Citations

Background Postoperative respiratory depression (PRD) is potentially preventable yet remains difficult to preemptively detect. We evaluated whether three post anesthesia care unit (PACU) events—oversedation, caffeine administration for impaired arousal, and naloxone administration—can serve as early markers of delayed PRD requiring naloxone administration on wards. Methods We retrospectively identified patients who underwent general anesthesia between 2018 and 2023 at a quaternary care academic medical center. From electronic medical records, we retrieved PACU naloxone and caffeine treatments, scores of sedation assessments using the Richmond Agitation-Sedation Scale (RASS), and ward naloxone administrations within 24 hours after PACU discharge. Results Among 95 870 patients, 186 (0.19%, 95% CI 0.17-0.22) required naloxone for respiratory depression after PACU discharge. Ward naloxone administration was independently associated with naloxone (OR 9.11, 95% CI 4.69-17.71, P < 0.001) and caffeine (OR 2.00, 95% CI 1.21-3.32, P = 0.007) administrations, and with PACU RASS scores ≤ −3 (OR 2.16, 95% CI 1.56-2.99, P < 0.001). Conclusions Naloxone administration in PACU was the strongest predictor of delayed PRD, followed by oversedation and PACU caffeine administration, indicating that information routinely collected during PACU recovery may offer insight into delayed respiratory risk before transition to hospital wards. In light of the overall low incidence of ward naloxone use, these findings support selective, risk-based vigilance for patients exhibiting these PACU events rather than broad adjustments to existing monitoring practices.

ABSTRACT Considerable advances have been made in our understanding of Bardet–Biedl syndrome (BBS), particularly in its core clinical features and molecular genetics, warranting an update to the existing diagnostic criteria framework. Using a rigorous, evidence‐based, and consensus‐driven process, a multidisciplinary group of international experts and patient‐led organizations developed an updated diagnostic algorithm. This algorithm provides practical, updated guidance for clinicians, including a pathway for accurately incorporating genetic findings into the diagnostic process. We recommend that a clinical diagnosis requires either 4 major criteria or 3 major and 2 minor criteria. Revised major criteria are retinal dystrophy, obesity (or overweight in individuals < 2 years old), congenital anomalies of the kidney and urinary tract or chronic kidney disease, hypogonadism/genital anomalies, neurodevelopmental/neurocognitive manifestations, and postaxial polydactyly. The diagnosis can also be established with a positive genetic testing result in patients exhibiting ≥ 1 major criterion, provided that genetic findings should be interpreted in the context of the patient's clinical presentation, age, family history, and overlap with related ciliopathies. These consensus criteria offer a simple algorithm incorporating updated definitions for major and minor criteria and genetic testing to support a timely and accurate diagnosis of patients with BBS, inform genetic counseling, and potentially facilitate earlier access to treatment. Trial Registration: CRIBBS Registry; ClinicalTrials.gov : NCT02329210

