Citations

Background: Although the embolic stroke of undetermined source (ESUS) construct was proposed as a unifying concept for embolic-appearing strokes without an identified cause, it includes patients with diverse and often unrecognized underlying mechanisms. This study investigates the differential rate of recurrent stroke according to the completeness of neurodiagnostic testing in a diverse multicenter cohort. Methods: This was a retrospective analysis of a multicenter observational cohort study (n=27 sites). Patients with ESUS were categorized into three groups: (1) established mechanism after further work up (ESUS-E), (2) patients who underwent a comprehensive diagnostic workup without an identified etiology (ESUS 2.0), and (3) no advanced workup (ESUS-NAW). The primary outcome of recurrent ischemic stroke was assessed by comparing ESUS 2.0 to both ESUS-E and ESUS-NAW groups using adjusted Cox proportional hazards models. Results: Of the 2,281 patients included, 694 (30%) were classified as ESUS-E, 344 (15%) as ESUS 2.0, and 1,443 (55%) as ESUS-NAW. The ESUS 2.0 group had a significantly lower annualized recurrence rate (1.98 per 100 person-years) compared to both the ESUS-NAW group (7.7 per 100 person-years; aHR 0.27, 95% CI: 0.11–0.62; p=0.002) and the ESUS-E group (6.10 per 100 person-years; aHR = 0.35; 95% CI 0.15–0.85, p=0.020). Within the ESUS-E group, cancer (aHR 5.33; 95% CI: 2.09–13.63; p < 0.001) and non-stenosing atherosclerotic disease or arch atheroma (aHR 3.40; 95% CI: 1.18–9.83; p = 0.023) were associated with significantly increased risk of recurrence when compared to ESUS 2.0. Conclusion: These findings demonstrate a lower risk of recurrent stroke in patients classified as ESUS 2.0, diverging from the 5–6% annual recurrence rates observed in prior ESUS trials. These findings suggest that patients who receive comprehensive diagnostic evaluation without identification of a specific etiology have a lower risk of recurrent stroke, an important consideration for the design of future ESUS studies.

INTRODUCTION: Reliable biomarkers for the diagnosis of chronic pancreatitis (CP) and pancreatic fibrosis severity are lacking, hindering effective treatment and management. Histologic fibrosis is a hallmark of late-stage CP, but noninvasive methods to evaluate fibrosis progression are limited. We used urine proteomics to discover biomarkers that identify patients with CP and predict fibrosis severity. METHODS: We performed a cross-sectional study of 130 total subjects (CP n = 50) selected based on clinical criteria in a tertiary care setting. Urine proteomics samples were quantified using data-independent acquisition mass spectrometry. Differential biomarker candidates were identified with false discovery rate-corrected pairwise comparisons. These proteins were validated with an independent paired urine and plasma sample cohort (n = 36). Machine learning was used to develop a protein panel that predicted Ammann scores for patients with histologic fibrosis. RESULTS: We found 34 proteins consistently differentially expressed between CP and controls in pairwise false discovery rate-controlled tests. Of these, 25 urine proteins outperformed 19 previously suggested CP blood-based biomarkers in an independent validation cohort. Isocitrate dehydrogenase (IDH1), calcyphosin (CAPS), synuclein gamma (SNCG), and protein S100-P (S100P) all produced receiver operator curve area under the curve values >0.95, while the best plasma marker was interleukin 2 receptor subunit alpha (receiver operator curve area under the curve = 0.80). A 12-protein panel of identified markers predicted fibrosis severity with a linear correlation R 2 value of 0.61. DISCUSSION: We identified a panel of proteins that may diagnose CP in children and developed a model to predict pancreatic fibrosis severity, offering promising tools for improving diagnostics and patient care.

