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PURPOSE The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged progression-free survival (PFS), but without improvement in overall survival (OS), likely because of toxicity. Acalabrutinib was shown to be efficacious and less toxic than ibrutinib in a head-to-head trial in chronic lymphocytic leukemia and therefore might lead to better outcomes in MCL. METHODS Patients 65 years and older with previously untreated MCL received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus six cycles of bendamustine (90 mg/m 2 once daily; days 1 and 2) and rituximab (375 mg/m 2 as a single dose; day 1) followed by rituximab maintenance in responding patients for 2 years. Crossover to acalabrutinib at disease progression was permitted. The primary end point was PFS per the independent review committee; overall response rate and OS were secondary end points. RESULTS In total, 598 patients were randomly assigned, with 299 in each arm. At a median follow-up of 49.8 months using the reverse Kaplan-Meier method, the median PFS was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.94]; P = .0160). Benefit was seen across all subgroups, including those with high-risk features. Overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% in the acalabrutinib and placebo arms, respectively. OS was not significantly different (HR, 0.86 [95% CI, 0.65 to 1.13]; P = .27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively. CONCLUSION The combination of acalabrutinib with bendamustine-rituximab significantly improved PFS. Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity.

Study Design: Analysis of prospectively collected data. Objective: To assess if systemic illness severity affects cervical spondylotic myelopathy (CSM) surgery outcomes. Summary of Background Data: It remains unclear if CSM patients with poor physical status/severe systemic illness benefit as much from surgery as those in good condition. Methods: Using the Quality Outcomes Database CSM cohort and the American Association of Anesthesiology (ASA) grade as a surrogate for illness burden, we compared patients with (ASA 3–4) and without (ASA 1–2) severe systemic illness, including rates of readmission and 24-month minimal clinically important differences (MCID) achievement for patient-reported outcomes (PROs)—numerical rating score (NRS) arm and neck pain, neck pain-related disability (NDI), and quality of life (EQ-5D). Results: Of 1141 CSM patients, 1062 had ASA grades recorded. Of these 1062 patients, 70.2% had a 2-year follow-up for mJOA, and 81%–84% had a follow-up for NRS arm and neck, NDI, and EQ-5D. Five hundred twenty-one patients (49.1%) had mild (ASA 1–2) and 541 (50.9%) had severe systemic illness (ASA 3–4). The severe disease cohort was older (63.3±11.0 vs. 57.4±11.7), had higher BMI (31.4±7.0 vs. 28.9±5.6), had more comorbidities (diabetes, coronary artery disease, depression), and had less independent ambulation (71.3% vs. 90.6%) ( P <0.05). At baseline, severe disease patients had worse NRS arm (5.2±3.5 vs. 4.7±3.4) and neck (5.5±3.2 vs. 5.1±3.3) pain, NDI (40.5±20.1 vs. 36.8±21.0), and EQ-5D (0.53±0.22 vs. 0.59±0.22) scores ( P <0.05). Perioperatively, the severe disease cohort had longer hospitalizations (2.4±2.6 vs. 1.7±2.0 days) and increased nonhome discharges (17% vs. 5%) ( P <0.05). The severe disease cohort had higher 90-day readmissions (7.6% vs. 2.5%), including surgery-related (3.7% vs. 1.5%) and non–surgery-related reasons (3.9% vs. 1.0%) ( P <0.05). On multivariate analysis, increased ASA grade was significantly associated with 90-day readmissions (OR: 2.55 per 1-grade increase, 95% CI: 1.38–4.83). However, both severe and mild disease cohorts had similarly high rates of achieving 2-year MCID for mJOA (67.5% vs. 66.0%), NRS arm (72.0% vs. 74.1%), neck (69.5% vs. 69.4%) pain, NDI (63.1% vs. 68.1%), and EQ-5D (67.9% vs. 66.9%) ( P >0.05). Conclusion: Patients with severe systemic illness (higher ASA) have worse baseline PROs and higher 90-day readmissions. However, they achieve similar MCID rates for mJOA and all measured PROs 2 years postoperatively.

