for ≥6 months completed an online, cross-sectional, observational survey; a subset of patients also participated in individual semi-structured qualitative interviews after completing the survey. The survey included the PROMIS® 29+2 Profile v2.1 (PROMIS 29+2) to measure HRQoL. The FACIT Fatigue, Neuro-QOL Item Bank v2.0 Cognitive Function Short Form, and PROMIS Item Bank v1.0 Dyspnea Functional Limitations 10a Short Form measured functional impairment associated with specific symptoms of PNH. For each patient with PNH who completed the online survey, up to 3 age- (+/- 3 years) and sex-matched adults without PNH also completed the survey. The HRQoL and functional impairment of the PNH sample was compared to that of general population (GP) sample using independent samples t-tests or Mann-Whitney tests. To further explore the experiences of patients with PNH, the association between HRQoL/functional impairment and fatigue severity was investigated. Patients with PNH were grouped according to their self-reported fatigue severity over the past 7 days (very mild or mild vs moderate, severe, or very severe [no patients reported no fatigue]). Differences in scores across these 2 groups were tested. Data from the qualitative interviews were coded using thematic analysis to explore key concepts related to HRQoL and impairment due to PNH symptoms. Data collection began in March 2023; results are based on interim data. Results: Demographic characteristics of the study samples (PNH survey sample: N=31, GP survey sample: N=62, PNH interview sample: N=10) are shown in Table 1. Patients were treated for PNH with eculizumab, pegcetacoplan, or ravulizumab, with an average duration of current PACI treatment of 3.4 years. Compared to the age and sex-matched GP sample, patients with PNH had significantly higher median scores on the PROMIS 29+2 fatigue domain (GP: 48.70 vs PNH: 57.10, p=0.041) and PROMIS Dyspnea Functional Limitations short form (GP: 40.70 vs PNH: 48.60, p=0.036), indicating that patients with PNH experience more fatigue and dyspnea limitations than the GP sample. Patients with PNH also had significantly lower median scores on the PROMIS 29+2 ability to participate in social roles/activities domain (GP: 53.50 vs PNH: 44.20, p=0.013), indicating greater role/activity limitations among patients with PNH. Compared to the GP sample, patients with PNH had numerically lower (i.e., worse) median PROMIS 29+2 cognitive functioning domain scores (GP: 50.00 vs PNH: 46.30, p=0.058) and FACIT Fatigue scores (GP: 39.50 vs PNH: 30.00, p=0.057). Within the PNH sample, statistically significant associations (p<0.05) were observed between fatigue severity and HRQoL/functional impairment for all outcomes except for the PROMIS 29+2 sleep disturbance and cognitive functioning domains (Table 2). Patients with more severe fatigue had worse HRQoL and more functional impairment than patients with less severe fatigue. Interview participants described fatigue-related functional impairments in their physical, social, and cognitive functioning. Fatigue made daily activities (e.g., cooking, cleaning, going for a walk) difficult and sometimes impossible. Planning social activities in advance was also challenging as patients could not predict how they would feel on any given day, and often found they had to miss, postpone, or cancel social engagements. Finally, patients described experiencing “brain fog” including difficulty concentrating, forgetfulness, and delayed cognitive processing. Conclusions: Despite receiving treatment for PNH, patients experienced deficits in areas of HRQoL related to fatigue, participation in social roles, cognitive function, and functional limitations due to dyspnea, relative to a sample of GP adults. During follow-up interviews, patients emphasized the deep and broad impacts that fatigue and cognitive functioning had, making daily activities and their social lives very difficult.