Abstract Background Global data demonstrate an inverse relationship between hospital ileoanal pouch volume and adverse outcomes, highlighting the need for quality metrics for this technically demanding procedure.1-4 Currently, there are no standardised quality indicators to define high-quality pouch surgery. This study aimed to establish international consensus on key performance indicators (KPIs) in pouch surgery. Methods A modified Delphi process was conducted among an international, multidisciplinary panel of experts. Participants were identified through professional networks, literature review, and direct email invitation; additional participants recruited via a snowball sampling approach over one month. Candidate KPIs were generated from literature review and expert input across 5 domains. Each item was rated on a 9-point Likert scale (1 = not important, 9 = critically important); consensus was predefined as ≥ 80% of respondents rating an item 7–9. Items not reaching consensus were re-rated in a second round following anonymized group feedback. Results Round 1 included 312 participants from 37 countries. Demographics (Table 1): 53% were age 45 years, 35.2% were female, and included surgeons (68.6%) and gastroenterologists (31.1%). Most (76.6%) practice at academic or university hospitals, with a median of 11 (5–17) years in practise; 78.9% perform &gt;1 pouchoscopy per month, and 39.5% of surgeons perform 5 pouches/year. Respondents’ regions included North America (51%), Europe (26%), Oceania (9%), Asia (6%), Latin America (4%), and the Middle East/Africa (4%). Seven (18%) countries (Denmark, Lithuania, Malaysia, Norway, United Arab Emirates, Sweden, and Switzerland) reported pouch surgery is already centralised, while 70.6% agreed pouch centralisation should be implemented. Cost/logistics and professional autonomy were the most important barriers to centralisation, whereas capacity and training exposure were least important. Overall, 37/59 (62.7%) candidate KPIs reached consensus after Round 1. The Round 2 response rate was 61%, and 2 additional KPIs reached consensus (preop ileitis and long-term risk of pouchitis). Additionally, 14 of 25 (56%) informed consent items reached consensus, and 64% of respondents felt informed consent for pouch surgery requires 2 or more office visits. Consensus items were used to populate a KPIPS Checklist (Figure 1). Conclusion Through an international Delphi process, the KPIPS study identified a consensus-derived set of key performance indicators to measure quality in pouch surgery. These quality metrics provide a foundation for benchmarking outcomes and represent a critical step towards centralization and the development of designated pouch centres of excellence to improve global standards of care for pouch patients. References: 1. Worley GHT, Fearnhead NS, Brown SR, et al. Review of current practice and outcomes following ileoanal pouch surgery: Lessons learned from the ileoanal pouch registry and the 2017 ileoanal pouch report. Colorectal Dis 2018;20:913–22. 2. Giddings HL, Yang PF, Steffens D, Solomon MJ, Ng KS. Influence of hospital-level and surgeon factors on the outcomes after ileo-anal pouch surgery for inflammatory bowel disease: Systematic review. Br J Surg 2024;111. 3. Hoang CM, Maykel JA, Davids JS, et al. Distribution of elective ileal pouch-anal anastomosis cases for ulcerative colitis: A study utilizing the university health system consortium database. J Gastrointest Surg 2020;24:2613–9. 4. Moojen TB, Visser E, Reijntjes MA, et al. One-year stoma-free survival of ileoanal pouches for uc in european centers: The miracle project. Ann Surg Open 2025;6:e596. Conflict of interest: Prof. Holubar, Stefan: No conflict of interest Soop, Mattias: No conflict of interest Poskus, Tomas: No conflict of interest Neary, Peter: No conflict of interest Uchino, Tairin: No conflict of interest Yang, Song-soo: No conflict of interest Adamina, Michel: No conflict of interest Avellaneda, Nicolas Luis: No conflict of interest Barnes, Edward: No conflict of interest Brouquet, Antoine: No conflict of interest Brown, Steven Ross: No conflict of interest De Buck Van Overstraeten, Anthony: No conflict of interest Buskens, Christianne J.: No conflict of interest Chiorean, Michael: No conflict of interest Clark, David: No conflict of interest Cohen, Benjamin: No conflict of interest El Ouali, Sara: No conflict of interest Faiz, Omar Darius: No conflict of interest Fichera, Alessandro: No conflict of interest Hahnloser, Dieter: No conflict of interest Hancock, Laura: No conflict of interest Herfarth, Hans: No conflict of interest Johnston, Michael: No conflict of interest Kayal, Maia: No conflict of interest Laharie, David: No conflict of interest Liberman, Sender: No conflict of interest Loftus, Jr, Edward: No conflict of interest Moeslein, Gabriela: No conflict of interest Myrelid, Pär: No conflict of interest Poylin, Vitaliy: No conflict of interest Qazi, Taha: No conflict of interest Raffals, Laura: No conflict of interest Rubin, David T.: No conflict of interest Spinelli, Antonino: No conflict of interest Steinhagen, Emily: No conflict of interest Tozer, Philip: No conflict of interest Verstockt, Bram: No conflict of interest Warusavitarne, Janindra: No conflict of interest Wexner, Steven: No conflict of interest Winter, Desmond: No conflict of interest

