Citations

Abstract Meaningful benefit is a much‐debated concept in Alzheimer's disease (AD). Research to date has primarily focused on change thresholds that are anchored in clinicians’ or care partners’ impressions; however, these thresholds are not inherently meaningful to people living with AD (PLWAD) and may not take their perspectives into account. By overlaying the lived experience of AD through the eyes of individual PLWAD and their care partners with clinical outcomes, we offer an important framework in which to consider meaningful benefit in terms of symptoms, functioning, and outcomes. The PLWAD and care partner interviews and surveys of the What Matters Most (WMM) research program have identified treatment‐related needs, preferences, and priorities of people at risk of or living with AD and their care partners across the AD continuum. A WMM conceptual model of disease—created and refined through interviews with PLWAD and care partners across the AD severity spectrum—includes 50 concepts across six domains (social life/activities, thought processing, communication, daily activities, mood/emotion, and general independence) considered important to all PLWAD and care partners. From the PLWAD and care partner perspectives, an increase in time to the onset, development, or worsening of the symptoms in any of these meaningful concepts was considered a meaningful benefit. No single commonly used clinical outcome assessment captures all concepts of importance, nor the importance of time in AD; considering the lived experience and priorities of individuals affected by AD is crucial to put the “meaning” in “meaningful.”

Abstract This article presents an updated framework from the Society of Hospital Medicine for individual learning objectives related to key procedures in hospital medicine. Building upon the 2017 framework, these objectives have been revised to reflect evolving clinical evidence, advancements, and shifts in hospital medicine practice patterns. The methodology included a comprehensive literature review, expert consensus panels, and feedback from practicing hospitalists across diverse clinical settings. The updated learning objectives address procedural competencies for the most common interventions in hospital medicine, including arthrocentesis, emergency procedures, interpretation of chest radiographs and electrocardiograms, lumbar puncture, paracentesis, thoracentesis, and vascular access. These revised learning objectives provide a framework to guide curricular development, continuing medical education, and hospital medicine practitioners in developing and maintaining procedural competence essential for high‐quality inpatient care.

ABSTRACT The stromal tumor environment (STE) plays a vital yet often underrecognized role in cancer progression, shaping tumor development. It influences complex interactions among stromal cells, immune cells, extracellular matrix (ECM) components, and signaling molecules. Stromal cells regulate integrin signaling and are involved in remodeling the tumor microenvironment, driving critical processes such as cell migration, survival, angiogenesis, and proliferation. Advances in understanding the STE are creating new opportunities for early cancer detection and treatment. Innovations in molecular imaging, particularly for melanoma, are transforming cancer diagnostics by providing deeper insights into tumor biology, cellular interactions, and angiogenesis, paving the way for more personalized and timely therapeutic interventions. Among these advancements, in vivo skin fluorescent imaging (SFI) stands out as a powerful tool, offering real‐time molecular insights at the point of care with the ability to improve patient management.

Objective Specific sedative hypnotic agents, administered to facilitate endotracheal intubation (ETI) in critically ill adults, may lead to adverse outcomes such as peri-intubation cardiovascular collapse. However, little is known from systematic investigations of the impact these individual agents have on cardiovascular function or other clinical outcomes. Data sources MEDLINE, Embase, CENTRAL, ClinicalTrials.gov, Scopus and Web of science databases. Study selection We conducted a systematic search for randomized and non-randomized studies that evaluated adult (≥18 years) critically ill patients who were sedated to facilitate ETI with ketamine, propofol, ketamine/propofol, etomidate, or a benzodiazepine and who had data on peri-intubation hemodynamics and at least one other outcome involving acute kidney injury, delirium, opioid use, intubation difficulty, sequential organ failure assessment, length of stay, or mortality. Eighty-five studies were identified for eligibility assessment with 23 included in the analysis. Data extraction Two reviewers independently screened articles, extracted data from selected articles, and assessed risk of bias using ROBINS-I for observational studies and revised Cochrane Risk of Bias tool for randomized controlled trials. Data synthesis Acute cardiovascular dysfunction (peri-intubation hemodynamic instability and/or cardiac arrest) was similar between etomidate and ketamine with more events seen when propofol versus non-propofol sedation was administered. However, exploratory meta-analysis demonstrated no difference between etomidate and ketamine (OR 1.05 [95%CI 0.60-1.84]) or between etomidate and propofol (OR 0.91 [95%CI 0.33-2.46]). Compared to ketamine, etomidate demonstrated lower survival to hospital discharge in the included studies in exploratory meta-analysis OR 0.76 (95%CI 0.62-0.92). Limited data existed for other outcomes with no discernible differences between sedative agents. Conclusions Acute cardiovascular dysfunction was more common when propofol, as compared to non-propofol sedation, was administered, although not statistically significant in exploratory meta-analysis. In addition, etomidate conferred lower survival to hospital discharge versus non-etomidate sedation, which was confirmed in exploratory meta-analysis of etomidate versus ketamine.

