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Importance If the success of Descemet membrane endothelial keratoplasty (DMEK) is not affected by whether the donor has diabetes, then the donor pool should expand. Objective To determine whether the 1-year DMEK success rate is affected by the presence of diabetes in the donor. Design, Setting, and Participants This was a multicenter, double-masked, randomized clinical trial conducted from February 2022 to July 2025 at 28 clinical sites (46 surgeons), with donor corneas provided by 13 eye banks in the US. Included in the study were individuals undergoing low to moderate risk DMEK (95% for Fuchs endothelial corneal dystrophy). Study data were analyzed from April to September 2025. Intervention DMEK performed with a cornea from a donor without or with diabetes, assigned using a minimization procedure (comparable with randomization) to achieve an approximate 2:1 distribution, respectively. Main Outcomes and Measures Graft success at 1 year Results A total of 1097 individuals (1421 study eyes; median [IQR] age, 71 [66-76] years; 631 female [57.5%]) were included in the study. The 1-year cumulative probability of graft success was 96.3% (95% CI, 95.0%-97.5%) among 912 study eyes (64.2%) receiving tissue from donors without diabetes and 97.1% (95% CI, 95.5%-98.4%) among 509 study eyes (35.8%) receiving tissue from donors with diabetes (difference between groups = 0.7 percentage points; 95% CI, −1.2 to 2.6; P = .63). The 1-year cumulative probability of graft success was 96.5% (95% CI, 93.6%-98.9%) in the mild donor diabetes severity subgroup (n = 173) and 97.3% (95% CI, 95.4%-98.8%) in the moderate to severe donor diabetes severity subgroup (n = 336), using a diabetes severity rating scale based on medical history. The rates of primary donor failure, early failure related to surgical complications, and subsequent failure were as follows: 2.5% (23 of 912), 0.7% (6 of 912), and 0.3% (3 of 912), respectively, in recipients of tissue from a donor without diabetes, and 2.6% (13 of 509), 0.4% (2 of 509), and 0%, respectively, among recipients of tissue from a donor with diabetes. There were no failures due to graft rejection. Conclusions and Relevance The 1-year success rate in eyes undergoing DMEK with successfully prepared tissue was very high regardless of donor diabetes status. These results, supported by the separately reported finding that endothelial cell loss and cornea morphometry after 1 year were not affected by donor diabetes status, provide strong support for having no restrictions on the use of tissue from donors with diabetes for DMEK. Trial Registration ClinicalTrials.gov Identifier: NCT05134480

Abstract Toxicology testing for drugs associated with scenarios such as recreational use or substance use disorder can be performed in support of the emergency department (ED) for specific patient populations such as pediatrics and trauma. These compounds were historically referred to as drugs of abuse (DOA); although the word “abuse” is recognized as potentially stigmatizing, no replacement terminology for DOA has emerged in current guidelines. This document refers to these compounds as drugs or substances of misuse, and acknowledges the need for less-stigmatizing language that more fully encompasses the range of uses for these drugs. This literature-driven, consensus guidance document provides recommendations primarily targeted to US hospital-based laboratories performing urine drug testing (UDT) in support of the ED. Indications for ordering UDT and related testing in both pediatric and adult populations are summarized. Further, recommendations are made for testing that should be available at all facilities with rapid turnaround, and how to perform and report testing. The advantages and disadvantages of immunoassays and mass spectrometry, as well as common challenges, are reviewed. Indications for mass-spectrometry assays and more extensive testing (e.g., novel psychoactive substances) are also provided. Future directions for improvements in laboratory technology to improve the utility of this testing are outlined. All laboratories should collaborate with ED leadership, medical toxicologists and poison control centers to optimize and update test menus to reflect local drug use patterns, ensure test methodologies and results meet clinical needs, and educate clinical staff regarding assay limitations and accurate test interpretation.

