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Background Tirzepatide is a dual agonist for glucose‐dependent insulinotropic polypeptide and glucagon‐like peptide‐1 receptors, with proven efficacy in weight loss and improvement in cardiovascular outcomes. However, the effects of tirzepatide on the incidence of atrial fibrillation in patients with overweight or obesity remain unclear. Methods PubMed, Embase, and Cochrane Library were searched for randomized controlled trials comparing tirzepatide versus placebo for individuals with overweight or obesity. Odds ratios (ORs) with 95% credible intervals (CrIs) were pooled using a Bayesian binomial‐normal hierarchical model, appropriate for rare‐event outcomes. Results Our meta‐analysis included 10 randomized controlled trials, including 6515 individuals, of whom 4491 (68.9%) were randomized to tirzepatide. The pooled OR was 2.20 (95% CrI, 0.81–6.75) for atrial fibrillation, 2.16 (95% CrI, 0.90–5.87) for atrial arrhythmia, and 1.84 (95% CrI, 1.04–3.90) for any arrhythmia. Conclusions Tirzepatide was not associated with atrial fibrillation or atrial arrhythmia. Although higher odds of overall arrhythmias were observed, event rates were low and the findings should be interpreted cautiously.

This slideshow presentation provides a practical image-based road map to essential spinal and pelvic radiographic measurements, with stepwise instructions and reference values, for assessment and management of spinal disorders.

Background: Alcohol-associated hepatitis (AH) is a severe inflammatory liver condition driven by dysregulated immune responses. CD8 T cells accumulate in the liver during AH, yet their functional role remains poorly defined. Methods: A murine NIAAA chronic-binge model with lipopolysaccharide (LPS) challenge was used. Single-cell RNA sequencing of liver and blood immune cells defined CD8 T cell subsets, followed by pathway analysis and reanalysis of human AH datasets. Spatial relationships were validated by immunohistochemistry of human AH liver tissue with CD8 T RM and liver sinusoidal endothelial cell (LSEC) co-staining. LSEC–CD8 T cell interactions were examined using in vitro co-culture, and signaling pathways were assessed by bulk RNA sequencing and phospho-protein analyses. IL15 function was evaluated by in vivo neutralization. Results: Single-cell RNA sequencing in the murine AH model revealed a distinct population of CD8 tissue-resident memory T cells (T RM ) with heightened activation and proinflammatory cytokine production. Analysis of human AH liver single-cell RNA sequencing data, along with immunohistochemistry validation, supported CD8 T RM enrichment in diseased tissue. IL15 emerged as a prominent pathway linked to T RM activation, and IL15 blockade reduced T RM abundance and attenuated EtOH/ lipopolysaccharide-induced liver injury. Mechanistically, LSECs not only provided a structural niche for T RM retention but also amplified IL15 signalling. In vitro, coculture experiments demonstrated that LSECs intensified activation in pre-stimulated CD8 T cells in a stimulus-dependent manner: under IL15 stimulation, LSECs boosted effector function without inducing cell death, whereas under T-cell receptor stimulation, LSECs drove hyperactivation and activation-induced cell death. Bulk RNA-seq and phospho-protein analysis identified the PI3K-AKT pathway as a shared pathway enhanced by LSEC coculture in activated CD8 T cells. These findings define a context-dependent mechanism in which LSECs promote IL15-driven signaling through AKT pathway amplification, promoting T RM persistence and inflammatory activity in AH. Conclusions: IL15-associated signaling within the hepatic microenvironment, shaped by LSEC-CD8 T-cell interactions, promotes activation and persistence of CD8 T RM cells in AH. Targeting the IL15-LSEC-AKT axis may disrupt pathogenic T RM niches and represent a promising therapeutic strategy for severe AH.

Accurate assessment of distal tibiofibular syndesmotic injuries is essential to prevent chronic instability and poor functional outcomes, and conventional radiography, CT, and MRI play complementary and critical roles in the imaging of these injuries.