Abstract Introduction Biliary fibrosis and inflammation are central to the pathogenesis of cholangiopathies such as primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC). Inflammatory and fibrogenic stimuli, such as transforming growth factor-β (TGFβ) and lipopolysaccharide (LPS) signaling, drive these processes, but their underlying transcriptional mechanisms in cholangiocytes remain incompletely defined. We investigated the role of Runt-related transcription factor 1 (RUNX1) as a transcriptional co-regulator of fibroinflammatory signaling in cholangiocytes. Methods Human PSC-derived cholangiocytes (PSC-Cs) and mouse large biliary epithelial cells (MLEs) were subjected to RUNX1 knockdown or pharmacologic inhibition (Ro5-3335 or AI-10-104). Cytokine secretion was profiled by Luminex multiplexing; RUNX1 genomic binding and protein interactome were assessed by ChIP-qPCR, ChIP-seq, and LC-MS/MS. In vivo , Mdr2 −/− mice received Ro5-3335, and cholangiocyte-selective Runx1 knockout mice (Krt19-CreERT) were challenged with a DDC diet, followed by evaluation of fibrosis and inflammation. Results RUNX1 expression was significantly increased in cholangiocytes from PSC and PBC patients, and Mdr2 −/− mice. RUNX1 knockdown or inhibition reduced IL6, TNFα, and other proinflammatory cytokines in PSC-Cs and attenuated TGFβ-, LPS-, and TNFα-induced Il6 and Ccl2 expression in MLEs. ChIP-qPCR and ChIP-seq revealed TGFβ-induced RUNX1 binding to the Il6 promoter and 727 additional genomic sites enriched for fibrosis and inflammatory pathways; predicted upstream regulators included TGFβ, TNF, and NFκB signaling. Proteomic analysis identified TGFβ-induced RUNX1 interactions with SMAD2 and NFκB2. In vivo , Ro5-3335 treatment in Mdr2 −/− mice reduced hepatic collagen, ECM gene expression, immune cell infiltration, and serum liver injury markers and bile acids. Similarly, cholangiocyte-specific Runx1 deletion mitigated fibrosis, inflammation, and liver injury in DDC-fed mice. Conclusion RUNX1 is a central transcriptional hub integrating TGFβ and inflammatory signals in cholangiocytes. Its inhibition attenuates biliary fibrosis and inflammation in cholestatic models, supporting RUNX1 as a potential therapeutic target in fibroinflammatory cholangiopathies.

Background: Ketamine and esketamine ((es)ketamine) rapidly reduce depressive symptoms and suicidal ideation (SI) in treatment-resistant depression (TRD), but whether early SI improvement during the acute phase of the treatment predicts reduced suicide-associated emergency department (SAED) visits over the longer term remains unclear. Objectives: To examine whether early improvements in SI, measured using item 12 of the Quick Inventory of Depressive Symptomatology – Self Reported (QIDS-SR), following (es)ketamine treatment are associated with SAED visits over 6 months Design: Retrospective cohort study. Methods: Individuals with TRD who had available data on SI measured using the QIDS-SR during the acute phase, as well as data on SAED visits over 6 months, were included. Participants were classified based on changes in SI as resolved, partially improved, or unchanged/worsened using the QIDS-SR item 12 during acute treatment (up to six intravenous (IV) or eight intranasal (IN) treatments) and were followed for SAED visits. Results: Among 96 patients with SI data, 73 (76%) had baseline SI. Following acute-phase treatment, 36 (49%) achieved SI resolution, 14 (19%) partially improved, and 23 (32%) were unchanged/worsened. During the 6-month follow-up, 8 (11%) had post-acute SAED visits. While not statistically significant, patients with resolved SI had lower odds of post-acute ED visits (OR = 0.16, p = 0.12). Kaplan–Meier estimates of SAED visit-free survival across three SI change groups trended toward significance ( p = 0.066), suggesting lower cumulative healthcare (ED) utilization in more favorable change groups. Secondary analysis among 57 patients who received IV ketamine and had baseline SI showed that, after two infusions, 33 (47.2%) demonstrated a reduction in SI. Early SI improvement (⩾50% reduction in SI) was associated with a lower likelihood of any post-treatment SAED visit at 6 months after adjusting for pre-treatment SAED (OR = 0.17, 95% CI: 0.02–0.98, p = 0.047), corresponding to numbers needed to treat of 4.3. Conclusion: Early SI changes may have prognostic implications, though larger studies are needed to confirm clinical significance.