OBJECTIVE: Volatile anesthetics (VAs) are gaining renewed interest as a sedation strategy in the intensive care, offering an alternative to traditional IV agents. VAs provide several pharmacologic advantages, including rapid onset and offset, minimal systemic metabolism, and favorable recovery profiles. Advances in delivery systems enabled the safe and practical administration of volatile agents in the ICU. Thus, we aimed to describe the pharmacology and safety aspects of inhaled agents as well as the systems designed to deliver VAs in the ICU. DATA SOURCES: Relevant literature was identified through PubMed and MEDLINE databases. STUDY SELECTION: Original research, review articles, commentaries, and guidelines addressing safety, efficacy, and use of VAs in adult ICU patients were included. DATA EXTRACTION: Studies were reviewed by the authors, with key findings summarized and organized by pharmacologic properties, delivery systems, and safety domains. DATA SYNTHESIS: VAs are halogenated hydrocarbons whose mechanism of action is not fully understood. Although the CNS is the primary site of action, the end-tidal concentration of exhaled anesthetic is used to monitor clinical effects such as immobility to a noxious stimulus. Inhaled agents have unique pharmacokinetics, minimal metabolisms, and distinct recovery. The side effect profile is also unique, with malignant hyperthermia being the most feared, yet rare complication. Two systems for inhalational sedation delivery are available internationally, with one currently under evaluation in the United States. The systems are composed of a miniature vaporizer, delivery controller, and a monitor. The systems have distinct safety considerations, such as tidal volume limits. CONCLUSIONS: VAs can be used as sedative agents in the ICU. This article comprehensively reviews the pharmacology of VAs along with their safety profile and describes the structure and function of miniature vaporizers currently available on the world market.

Individuals with congenital heart disease are living well into adulthood, resulting in a growing population at risk for neurocognitive and psychosocial challenges. Numerous studies have described these risks in childhood, but significant gaps remain in our understanding of how those challenges evolve across stages of adulthood and how to optimally integrate neurocognitive and psychosocial care for adults with congenital heart disease. A multidisciplinary group of experts and patient partners assembled in April 2024 in Atlanta, GA, forming 3 working groups: (1) Genetics and Brain Health, (2) Characterizing Neuropsychological and Psychological Outcomes, and (3) Neuropsychological and Psychosocial Interventions. Current knowledge was reviewed, knowledge gaps were identified, and recommendations to address these gaps were formulated. Five critical questions regarding the characterization of neuropsychological and psychological outcomes of adults with congenital heart disease were prioritized for discussion: which neurocognitive and psychosocial domains should be prioritized in research and clinical care, what are the trajectories of neurocognitive and psychosocial functioning over the lifespan, how should neurocognitive and psychosocial screening be deployed, what should neurocognitive and psychosocial assessments include, and how do we make comprehensive neurocognitive and psychosocial care a reality. Although many gaps in knowledge were identified, particularly around characterizing neurocognitive trajectories throughout adulthood, there is substantial evidence of increased risk for poor psychosocial outcomes among adults with with congenital heart disease. Clinical and research advances must progress in tandem to address these risks. Specific recommendations for advancing this field over the next decade are offered.

Objectives: Smoking is a key risk factor for pancreatitis, contributing to pathogenesis and disease progression. Data regarding second-hand smoking, or passive smoking (PS) exposure, are lacking. We therefore aimed to assess the impact of PS exposure across the pancreatitis spectrum. Methods: We analyzed baseline data from the PROCEED study, a multicenter study in the United States including patients with acute (AP), recurrent acute (RAP), and chronic (CP) pancreatitis. Participants detailed their individual smoking history and PS exposure, which was compared between AP, RAP, and CP subgroups. Participant factors and clinical characteristics were compared by level of individual and PS exposure. Results: Among 1369 participants (190 AP, 498 RAP, 681 CP), 346 (25.3%) were current and 409 (29.9%) were former smokers. The CP subgroup had the highest proportion of current smokers (36.7% CP vs 15.1% RAP, 11.1% AP, P < 0.001). PS exposure was also significantly higher in the CP subgroup (68.6% CP vs 58.2% RAP, 55.3% AP, P < 0.001). A minority (16.3%) with CP reported no smoking exposure (by self or passive) while nearly half smoked ≥20 pack-years. The mean PS duration was significantly higher in CP participants (21.8 y) compared with those with AP (17.8 y) or RAP (18.9 y) ( P < 0.0166). Conclusions: In this multicenter study, we affirmed an association with smoking use and intensity with CP-related complications. For the first time, we report a high prevalence of prior exposure to passive smoking in all pancreatitis subtypes, which requires further study to understand the impact on disease outcomes.