Importance The choice of induction agent during rapid sequence intubation (RSI) of critically ill adults may affect clinical outcomes. Although ketamine and etomidate are frequently used for RSI, their comparative effectiveness remains controversial. Objective To compare the safety of etomidate vs ketamine for emergency RSI in critically ill adults. Design, Setting, and Participants This cohort study used a target trial emulation with observational data collected between March 1, 2022, and April 30, 2024, from 18 emergency departments across Brazil, with data from the Brazilian Airway Registry Cooperation. Adults who underwent RSI and received either etomidate or ketamine as a sole hypnotic agent were included; those with preintubation cardiac arrest or immediate postintubation transfer were excluded. Exposure Administration of etomidate or ketamine as the induction agent for RSI. Main Outcomes and Measures The primary outcome was 28-day in-hospital mortality. Secondary outcomes included 7-day in-hospital mortality, first-attempt intubation success, and major adverse events (new hemodynamic instability, severe hypoxemia, and cardiac arrest) within 30 minutes after intubation. Inverse probability of treatment weighting was used to adjust for confounding. Risk ratios (RRs) and risk differences (RDs) with 95% CIs were used to compare outcomes between groups. Results Among 1810 patients (median age, 64 years [IQR, 50-74 years]; 1048 men [57.9%]), 514 received ketamine and 1296 received etomidate. The median shock index was higher in the ketamine group than the etomidate group (0.81 [IQR, 0.65-1.01] vs 0.76 [IQR, 0.59-0.99]), and preintubation vasopressor use was more common in the ketamine group than the etomidate group (191 of 514 [37.2%] vs 391 of 1296 [30.2%]). Weighted 28-day mortality was higher with etomidate than ketamine (60.5% [95% CI, 57.2%-63.8%] vs 54.4% [95% CI, 45.0%-63.9%]; RR, 1.14 [95% CI, 1.03-1.27]; RD, 7.6% [95% CI, 2.0%-13.3%]). Seven-day mortality was also higher with etomidate than ketamine (35.2% [95% CI, 32.0%-38.3%] vs 30.1% [95% CI, 23.5%-36.7%]; RR, 1.19 [95% CI, 1.04-1.35]). New hemodynamic instability within 30 minutes after intubation was more frequent with ketamine (24.2% [95% CI, 20.4%-28.0%] vs 18.9% [95% CI, 16.7%-21.0%]; RR, 0.78 [0.64-0.95]). There were no statistically significant differences in the other secondary outcomes. Conclusions and Relevance In this cohort study of critically ill adults undergoing RSI, etomidate use was associated with higher in-hospital mortality at 7 and 28 days compared with ketamine. These findings highlight the need for definitive randomized clinical trials to compare both agents.