Ciltacabtagene autoleucel (cilta-cel) consists of autologous T cells genetically modified to express a two-binding domain chimeric antigen receptor (CAR). The target antigen of the CAR is B-cell maturation antigen (BCMA), which is highly expressed on malignant plasma cells (PC) from multiple myeloma subjects. In the Phase 1b/2 CARTITUDE-1 study, cilta-cel led to early, deep, and durable responses and was approved for the treatment of patients with relapsed or refractory multiple myeloma (RRMM) after four or more prior lines of therapy by FDA. Despite cilta-cel's outstanding overall response rate (97.9%) and duration of response (DOR) in RRMM patients, relapse still occurs. Biomarkers associated with this durable response and acquired resistance remain to be elucidated. We present updated correlative data from the CARTITUDE-1 study. At the ~3 year follow-up (October 2022 data cutoff), 97 patients had received a single infusion of cilta-cel (median 0.71 x10 6 cells/kg [range 0.52 x10 6-0.94 x10 6]); the median follow up was 33.4 months (range 1.5-45.2), median DOR was 33.9 months (95% CI, 25.5-not estimable [NE]) and median PFS was 34.9 months (95% CI, 25.2-NE) (Lin Y et al, ASCO 2023). Drug product (DP), baseline and on-treatment whole blood and bone marrow samples from enrolled patients were analyzed by methods including flow cytometry, MSD immunoassays, Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) and TCR sequencing. In CARTITUDE-1, the DP contained a mixture of transduced and non-transduced T cells; the median transduction efficiency was 16% (range 5-32%), with a balanced distribution of CAR+CD4+ and CAR+CD8+ cells, median frequency 12% (range 2-28%) and 6% (range 2-20%), respectively. Further, the DP T cell subset composition was variable but balanced between central (Tcm) and effector memory (Tem) phenotypes. CAR+ T cells expanded reaching a median peak concentration (C max of 730 cells/µL; range 3-13805 cells/µL) in blood between days 12-14 post-infusion and persisted in circulation for a median of 100 days (range 20-912 days). High efficacy (best response) and DOR were achieved despite variable CAR-T cell expansion and lack of detectable CAR-T cell persistence over time. At C max, the CD4:CD8 ratio (based on % of CAR+ cells) was 0.29, demonstrating a CAR+CD8+ T cell preferential expansion, and both CAR+CD4+ and CAR+CD8+ T cells were predominantly of a Tcm phenotype, median 95% (range 62-99.5%) and 96% (range 33-99.7%), respectively. Higher frequency of early-memory T cell phenotypes has been associated with clinical responses to CAR-T therapies in MM (Dancy et al., Blood 2018). CITE-seq analyses showed that DP characteristics such as a high CD8+ stem-like phenotype and a low CD4+ Treg-like phenotype in the CAR+ T cell compartment associated with longer DOR. Some of the most abundant clones in the DP single cell TCR data were CAR+CD8+ T cells expressing granzyme B, suggesting high cytotoxic potential. Additional bulk TCR sequencing data suggest both diversity and individual clonal expansion longitudinally after cilta-cel infusion. We also evaluated tumor and patient intrinsic characteristics at baseline. BCMA expression on bone marrow PC was prevalent and highly variable among RRMM patients; however, expression did not associate with best response or DOR. Further, high ORR was observed in patients with high-risk cytogenetics, high tumor burden (>= 60% bone marrow PC), or baseline plasmacytomas, although with a non-statistically significant shorter PFS. Sustained MRD negativity strongly associated with longer DOR. Conversely, patient-intrinsic characteristics associated with inflammation (CRP, ferritin, neutrophils, pro-inflammatory cytokines) correlated with shorter DOR. Treatment benefit of the magnitude seen with cilta-cel had not been reported with any other approved therapy in this setting. Correlative analyses suggest an emerging profile to help understand such outstanding clinical activity: a balanced CD4/CD8 ratio and Tcm/Tem phenotype of the manufactured DP and preferential expansion of CAR+CD8+ Tcm cells. Further, certain baseline patient-intrinsic and tumor characteristics may explain the longer DOR in the RRMM setting. These investigations help identify markers of response to cilta-cel and may lead to CAR-T cell design or manufacturing strategies that enhance drug product characteristics and thus clinical efficacy.

Background Socioeconomic status (SES) is associated with cardiovascular health (CVH). Potential differences by sex in this association remain incompletely understood in Black Americans, where SES disparities are posited to be partially responsible for cardiovascular inequities. The association of SES measures (income, education, occupation, and insurance) with CVH scores was examined in the Jackson Heart Study. Methods and Results American Heart Association CVH components (non–high‐density‐lipoprotein cholesterol, blood pressure, diet, tobacco use, physical activity, sleep, glycemia, and body mass index) were scored cross‐sectionally at baseline (scale: 0–100). Differences in CVH and 95% CIs (Estimate, 95% CI) were calculated using linear regression, adjusting for age, sex, and discrimination. Heterogeneity by sex was assessed. Participants had a mean age of 54.8 years (SD 12.6 years), and 65% were women. Lower income, education, occupation (non‐management/professional versus management/professional occupations), and insurance status (uninsured, Medicaid, Veterans Affairs, or Medicare versus private insurance) were associated with lower CVH scores (all P <0.01). There was heterogeneity by sex, with greater magnitude of associations of SES measures with CVH in women versus men. The lowest education level (<high school) versus highest (>high school) was associated with 8.8‐point lower (95% CI: −10.2 to −7.3) and 5.4‐point lower (95% CI: −7.2 to −3.6) CVH scores in women and men, respectively (interaction P =0.003). The lowest (<25 000) versus highest level of income (≥$75 000) was associated with a greater reduction in CVH scores in women than men (interaction P =0.1142). Conclusions Among Black Americans, measures of SES were associated with CVH, with a greater magnitude in women compared with men for education and income. Interventions aimed to address CVH through SES should consider the role of sex.