Background: Cardiac rehabilitation (CR) is essential to secondary cardiovascular disease prevention and management of cardiac patients. Despite its proven benefits, CR remains underutilized with enrollment and completion rates ranging from 10-30% in the US. Yet, there is a scarcity of nationally representative data among diverse populations on socioeconomic differences in barriers and beliefs of CR participation and delivery mode preferences. Hypothesis: The perceptions (barriers, beliefs), CR delivery mode preferences, and CR utilization (prior enrollment) varies by socioeconomic status (SES) among CR-eligible individuals. Methods: We conducted an anonymous national electronic survey from March 2023 to January 2024 of individuals self-reporting a prior CR-eligible diagnosis. The 22-item CR Barriers Scale assessed perceived barriers to CR enrollment and participation using a 5-point Likert scale (strongly disagree to strongly agree). A 13-item, validated questionnaire assessed 4 subscales pertaining to patients’ beliefs about CR, each rated on a 5-point Likert scale (strongly disagree to strongly agree): perceived necessity, concerns about exercise, practical barriers and perceived suitability. CR delivery mode preferences were ascertained (eg, virtual, at-home, etc.). Mean barriers and belief scores as well as delivery mode preferences were stratified by SES. Low SES was defined as ≤ high school education, Medicaid insurance, or uninsured. High SES was defined as > high school education and non-Medicaid health insurance. Responses were analyzed using descriptive statistics with R software. Results: A total of 466 participants completed the survey (38.1% women, 30.6% minoritized racial/ethnic group, 29.6% low SES, 95% response rate) ( Table 1 ). The majority indicated prior enrollment in CR (81.5%) with no difference by SES. CR barrier scores did not differ significantly by SES (p=0.331) ( Table 2 ). Beliefs about CR perceived necessity and perceived suitability differed by SES (p<0.001 and p=0.025), but beliefs regarding concerns about exercise and practical barriers did not. The low SES group reported a higher preference for completely at-home CR compared to the high SES group (33.6% vs 7.4%, p<0.001). Conclusion: Our findings suggest that CR beliefs varied by SES while utilization did not. For CR-eligible patients experiencing socioeconomic disadvantage, at-home CR may be a preferred alternative to center-based CR to increase CR participation and adherence.

Background/Objectives: This study aimed to establish the clinical utility of a therapeutic drug monitoring (TDM)-supported, model-informed precision dosing (MIPD) approach (precision-guided dosing [PGD]) by assessing the impact of pharmacokinetic (clearance [CL]) and clinical laboratory parameters on adalimumab (ADA) dosage adjustments during maintenance therapy for inflammatory bowel disease (IBD). Methods: In the EMPOWER study, blood was collected at any time post-ADA injection. Pharmacokinetic (PK) testing was conducted in an accredited lab. Inputs for the PGD test included ADA concentrations, antibodies to ADA, albumin levels, and the current dosing regimen. CL was calculated using nonlinear mixed-effect models. Results were reported to health care providers (HCPs) within 3 days. HCPs’ treatment decisions were recorded and classified as treatment reduction, continuation, intensification, or ADA discontinuation. The physician global assessment (PGA) of disease activity was collected. Relationships between drug concentrations, CL, disease activity, and physician decision-making were assessed using logistic regression. Results: A total of 213 cases were assessed by 21 HCPs. ADA treatment was intensified in 24% and discontinued in 13% of cases. An ADA concentration ≤ 10 μg/mL was associated with a 23.7-fold and 3.0-fold higher likelihood of therapy intensification and PGA > 0, respectively, compared to concentrations > 10 μg/mL. An ADA concentration < 5 μg/mL was associated with a 3.3-fold higher likelihood of treatment discontinuation. CL ≥ 0.318 L/day was associated with a 10.4-fold higher likelihood of therapy intensification. Higher CL (>0.8 L/day) was associated with a 3.5-fold and 4.2-fold higher likelihood of treatment discontinuation and PGA > 0, respectively. Conclusions: PGD enables earlier and precise optimization of ADA dosing by predicting trough levels at any time during the therapy cycle. Optimized dosing to achieve target ADA concentrations and low clearance is crucial to mitigate therapy discontinuation and active disease in IBD patients.

Abstract Introduction We describe the safety of sotorasib monotherapy in patients with KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC) and discuss practical recommendations for managing key risks. Methods Incidence rates of treatment-related adverse events (TRAEs) were pooled from 4 clinical trials: CodeBreaK 100 (NCT03600883), CodeBreaK 101 (NCT04185883), CodeBreaK 105 (NCT04380753), and CodeBreaK 200 (NCT04303780) and graded according to CTCAE v5.0. Adverse events were deemed sotorasib-related per investigator causality assessment. Results In the pooled population (n = 549), TRAEs were reported in 388 (70.7%) patients (grade 1: 124 [22.6%]; grade 2: 117 [21.3%]; grade ≥ 3: 147 [26.8%]). Gastrointestinal and hepatic TRAEs, including diarrhea (171 [31.1%]), nausea (80 [14.6%]), elevated alanine aminotransferase (ALT; 68 [12.4%]), and elevated aspartate aminotransferase (AST; 67 [12.2%]) were the most common (≥10%). Dose interruption and dose reduction of sotorasib resulted in the resolution of &gt;90% of diarrhea events; median time to resolution were 18.0 days and 22.0 days, respectively. Similar trends were observed for elevated ALT and AST events. Patients who stopped immunotherapy &lt;3 months before initiating sotorasib had a higher incidence of treatment-related hepatotoxicity (80/240 [33.3%]) than those who stopped immunotherapy ≥3 months before initiating sotorasib (26/188 [13.8%]). Treatment-related pneumonitis/interstitial lung disease (ILD) and corrected QT (QTc) prolongation were observed in 9 (1.6%) and 4 (0.7%) patients, respectively. Two (0.4%) patients died with TRAEs, 1 with ILD whose ultimate cause of death was disease progression, and the other with an unknown cause. Conclusions Sotorasib has a well-characterized safety profile in patients with KRAS G12C-mutated advanced NSCLC, and key risks are manageable with dose modification.