INTRODUCTION: There is an urgent need for effective and safe treatment of gastroparesis. Metopimazine, a selective, peripherally restricted dopamine D 2 receptor antagonist, is used in France for the symptomatic treatment of nausea and vomiting and chemotherapy-induced nausea and vomiting. The aim of this study is to assess the safety and efficacy of oral NG101, the mesylate salt of metopimazine, for the treatment of gastroparesis. METHODS: We conducted a 12-week phase 2 multicenter trial with NG101 5, 10, and 20 mg 4 times a day versus placebo. The primary end point was the change in mean nausea severity from the Diabetic and Idiopathic Gastroparesis Symptoms Daily Diary (DIGS-DD) during weeks 7–12 of the Treatment Period from baseline. The DIGS-DD measured nausea, abdominal pain, early satiety, postprandial fullness, and vomiting at their worst in the past 24 hours using a 0-10 point numeric rating scale. Patient Global Impression of Change questionnaires, including nausea, were assessed weekly using a 7-point balanced ordinal score. RESULTS: Of 161 randomized participants (45.3% diabetic and 54.7% idiopathic), mean DIGS-DD nausea severity scores decreased from baseline during weeks 7–12 in all treatment groups, but these improvements were not statistically significant compared with placebo. However, there were statistically significant improvements in nausea Patient Global Impression of Change during weeks 1–12 for all treatment groups compared with placebo. Trends in safety and efficacy favored patients with idiopathic gastroparesis compared with those with diabetic gastroparesis. DISCUSSION: While NG101 did not meet statistical significance in its primary end point for reducing nausea severity, it demonstrated a favorable safety profile and significant improvement in some secondary end points. Further study is needed to determine whether NG101 is an effective treatment for patients with idiopathic gastroparesis.

Abstract Extramedullary disease (EMD) is associated with an inferior prognosis and lower response rates to conventional multiple myeloma (MM)–directed therapies compared to MM without EMD. A deeper understanding of the molecular landscape and underlying drivers of EMD is essential to identify potential targets for novel therapeutic strategies. To address this, we performed whole-exome sequencing on EMD tumor tissue from 18 unique patients and bone marrow aspirates (BMAs) from 20 patients at the time of EMD development. Notably, paired EMD and BMA samples were collected from 6 patients at the point of EMD diagnosis, allowing for direct comparison of molecular profiles. Our analysis revealed a near-universal presence of mutations within the MAPK pathway in EMD samples (94%), compared to BMAs (60%; odds ratio, 10.7; P = .02; q < 0.1). Additionally, mutations in established driver genes (NRAS, KRAS, and BRAF) were common and frequently clonal, suggesting their central role in EMD pathogenesis. We also identified alterations in genes associated with cell adhesion and migration (ROBO1, ROBO2, and FAT1) and the SWI/SNF complex and epigenetic regulators (ARID1A, KMT2C, KMT2D, and EP300), although these were predominantly subclonal. Furthermore, we frequently detected biallelic alterations in the tumor suppressor genes MAX (22%), a binding partner for MYC, and CDKN2C (17%). Genomic complexity was significantly higher in EMD samples than BMAs, as evidenced by increased tumor mutational burden and the enrichment of 1q gain/amplifications. These findings underscore the distinct molecular profile of EMD compared to BMA and highlight the genomically complex and heterogeneous nature of extramedullary disease in MM.

ImportanceThe rates of suicide and suicide attempts are rising precipitously among early adolescents aged 10 to 14 years in the US. While suicide attempts in this age group are more common and associated with lower lethality than in older age groups, very little is known about these individuals’ long-term social and psychiatric outcomes.ObjectivesTo examine the adult outcomes of individuals making index suicide attempts that came to medical attention between the ages of 10 and 14 years.Design, Setting, and ParticipantsThis population-based cohort constitutes a subsample (n = 164) of a previously reported retrospective-prospective study examining individuals who made index suicide attempts during a 22-year period (1986-2007) in Olmsted County, Minnesota.Main Outcomes and MeasuresTo collect outcome measures, the medical records of all individuals were queried until March 31, 2023, comprising up to 36 years of follow-up data after the index attempt. Measures included current social, psychiatric, and mortality outcomes as well as lifetime measures of psychiatric hospitalizations and repeat suicide attempts. K-means clustering generated adult groupings based on aggregates of psychiatric hospitalizations and repeat attempts. Multivariable logistic regression identified index attempt factors associated with poor adult outcomes.ResultsOf 164 individuals aged 10 to 14 years who made index attempts (128 [78.0%] female; mean [SD] age at index attempt, 13.7 [1.1] years), 3 (1.8%) died on the index attempt. In the follow-up period, no individuals died by suicide. K-means clustering generated a 2-group solution reflecting low (120 [80%]) and high (30 [20%]) rates of adult psychopathology. While a minority of the sample belonged to the high-rate group, characterized by multiple repeat attempts and hospitalizations, the majority had favorable social indicators and fewer reattempts and hospitalizations. Poor adult outcomes were associated with being male (odds ratio, 2.44; 95% CI, 1.00-5.80; P = .04) and having a psychiatric diagnosis prior to the index attempt (odds ratio, 3.27; 95% CI, 1.42-8.07; P = .007).Conclusions and RelevanceIn this sample of early adolescents with index suicide attempts followed into adulthood, all who died by suicide did so on the index attempt. While a small number of individuals went on to develop chronic severe psychopathology, the majority demonstrated little evidence of long-term impairment. Given this discrepancy, future studies should focus on using risk stratification after index attempts to direct postvention resources toward adolescents more susceptible to poor outcomes.