Abstract The proliferation of advanced endoscopic resection techniques has provided a minimally invasive alternative to esophagectomy and revolutionized outcomes for patients with early-stage esophageal adenocarcinoma (EAC). This paradigm shift and the resulting research data on clinical and histologic determinants of treatment outcome have highlighted the heterogeneity of outcomes within EAC staged as T1 by invasion depth. Multidisciplinary cancer care teams are now routinely facing difficult decisions regarding the management of high-risk T1 EAC to balance the risk of long-term lymph node (LNM) or distant metastasis against the risks of surgical resection. In this review, we summarize the current state of knowledge regarding the staging and risk stratification of T1 EAC, with particular attention to features that contribute to a higher risk of LNM and cancer mortality. We review recent clinical trial data on positioning the use of endoscopic resection (cap-assisted or submucosal dissection) versus surgical resection in high-risk T1 EAC patients and describe adjunctive techniques to further improve risk stratification and treatment. Finally, we explore emerging and future directions, such as artificial intelligence and advanced biomarker analysis to further aid decision-making and enhance patient outcomes.

PURPOSE Integrating external control data into clinical trial designs and analyses has the potential to accelerate drug development processes. We reanalyzed the three experimental arms of the Individual Screening Trial of Innovative Glioblastoma Therapy (INSIGhT), a randomized phase II platform trial in newly diagnosed O 6 -methylguanine-DNA methyltransferase-unmethylated glioblastoma (ClinicalTrials.gov identifier: NCT02977780 ). To evaluate the validity of using external data sets, we compared treatment effect estimates based on internal INSIGhT control data and matched external control data. METHODS The three experimental arms of INSIGhT (abemaciclib [n = 72], neratinib [n = 80], and CC-115 [n = 12]) did not improve survival compared with internal controls (standard chemoradiation [n = 70]). We derived external control patient-level data from multiple real-world and clinical trial data sets. We applied propensity score matching and Cox proportional hazards models to estimate treatment effects with external controls. Additionally, using this glioblastoma (GBM) data collection, we specified simulation scenarios to evaluate trial designs that integrate external controls. RESULTS After matching to external controls, no survival benefit was observed for patients receiving abemaciclib (hazard ratio [HR], 1.00 [95% CI, 0.75 to 1.34]), neratinib (HR, 0.93 [95% CI, 0.70 to 1.24]), or CC-115 (HR, 0.88 [95% CI, 0.41 to 1.88]). Simulations, together with the INSIGhT data and a collection of GBM data sets, allowed us to examine efficiencies and risks of clinical trial designs that leverage external control data. CONCLUSION The use of carefully matched external controls, to replace or augment the internal controls of INSIGhT, produced treatment effect estimates that were similar to previously published analyses. Single-arm trial designs and hybrid randomized designs incorporating propensity score–matched external control data evaluated treatment effects in the early-phase testing of experimental therapies in newly diagnosed GBM. The validity of this approach and risks of bias depended on the availability of comprehensive and accurate data on all potential confounders, in the absence of unmeasured confounding.

Chronic hepatitis B (CHB), a major global public health burden, is characterized by the presence of high circulating levels of non-infectious subviral particles (SVPs). These SVPs are mainly composed of small hepatitis B surface antigen (SHBs) and are associated with a dysfunctional HBV-specific immune response. Previous studies exploring the cellular mechanisms and molecular pathways by which SVPs are secreted from hepatocytes have utilized either non-hepatic cells or whole-genome HBV-integrated hepatoma cell lines in which SHBs can also be secreted as a component of the virion envelope. In this study, we provide a detailed examination of SHBs trafficking using biochemical approaches coupled with high-resolution confocal microscopy and live-cell imaging via a novel fluorophore-tagged SHBs probe in both HepG2 and primary human hepatocytes stably expressing SHBs. Our results provide evidence that SHBs utilize a modified ER-Golgi secretory pathway with transit from the ER to the multivesicular body and lysosomal/late endosomal compartments. Importantly, we identified the autophagy adapters ATG5 and LC3B, and the ER-phagy protein atlastin 3 (ATL3), central to mediating SHBs secretion. These findings suggest that SHBs is trafficked through a non-canonical path for secretion and provides new potential therapeutic targets for the treatment of CHB.