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2011 Background: Radiation therapy forms the mainstay of management for patients with brain metastases. Published randomized trials have found improved quality of life with stereotactic radiation (SRS/SRT) over whole brain radiation (WBRT) in patients with ≤ 4 brain metastases; comparative trials in patients with >4 brain metastases are lacking. In addition, prior randomized trials have demonstrated the superiority of hippocampal avoidance WBRT (HA-WBRT) over traditional WBRT, but no study has compared SRS/SRT to HA-WBRT. Accordingly, we conducted a multicenter, phase 3 randomized trial comparing SRS/SRT to HA-WBRT in patients with 5-20 brain metastases. Methods: Eligible patients were age 18-80 with 5-20 brain metastases secondary to a solid primary other than small cell lung cancer, were naïve to prior brain-directed radiation, and lacked leptomeningeal disease. The primary endpoint was the average of patient-reported symptom severity and interference over the first six months post-baseline relative to baseline, using the MD Anderson Symptom Inventory–Brain Tumor (MDASI-BT) module, a validated instrument assessing 22 symptoms and 6 interference measures integral to quality of life, each scored 0-10 with higher scores indicating greater symptomatology/interference in function. The target effect size was a symptom severity of 0.70, corresponding to 50% of the observed difference between patients with a good (90-100) versus poor (≤80) Karnofsky performance status; with 80% power and a two-sided alpha of 0.05, 196 patients were required. Results: Between 4/2017-5/2024, 196 patients enrolled, 98 in each arm. The median number of brain metastases was 14 (IQR 11-18); 25% of patients underwent prior neurosurgical resection. Baseline mean MDASI-BT symptom severity scores were 2.2 (SRS/SRT arm) and 1.9 (HA-WBRT arm), p=0.20; respective interference scores were 3.5 and 3.2 (p=0.40). The average of weighted post-baseline severity and interference scores relative to baseline indicated lower symptomatology/inference in the SRS/SRT arm, meeting the primary endpoint of the study (difference between SRS/SRT and HA-WBRT: -1.06, p<0.001). Averaged post-baseline symptom severity scores minus baseline were -0.03 and 0.59 in the SRS/SRT and HA-WBRT arms, respectively (difference -0.62, with lower symptom severity in the SRS/SRT arm, p<0.001); respective interference estimates were -0.62 and 0.89 (difference -1.50, with lower interference in the SRS/SRT arm, p<0.001). Median survival was 8.3 and 8.5 months in the SRS/SRT and HA-WBRT arms, respectively (p=0.30). Conclusions: This phase 3 randomized trial indicates that patients with 5-20 brain metastases experience fewer symptoms and less interference in function after SRS/SRT as opposed to HA-WBRT, without compromise of survival, supporting SRS/SRT as the standard of care in this population. Clinical trial information: NCT03075072 .

Introductory paragraph The extracellular Calcium-sensing receptor (CaSR) regulates cellular responsiveness to physiological changes in ionized calcium (Ca 2+ ) concentrations. The CaSR is expressed in the brain, including in hypothalamic growth hormone stimulating GHRH and anorectic POMC neurons that control growth and energy homeostasis. We embryonically deleted the Casr gene in neurons to create Neuron CaSR -/- mice to delineate the role of this receptor in regulating growth, skeletal development, and energy metabolism. Neuron CaSR -/- mice had reduced size, weight and bone mass compared to littermate controls, with a dysregulated growth hormone axis. They also showed increased adiposity and circulating leptin levels, leptin resistance, and decreased glucose tolerance, along with reduced expression of the anorectic precursor peptide POMC and secondary increases in the expression of the anorectic peptide AgRP in the hypothalamus of Neuron CaSR -/- mice. Knockdown of CaSR in adult mice specifically in the hypothalamic arcuate nucleus, where GHRH, POMC and AgRP neurons reside, also resulted in increased body weight, adiposity, leptin resistance, and glucose intolerance, and reduced bone mass. Together these data suggest that neuronal CaSR critically regulates energy and skeletal metabolism and body growth by modulating hypothalamic function, representing a new paradigm for central integration of calcaemic activities with body function.