Abstract Introduction: Patients diagnosed with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) exhibit an elevated risk of developing other cancers (OC) relative to the general population. Historically, chemoimmunotherapy (CIT) represented the cornerstone of CLL/SLL management. A systematic review of clinical trials of CIT for CLL that included 28 studies reported 352/3297 (12.6%) patients developed OC (Csanadi 2022). The introduction of targeted agents beginning in the mid-2010's, including Bruton tyrosine kinase inhibitors (BTKi) and BCL2 inhibitors, has shifted the standard of care toward these novel therapies. In this study, we determined the risk of OC in newly diagnosed CLL/SLL patients cared for at the US Department of Veteran Affairs (VA), The University of Texas MD Anderson Cancer Center, and Mayo Clinic in Rochester, MN. Methods: We identified patients with newly diagnosed CLL/SLL after 1/1/2016 using the VA Central Cancer Registry, MD Anderson, and the Mayo Clinic CLL Databases. The baseline clinical characteristics, CLL treatments, and the occurrence of OC were abstracted by electronic health record (EHR) review. Receipt of CLL directed therapy was categorized into a) CIT only; b) targeted therapy only; c) CIT and targeted therapy; and d) other (including monotherapy with monoclonal antibody therapy). The occurrence of OC was modeled using CLL treatment as a time-dependent variable. Prior and concurrent OC diagnosed within 3 months of CLL/SLL were excluded from analyses, to reduce ascertainment bias. Results: We identified 6844 patients with CLL/SLL who met inclusion criteria. Median follow up was 3.6 years (interquartile range [IQR] 1.9-5.8). The median age at diagnosis of CLL/SLL was 71 years (range, 23 - 102); most patients were white (81%) and male (90%). Although many patients had missing values, among those with available information, IGHV genes were unmutated in 884 (51%), CLL FISH panel showed del17 in 213 (7%), del11q in 389 (13%), trisomy 12 in 674 (23%), and del13q in 1508 patients (50%). A total of 2344 patients received CLL directed therapy during follow-up: 278 (12%) received CIT only, 1809 (77%) received targeted therapy (+/- monoclonal antibody), only 99 (4%) received CIT and targeted therapy and 150 (6%) monoclonal antibody therapy only. Among patients treated with targeted therapies, 950 (50%) received ibrutinib, 381 (20%) received acalabrutinib, 164 (9%) received zanubrutinib, 4 (<1%) received orelabrutinib, 280 (15%) received venetoclax, and 3 (<1%) received sonrotoclax. Other treatments included combinations of a covalent BTKi (cBTKi) and BCL2i in 52 (3%) patients, among others. A total of 583 patients were diagnosed with OC during the study period. Types of OC observed included neoplasms of the prostate (n=129, 22%), lung (n=118, 20%), hematologic malignancies (n=91, 16%), gastrointestinal tract (n=68, 12%), melanoma (n=66, 11%), kidney and bladder (n=44, 8%), head and neck (n=19, 3%), and other/unknown (n=48, 8%). Estimated risk of occurrence of OC was 4.2% (95%CI 3.8-4.8%) at 24 months and 9.7% (95%CI 8.9-10.6%) at 60 months after a diagnosis of CLL/SLL. Multivariable analyses demonstrated that older age (HR: 1.013, 95%CI: 1.00-1.021), male sex (HR: 1.6, 95%CI: 1.1-2.3), and receipt of CLL directed therapy (HR: 1.4, 95%CI: 1.2-1.7) were associated with an increased risk of OC. When considering different types of CLL directed treatments, those who received CIT with or without targeted therapies had the highest risk of development of OC (HR: 1.6, 95%CI: 1.2-2.1). Risk of OC were also increased for those who received CIT only (HR: 1.41, 95%CI: 0.97-2.05) and those who received targeted treatments alone (HR: 1.27, 95%CI: 1.02-1.58). Conclusion: In this large dataset of newly diagnosed patients with CLL/SLL in the past ten years, approximately 10% patients developed OC at 5 years. Receipt of CLL directed therapy was associated with a 40% increased risk of development of OC compared to those patients who did not receive therapy. The risk was highest among patients who received CIT with or without targeted therapy and was still elevated in those who received CIT only or targeted therapy only.

ABSTRACT Anesthetic technique affects surgical outcomes and oncological prognosis. Recognizing the critical role of surgery in cancer treatment, this narrative review aims to improve anesthesiology practices for cancer patients by evaluating actions that positively influence outcomes. Anesthesiologist experience helps guide technique choice in complex cases. Decisions should be customized based on the type of surgery and patient condition, as different techniques can significantly impact results. The expertise of the entire team at specialized centers further enhances outcomes.