ABSTRACT Objective With regulatory approval of HPV‐specific immunotherapy for recurrent respiratory papillomatosis (RRP) and growing experience with systemic bevacizumab, a management algorithm incorporating these medical treatments is warranted. Data Sources and Methods RRP Foundation (RRPF) Key Opinion Leaders offer a proposed management algorithm for adults with RRP considering published literature and commercial drug availability. Results Preventative HPV vaccination should be considered for all patients. Determination of HPV type and pulmonary imaging are important for contemporary RRP patient care and assist in decision making. Risks and benefits of papilloma debulking as needed versus medical management of RRP must be deliberated on a patient case‐by‐case basis. HPV ‐specific immunotherapy that induces an HPV ‐specific T cell response to target the underlying HPV infection that is the cause of RRP is safe, offers the possibility of durable disease control following a short treatment course and is the recommended first‐line medical treatment for patients who wish to avoid the risks of repeat procedural management. Papilloma disease control with systemic bevacizumab, which carries defined risks and must be continued for clinical benefit is the recommended second‐line medical treatment for patients who do not achieve a complete response with immunotherapy and wish to continue medical management. For patients who elect to be treated with debulking procedures as needed, use of locally‐administered adjuvant should be considered. Conclusion This proposed management algorithm from the RRPF serves as a contemporary resource and information guide for adult patients with RRP and their physicians considering treatment options. Level of Evidence 5

ABSTRACT Obstructive sleep apnea (OSA) is a common, heritable disorder with diverse clinical presentations and etiologies. We conducted a genome-wide association meta-analysis of 492,107 individuals, including 46,028 OSA cases, identifying 14 genome-wide significant loci, eight of which are novel. Analyses adjusting for body mass index (BMI) revealed three loci independent of obesity, implicating alternative biological pathways contributing to disease. Integrative functional analyses, including chromatin interaction mapping, fine-mapping, and eQTL colocalization, prioritized candidate effector genes. Notably, implicated genes in chondrocytes were associated with craniofacial morphology in both mouse and human multivariate genotype-phenotype mapping, supporting a role for craniofacial structure in OSA risk. These findings highlight key genetic pathways (obesity-related, neurological, and craniofacial) underlying the development of OSA, offering new insights into its complex etiology.

Abstract Background Despite advancements in care, pregnant individuals with congenital heart disease (CHD) face disproportionately high risks. Objectives To address these challenges, a national consortium was established to improve maternal outcomes in CHD through multidisciplinary collaboration and patient engagement. Study design As part of a 2.5‐year multi‐phase consortium initiative, an in‐person research summit followed by three virtual focus groups (Project PHASE 3) was conducted with patients, clinicians, researchers, advocates, and policy representatives. Qualitative data were collected, and reflexive thematic analysis was performed to identify shared priorities. Results A total of 48 individuals participated in the in‐person meeting, including 18 patients (83% female; 11% Black/African American, 17% Asian, 11% Hispanic, 61% White) and 30 clinicians/researchers. An additional 19 patients (100% female; 32% rural/non‐urban; 16% Black/African American, 10% Hispanic, 74% White) participated in virtual focus groups. Key priorities identified included improved patient–healthcare provider communication, expanded access to multidisciplinary and adult CHD‐specialized care, and greater inclusion of patient voices in reproductive planning and research. Focus groups underscored racial disparities in care, limited CHD education for patients of color, and the need for culturally tailored resources. Participants emphasized the importance of representative research cohorts, integration of genetic counseling, and dissemination of research in accessible, plain‐language formats. Conclusions Findings demonstrate the value of integrating patient expertise and partnership in shaping cardio‐obstetric research, care models, and education. Addressing maternal health concerns in CHD research requires both structural changes and community‐driven, inclusive research strategies.