Background and Objectives The genetic basis of adult-onset multiple sclerosis (MS) is well-studied, but less is known about pediatric-onset MS (pedMS), comprising approximately 5% of all MS onsets. Mendelian randomization (MR) studies have demonstrated evidence for a causal association between MS and both 25-hydroxyvitamin D [25(OH)D] serum levels and genetic variation related to vitamin D receptor (VDR) binding. The objective was to identify whether VDR binding variants (VDR-BVs) previously implicated in adult-onset MS were associated with pedMS using genetic instrumental variables (GIVs). Methods Using previously identified VDR-BVs to construct individual GIVs with two-sample MR, we investigated associations with pedMS in 725 cases and 592 controls of European ancestry from the US Network of Pediatric MS Centers. Associations between each VDR-BV and pedMS were estimated using logistic regression adjusting for the first three genome-wide principal components. A significant interaction between a VDR-BV and 25(OH)D GIV provided evidence for a causal association unbiased by pleiotropy. Results One VDR-BV, rs2531804, previously associated with adult-onset MS, was also significantly associated with pedMS after multiple testing correction. Discussion This study is the first to use VDR-BVs from previous MR studies to demonstrate causal differences in VDR binding at a locus contributing to pedMS susceptibility.

Patient complaints are valuable sources of information for quality improvement and provide an avenue for patient self-advocacy. This paper outlines the development and implementation of a novel training program, termed CODE (Compassion, Operational Support, De-escalation, Empowerment), for patient experience complaint management staff. The program consists of 2 core tracks: procedural training on operational systems and resources, and interpersonal communication training. A dual-track framework ensures practical knowledge to access resources to assist complainants is paired with communication for empathy and human connection. The CODE program's dual-track structure is a key strength, bridging the gap between operational efficiency and compassionate communication. By emphasizing both procedural knowledge and interpersonal skills, it equips healthcare professionals to manage patient complaints successfully. The CODE program represents a novel approach for healthcare institutions seeking to optimize patient experience and complaint-handling performance.

Abstract The Alzheimer's disease (AD) scientific field continues to make significant advances in early detection and treatments, which importantly rest on advances in our fundamental understanding of AD pathobiology and its contribution to cognitive decline. Clinical readouts of monoclonal antibodies against various forms of the amyloid beta (Aβ) protein indicate that the impact of these treatments may extend beyond reduction in amyloid plaques. The Alzheimer's Association Research Roundtable meeting held on May 17 and 18, 2022, reviewed our understanding to date of the impact of treatments targeting various species of Aβ; its impact on other related pathophysiology including tau; and ultimately, its effects on neurodegeneration and clinical decline, driven by the latest available data. Participants discussed the current evidence for a causal relationship among amyloid accumulation, tau alteration, and cognitive decline; the effect of anti‐amyloid therapies on clinical and biomarker endpoints; and how we can accelerate the pathway to therapeutic approval and what should guide us for the near future. Highlights The Alzheimer's Association Research Roundtable convened leaders from industry and academia, as well as patients, clinicians, and government and regulatory agency scientists to discuss the topic “Current Understanding of AD Pathophysiology & Impact of Amyloid‐beta Targeted Treatments on Biomarkers and Clinical Endpoints.” The totality of scientific evidence (clinical trials, animal data, modeling, and observational studies) on the relationship between amyloid beta (Aβ), amyloid, tau, and cognitive impairment is helping our understanding of the downstream effects and overall importance of lowering amyloid plaque load. Based on data from multiple phase 2 and 3 clinical trials of anti‐amyloid monoclonal antibodies, there is strong evidence to support that a sufficiently large reduction in amyloid plaque load to near‐normal levels is associated with positive changes in tau biomarkers and clinical endpoints. Reduction of Aβ plaque, measured easily by plasma amyloid biomarkers, is reasonably likely to predict benefit in clinical outcome measures.