Immune checkpoint inhibitors (ICIs) are an important class of cancer treatment. Endocrine immune-related adverse events (E-irAEs) account for a significant proportion of irAEs in ICI-treated patients. Diagnosing E-irAEs accurately and timely can be challenging in the absence of clear categorization and standardization across oncology, endocrinology and other specialties. While existing guidelines provide some broad directions to diagnosis and management, they lack clarity on irAE-specific symptom evaluation and work-up, as well as assessment of severity. These limitations can then impact triage, time-sensitive management and care escalation to specialists such as oncoendocrinologists. The objective of this study was to develop consensus-based statements on disease definitions for E-irAEs. A core working group of endocrinologists with expertise in the oncoendocrinology field drafted a survey with statements outlining the general approach to E-irAEs, disease definition and management approach of six specific diagnoses: ir-thyroiditis thyrotoxic phase, ir-thyroiditis hypothyroidism, ir-Graves’ disease, ir-hypophysitis, ir-adrenalitis and ir-type 1 diabetes mellitus. Severity grading tables were drafted for three disease categories—“thyroid”, “pituitary and adrenal”, and “diabetes mellitus”. A two-round modified Delphi process, using the RAND/University of California Los Angeles (RAND/UCLA) Appropriateness Method, was employed. In this process, a 25-member voting panel consisting of endocrinologists, oncologists and other specialists and healthcare providers with experience in management of ICI-treated patients and irAEs was recruited. The panel rated anonymously on usability, accuracy, appropriateness or agreement of 41 items on a 9-point scale in Survey 1, after which a meeting was convened. Statements were modified based on voting results from Survey 1 and Meeting 1, and the process was repeated in Survey 2 and Meeting 2. At the end of this process, consensus was achieved for all statements. Our study findings address the gap in standardized nomenclature, clinical, laboratory and radiological evaluations, and management principles of E-irAEs. With consensus achieved from a panel of experts from a variety of disciplines, we anticipate that the statements can form the basis for standardization of the diagnostic process and improvement of patient care.

Obesity is an epidemic with myriad health effects, but little is understood regarding individual obese phenotypes and how they may respond to therapy. Epigenetic changes associated with obesity have been detected in blood, liver, pancreas, and adipose tissues. Previous work using human organoids found that dietary glucose hyperabsorption is a steadfast trait in cultures derived from some obese subjects, but detailed transcriptional or epigenomic features of the intestinal epithelia associated with this persistent phenotype are unknown. This study evaluated differentially expressed genes and relative chromatin accessibility in intestinal organoids established from donors classified as non-obese, obese, or obese hyperabsorptive by body mass index and glucose transport assays. Transcriptomic analysis indicated that obese hyperabsorptive subject organoids have significantly upregulated dietary nutrient absorption transcripts and downregulated type I interferon targets. Chromatin accessibility and transcription factor footprinting predicted that enhanced HNF4G binding may promote the obese hyperabsorption phenotype. Quantitative RT-PCR assessment in organoids representing a larger subject cohort suggested that intestinal epithelial expression of CUBN, GIP, SLC5A11, and SLC2A5 were highly correlated with hyperabsorption. Thus, the obese hyperabsorption phenotype was characterized by transcriptional changes that support increased nutrient uptake by intestinal epithelia, potentially driven by differentially accessible chromatin. Recognizing unique intestinal phenotypes in obesity provides a new perspective in considering therapeutic targets and options with which to manage the disease.

Lacking effective therapeutics, cholangiocarcinoma (CCA) remains a deadly malignancy of the biliary tract. The Hippo pathway effector protein Yes-associated protein (YAP) is implicated in CCA pathogenesis and chemotherapeutic resistance; however, the oncogenic mechanisms underlying YAP regulation remain incompletely understood. An enhanced understanding of YAP and its role in CCA may uncover novel therapeutic targets and better define resistance pathways. Human CCA cells and murine syngeneic CCA models were utilized to explore the molecular relationship of YAP and protein tyrosine phosphatase 1B (PTP1B). Previous work in CCA has demonstrated that YAP interacts with multiple protein tyrosine phosphatases, including SHP2 and PTP1B. We observed that PTP1B pharmacologic inhibition was associated with increased cell proliferation and YAP target gene expression, while genetically enforced overexpression of PTP1B was associated with a decrease in YAP activation. Treatment of CCA cells in vitro and syngeneic, orthotopically implanted CCA murine tumors in vivo with standard cytotoxic chemotherapy, gemcitabine/cisplatin, had enhanced efficacy in the setting of PTP1B overexpression. These findings demonstrate that pYAPY357 can be modulated through protein tyrosine 1B phosphatase activity, and reducing pYAPY357 through enhanced phosphatase levels can sensitize CCA to chemotherapy.