Background Innovative restructuring of cardiac rehabilitation (CR) delivery remains critical to reduce barriers and improve access to diverse populations. Destination Cardiac Rehab is a novel virtual world technology‐based CR program delivered through the virtual world platform, Second Life, which previously demonstrated high acceptability as an extension of traditional center‐based CR. This study aims to evaluate efficacy and adherence of the virtual world–based CR program compared with center‐based CR within a community‐informed, implementation science framework. Methods Using a noninferiority, hybrid type 1 effectiveness‐implementation, randomized controlled trial, 150 patients with an eligible cardiovascular event will be recruited from 6 geographically diverse CR centers across the United States. Participants will be randomized 1:1 to either the 12‐week Destination Cardiac Rehab or the center‐based CR control groups. The primary efficacy outcome is a composite cardiovascular health score based on the American Heart Association Life's Essential 8 at 3 and 6 months. Adherence outcomes include CR session attendance and participation in exercise sessions. A diverse patient/caregiver/stakeholder advisory board was assembled to guide recruitment, implementation, and dissemination plans and to contextualize study findings. The institutional review board–approved randomized controlled trial will enroll and randomize patients to the intervention (or control group) in 3 consecutive waves/year over 3 years. The results will be published at data collection and analyses completion. Conclusions The Destination Cardiac Rehab randomized controlled trial tests an innovative and potentially scalable model to enhance CR participation and advance health equity. Our findings will inform the use of effective virtual CR programs to expand equitable access to diverse patient populations. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05897710.

Key Points Using multiple markers may improve GFR estimation especially in settings where creatinine and cystatin C are known to be limited. Panel eGFR is a novel multimarker eGFR equation consisting of age, sex, cystatin C, and nuclear magnetic resonance–measured creatinine, valine, and myo-inositol. eGFR-Cr and eGFR-Cr-CysC may underestimate measured GFR, while panel eGFR was unbiased among younger Black male individuals. Background Using multiple markers may improve accuracy in GFR estimation. We sought to externally validate and compare the performance of a novel multimarker eGFR (panel eGFR) equation among Black and White persons using the Genetic Epidemiology Network of Arteriopathy cohort. Methods We included 224 sex, race/ethnicity, and measured GFR (mGFR) category–matched persons, with GFR measured using urinary clearance of iothalamate. We calculated panel eGFR using serum creatinine, valine, myo-inositol, cystatin C, age, and sex. We compared its reliability with current eGFR equations (2021 CKD Epidemiology Collaboration creatinine [eGFR-Cr] and creatinine with cystatin C [eGFR-Cr-CysC]) using median bias, precision, and accuracy metrics. We evaluated each equation's performance in age, sex, and race subgroups. Results In the overall cohort, 49% were Black individuals, and mean mGFR was 79 ml/min per 1.73 m 2 . Panel eGFR overestimated mGFR (bias: −2.4 ml/min per 1.73 m 2 ; 95% confidence interval [CI], −4.4 to −0.7), eGFR-Cr-CysC underestimated mGFR (bias: 4.8 ml/min per 1.73 m 2 ; 95% CI, 2.1 to 6.7), while eGFR-Cr was unbiased (bias: 2.0 ml/min per 1.73 m 2 ; 95% CI, −1.1 to 4.6). All equations had comparable accuracy. Among Black male individuals younger than 65 years, both eGFR-Cr (bias: 17.0 ml/min per 1.73 m 2 ; 95% CI, 8.6 to 23.5) and eGFR-Cr-CysC (bias: 14.5 ml/min per 1.73 m 2 ; 95% CI, 6.0 to 19.7) underestimated mGFR, whereas panel eGFR was unbiased (bias: 1.7 ml/min per 1.73 m 2 ; 95% CI, −3.4 to 10.0). Metrics of accuracy for all eGFRs were acceptable in all subgroups except for panel eGFR in Black female individuals younger than 65 years (P30: 73.3%). Conclusions Panel eGFR can be used to estimate mGFR and may have utility among Black male individuals younger than 65 years where current CKD Epidemiology Collaboration equations are biased.