PURPOSE Many trials ask patients to complete patient-reported outcome measures (PROMs) via the web, excluding patients unable to use/access the Internet. The PRO-TECT trial (AFT-39, ClinicalTrials.gov identifier: NCT03249090 ) also offered a telephone interface option (interactive voice response [IVR]). We compared patients choosing IVR versus web on alert rates to nurses and clinical outcomes to determine if a telephone option can close disparities in symptom management. METHODS PRO-TECT randomized 26 community oncology practices to the PROM intervention arm where concerning symptoms generated automated alerts to nurses. IVR and web patients were compared for social determinants of health (SDOH) using analysis of variance and chi-square tests. After accounting for clustering and confounders, we used generalized estimating equations to compare alert rates, mixed models for quality of life (QOL) at 3 months, and Cox regression for emergency visits and survival at 12 months. RESULTS Among 593 patients, 215 (36%) chose IVR and 378 (64%) chose web. IVR patients were older (65.2 v 60.8 years) and were more often rural residents (32% v 23%), Black (27% v 11%), and with less education (54% v 27% ≤high school; all P < .01). Patients choosing IVR had more surveys with concerning symptoms (49% v 37%) and nurses felt clinical attention was warranted more often (4.8 surveys v 3.4 surveys; all P < .001) but ultimately experienced similar benefits as web in QOL, emergency visits, and survival. CONCLUSION One third of community patients choose a telephone option over the web for reporting PROMs during cancer care. These patients are disproportionately from SDOH backgrounds at risk of poor clinical outcomes and have higher symptom management needs but ultimately experience similar clinical benefits as patients choosing the web. PROM programs should offer web alternatives to close disparities in symptom management.

Background Right ventricular (RV) maladaptation to elevated pulmonary afterload is the primary determinant of outcomes in pulmonary artery (PA) hypertension; however, the pathobiological mechanisms underlying RV decompensation remain poorly understood. Methods We performed global untargeted metabolomics on plasma from 55 patients who underwent gold‐standard RV‐PA coupling measurements using multibeat pressure volume loop assessment in a single‐center cohort and from 1027 patients with coupling surrogate measurements in a larger multicenter cohort, the PVDOMICS (Pulmonary Vascular Disease Phenomics) study. Age and sex‐adjusted linear regression was performed to identify associations between metabolites and coupling metrics. Additionally, we performed a metabolic flux analysis using gene expression data from RV tissue in an independent cohort of 32 patients. Partial least squares–discriminant analysis was used to identify metabolites and reactions characteristic of the decompensated RV. Results RV‐PA coupling was negatively associated with tricarboxylic acid (TCA) cycle intermediate levels. Specifically, plasma α‐ketoglutarate and fumarate were significantly associated with all coupling metrics in both cohorts. Metabolic flux analysis indicated that decompensated RVs exhibited aberrant TCA cycle activity, including reduced acetyl coenzyme A entry and increased lactate elimination, suggesting a shift from the TCA cycle toward glycolysis at the RV tissue level. Conclusions We identify an association between circulating TCA cycle intermediate levels and RV‐PA uncoupling in 2 independent cohorts, and dysregulated TCA cycle metabolism in decompensated PA hypertension RVs, suggesting that aberrant TCA cycle metabolism could represent a hallmark of RV maladaptation in PA hypertension. Further study of this pathway is warranted to develop novel biomarkers of RV function or RV‐targeted therapies.

Abstract Background Hospital‐at‐home programs (HaH) in the United States have evolved to include a virtual‐hybrid delivery model, where all physician encounters are virtual and partnered with a home care team. Objective To examine whether a virtual hybrid HaH program enabled by technology has similar clinical outcomes to traditional brick‐and‐mortar (B&M) hospital care. Methods We conducted a pragmatic trial at three hospitals, randomizing 1150 acutely ill patients requiring hospital care between July 10, 2023, and October 31, 2023 one‐to‐one into two groups: intervention (HaH) and control (B&M). The primary analysis was an intention‐to‐treat non‐inferiority analysis of the primary outcome, which was a composite of 30‐day all‐cause mortality and unplanned readmissions. Secondary outcomes included 30‐day readmission, all‐cause mortality, and patient experience. Results The mean age was 67.8 (standard deviation [SD] 16.3) years, and 52.2% were female. The primary outcome occurred in 99 (17.3%) HaH patients and 114 (19.8%) B&M patients (odds ratio [OR] 0.85, 95% confidence interval [CI] 0.63–1.14, p = .28), meeting the non‐inferiority criterion. Thirty‐day unplanned readmission occurred in 84 (14.7%) HaH patients and 101 (17.5%) B&M patients (OR 0.81, 95% CI 0.59–1.11, p = .19). Thirty‐day all‐cause mortality occurred in 25 (4.4%) HaH patients and 19 (3.3%) B&M patients (OR 1.34, 95% CI 0.73–2.46, p = .35). No HaH patients died while receiving their hospital care at home. HaH program was associated with a higher likelihood of patients reporting feeling extremely comfortable or very comfortable (84.4% HaH; 60.9% B&M, p = .001). Conclusion A hybrid HaH model is a safe and comfortable alternative to traditional B&M hospital care.