Importance The emergency department (ED) offers an opportunity to initiate palliative care for older adults with serious, life-limiting illness. Objective To assess the effect of a multicomponent intervention to initiate palliative care in the ED on hospital admission, subsequent health care use, and survival in older adults with serious, life-limiting illness. Design, Setting, and Participants Cluster randomized, stepped-wedge, clinical trial including patients aged 66 years or older who visited 1 of 29 EDs across the US between May 1, 2018, and December 31, 2022, had 12 months of prior Medicare enrollment, and a Gagne comorbidity score greater than 6, representing a risk of short-term mortality greater than 30%. Nursing home patients were excluded. Intervention A multicomponent intervention (the Primary Palliative Care for Emergency Medicine intervention) included (1) evidence-based multidisciplinary education; (2) simulation-based workshops on serious illness communication; (3) clinical decision support; and (4) audit and feedback for ED clinical staff. Main Outcome and Measures The primary outcome was hospital admission. The secondary outcomes included subsequent health care use and survival at 6 months. Results There were 98 922 initial ED visits during the study period (median age, 77 years [IQR, 71-84 years]; 50% were female; 13% were Black and 78% were White; and the median Gagne comorbidity score was 8 [IQR, 7-10]). The rate of hospital admission was 64.4% during the preintervention period vs 61.3% during the postintervention period (absolute difference, −3.1% [95% CI, −3.7% to −2.5%]; adjusted odds ratio [OR], 1.03 [95% CI, 0.93 to 1.14]). There was no difference in the secondary outcomes before vs after the intervention. The rate of admission to an intensive care unit was 7.8% during the preintervention period vs 6.7% during the postintervention period (adjusted OR, 0.98 [95% CI, 0.83 to 1.15]). The rate of at least 1 revisit to the ED was 34.2% during the preintervention period vs 32.2% during the postintervention period (adjusted OR, 1.00 [95% CI, 0.91 to 1.09]). The rate of hospice use was 17.7% during the preintervention period vs 17.2% during the postintervention period (adjusted OR, 1.04 [95% CI, 0.93 to 1.16]). The rate of home health use was 42.0% during the preintervention period vs 38.1% during the postintervention period (adjusted OR, 1.01 [95% CI, 0.92 to 1.10]). The rate of at least 1 hospital readmission was 41.0% during the preintervention period vs 36.6% during the postintervention period (adjusted OR, 1.01 [95% CI, 0.92 to 1.10]). The rate of death was 28.1% during the preintervention period vs 28.7% during the postintervention period (adjusted OR, 1.07 [95% CI, 0.98 to 1.18]). Conclusions and Relevance This multicomponent intervention to initiate palliative care in the ED did not have an effect on hospital admission, subsequent health care use, or short-term mortality in older adults with serious, life-limiting illness. Trial Registration ClinicalTrials.gov Identifier: NCT03424109

Abstract Worldwide, valvular heart disease (VHD) is a common cause of hospitalization for acute heart failure. In acute heart failure caused by VHD, symptoms result from rapid haemodynamic changes and subsequent decline in cardiac function, and if left untreated, leads to acute decompensation and cardiogenic shock. Current evidence remains scarce and recommendations regarding the management of acute heart failure caused by VHD are lacking in most recent international guidelines. Herein, we review the management of acute heart failure caused by VHD with a focus on transcatheter therapies and describe currently available evidence based on a systematic literature search on the following valve pathologies: (i) aortic stenosis, (ii) aortic regurgitation, (iii) mitral regurgitation, and (iv) mitral stenosis. Articles reporting outcomes following urgent or emergent valve intervention in the setting of cardiogenic shock or acute heart failure were considered. After screening a total of 2234 articles, 76 published between 1994 and 2023 were included in subsequent analysis. Based on available evidence, proposed treatment algorithms to guide optimal management of acute heart failure caused by VHD were created. As the number of patients presenting with acute heart failure caused by VHD continues to rise and outcomes following transcatheter valve interventions continue to improve, it is inevitable that minimally invasive options will play an increasingly important role in the acute setting, especially given these patients are at an increased operative risk. This review aims to present an organized approach to the complex management and interventional treatment of patients with acute heart failure caused by VHD.

ABSTRACTAlzheimer's disease (AD) is the most common neurodegenerative dementia with multi‐layered complexity in its molecular etiology. Multiple omics‐based approaches, such as genomics, epigenomics, transcriptomics, proteomics, metabolomics, and lipidomics are enabling researchers to dissect this molecular complexity, and to uncover a plethora of alterations yielding insights into the pathophysiology of this disease. These approaches reveal multi‐omics alterations essentially in all cell types of the brain, including glia. In this systematic review, we screen the literature for human studies implementing any omics approach within the last 10 years, to discover AD‐associated molecular perturbations in brain glial cells. The findings from over 200 AD‐related studies are reviewed under four different glial cell categories: microglia, oligodendrocytes, astrocytes and brain vascular cells. Under each category, we summarize the shared and unique molecular alterations identified in glial cells through complementary omics approaches. We discuss the implications of these findings for the development, progression and ultimately treatment of this complex disease as well as directions for future omics studies in glia cells.