Background Approximately 20% of hospice patients in the US are discharged alive, often due to Medicare regulations. Such discharges are frequently perceived by caregivers as abandonment or expulsion, especially when they occur without follow-up or planning for care transition. Methods This study explored caregiver experiences with live hospice discharge through 2 narrative interviews and institutional data from a Midwest medical center (January 2020 through December 2022). Caregiver stories were analyzed thematically to identify emotional and logistical challenges. Retrospective patient data were also reviewed to provide descriptive statistics on patient volume. Results Of 1556 hospice patients discharged, 107 (6.9%) were discharged alive, with a mean length of stay of 205 days—substantially longer than that for the general hospice population. Most patients were women who were diagnosed with cerebrovascular or neurologic conditions and discharged from skilled-care facilities. One of the caregivers described discharge as distressing and poorly coordinated; the other reported a positive experience shaped by prior knowledge and financial resources. Both emphasized the importance of clear communication, care planning (eg, to avoid loss of durable medical equipment), and interdisciplinary support. The caregiver’s financial stability likely influenced discharge decisions and preparedness. Conclusions Live hospice discharge can cause emotional and practical disruption, especially when not accompanied by a care transition plan or access to durable medical equipment. This study highlights the need for team-based communication, sensitivity in language, and continued support. Engaging all members of the interdisciplinary team and ensuring access to essential resources may improve caregiver confidence and continuity of care.

Background: Patient safety event reporting systems are essential for identifying potential risks and improving patient outcomes. However, traditional systems frequently face issues of under-reporting, particularly concerning near-miss and no-harm events, thereby limiting opportunities for organizational learning and harm prevention. This initiative used quality improvement principles to design a new reporting system at our institution to enhance safety culture. Methods: Following extensive stakeholder feedback and multidisciplinary collaboration, a new system was implemented on July 22, 2022. Key features included streamlined reporting, centralized data analysis, and enhanced transparency. Results: Overall event reporting as well as proportional reporting of near-miss and no-harm events increased significantly from around 60% preimplementation to 80% after implementation. Staff engagement also improved, as shown by a steady rise in the number of unique event reporters and reviewers. Conclusions: The new reporting system has improved reporting overall, with increases in near-miss and no-harm events, along with increased staff engagement with the reporting and review process. Our experience offers practical lessons for institutions seeking to strengthen the learning value of event reporting systems. The principles we identified with simplifying ease of use, integrating into the EHR, improving data transparency, and encouraging greater involvement with event review, along with clear oversight protocols, apply beyond our institution and are not limited to a specific PSRS product or system. These initial outcomes support a culture of safety and bolster organizational learning, with future study needed on long-term effects on patient safety outcomes, staff involvement, and increased trust.

459 Background: Quality improvement (QI) addresses local quality gaps to optimize care delivery, while implementation science (IS) seeks to increase adoption of evidence-based practices (EBPs) to close research-practice gaps and improve population health. Identifying opportunities for QI-IS synergy can foster collaboration and ensure attention to rapid and sustainable improvements in evidence-based care. Our objectives were to 1) assess how QI projects submitted for silver or gold certification in our academic medical center addressed evidence-based gaps in cancer care and 2) consider how their methods align with IS approaches. Methods: The QI project database was keyword searched to identify proposals in cancer. Data including detailed description of the quality gap and methods to identify and evaluate interventions were abstracted and entered in a database organized by the DMAIC framework (Define, Measure, Analyze, Improve, and Control). Two investigators reviewed data to identify EBPs and describe evidence using a typology for IS (Type 1 etiology and burden, Type 2 intervention effectiveness, and Type 3 dissemination and implementation in context). Data in DMAIC domains were mapped to relevant IS constructs for side-by-side comparison. Results: The search identified 81 proposals submitted between May 2017 and April 2025, of which 62 targeted cancer-related care gaps (5.2% of applications). Fourteen referenced published EBPs, including American Society for Clinical Oncology or National Comprehensive Cancer Network guidelines and state or federal quality metrics on cancer screening or evaluations for diagnosis and treatment. An additional 17 addressed processes relevant to EBPs, e.g., screening documentation. QI tools like cause-and-effect diagrams identified multilevel causes, but few proposals deployed multilevel interventions (strategies in IS), and none referenced theory. Reported “lessons learned” further detailed unanticipated patient, care team, and system-level challenges. Most (n=24, 77%) of EBP-related proposals addressed Type 2 evidence (e.g., performance, quality, efficiency) but could have also been framed as Type 3 evidence on implementation context/strategies targeting implementation outcomes (e.g., clinician adoption, patient reach, implementation fidelity). Conclusions: Although focused on local improvement, about 1 in every 20 QI proposals addressed implementation of cancer EBPs. Framing QI purpose as addressing Type 3 evidence could help link local QI projects to IS theory and methods to inform strategy selection and evaluation of implementation outcomes that precede service-level outcomes. Organizations that combine rapid-cycle QI improvements and rigorous IS methodologies may more effectively close care gaps and tackle persistent healthcare challenges.