PURPOSE Tumor treating fields (TTFields) use alternating electric fields to disrupt cancer cell proliferation. Feasibility of TTFields therapy with gemcitabine/nab-paclitaxel was previously demonstrated in patients with advanced pancreatic adenocarcinoma. PANOVA-3 was designed to confirm safety and efficacy of TTFields in patients with unresectable locally advanced pancreatic adenocarcinoma (LA-PAC). METHODS In this global phase III trial, 571 patients with newly diagnosed LA-PAC were randomly assigned to receive gemcitabine 1,000 mg/m 2 and nab-paclitaxel 125 mg/m 2 by intravenous infusion once a day on days 1, 8, and 15 of a 28-day cycle with or without TTFields. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), local PFS, pain-free survival, and overall response rate (ORR). Distant PFS was analyzed post hoc. RESULTS OS was significantly prolonged using TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel (median, 16.2 months [95% CI, 15.0 to 18.0] v 14.2 months [95% CI, 12.8 to 15.4]; hazard ratio [HR], 0.82 [95% CI, 0.68 to 0.99]; P = .039). PFS, local PFS, and ORR were not improved. Pain-free survival was significantly prolonged with TTFields with gemcitabine/nab-paclitaxel (median, 15.2 months [95% CI, 10.3 to 22.8] v 9.1 months [95% CI, 7.4 to 12.7]; HR, 0.74 [95% CI, 0.56 to 0.97]; P = .027), as was distant PFS (median, 13.9 months [95% CI, 12.2 to 16.8] v 11.5 months [95% CI, 10.4 to 12.9]; HR, 0.74 [95% CI, 0.57 to 0.96]; P = .022). Device-related skin adverse events (AEs) were experienced by 76.3% of patients. Most device-related skin AEs were mild to moderate, with 7.7% of patients reporting a grade 3 AE. CONCLUSION This study demonstrated significant OS, pain-free survival, and distant PFS benefits for TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel in patients with unresectable LA-PAC, with no additive systemic toxicity.

PURPOSE The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged progression-free survival (PFS), but without improvement in overall survival (OS), likely because of toxicity. Acalabrutinib was shown to be efficacious and less toxic than ibrutinib in a head-to-head trial in chronic lymphocytic leukemia and therefore might lead to better outcomes in MCL. METHODS Patients 65 years and older with previously untreated MCL received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus six cycles of bendamustine (90 mg/m 2 once daily; days 1 and 2) and rituximab (375 mg/m 2 as a single dose; day 1) followed by rituximab maintenance in responding patients for 2 years. Crossover to acalabrutinib at disease progression was permitted. The primary end point was PFS per the independent review committee; overall response rate and OS were secondary end points. RESULTS In total, 598 patients were randomly assigned, with 299 in each arm. At a median follow-up of 49.8 months using the reverse Kaplan-Meier method, the median PFS was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.94]; P = .0160). Benefit was seen across all subgroups, including those with high-risk features. Overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% in the acalabrutinib and placebo arms, respectively. OS was not significantly different (HR, 0.86 [95% CI, 0.65 to 1.13]; P = .27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively. CONCLUSION The combination of acalabrutinib with bendamustine-rituximab significantly improved PFS. Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity.

Importance There is a lack of long-term efficacy and safety data on hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) and on RNA interference (RNAi) therapeutics in general. This study presents the longest-term data to date on patisiran for hATTR-PN. Objective To present the long-term efficacy and safety of patisiran in adults with hATTR-PN. Design, Setting, and Participants This global open-label extension (OLE) of the APOLLO randomized clinical trial and phase 2 OLE study enrolled patients from 43 hospitals or clinical centers across 19 countries between July 2015 and August 2017, with follow-up until November 2022. Of 212 eligible patients with hATTR who completed the phase 3 APOLLO or phase 2 OLE parent studies, 211 enrolled in and 138 completed the global OLE. Intervention Patisiran, 0.3 mg/kg, intravenously once every 3 weeks for up to 5 years. Main Outcomes and Measures Outcomes evaluated at year 5 of the global OLE included disability (polyneuropathy disability [PND] score); polyneuropathy severity (Neuropathy Impairment Score [NIS]), nutritional status (modified body mass index [mBMI]), quality of life (Norfolk Quality of Life–Diabetic Neuropathy [Norfolk QOL-DN]), and Rasch-Built Overall Disability Scale (R-ODS), with no statistical hierarchy. Safety, survival probability, and mortality were also assessed. Results At the global OLE baseline, the mean (SD) age was 61.3 (12.3) years, and 156 patients (73.9%) were male. In 138 patients completing the study, PND scores remained stable or improved in 89 patients (65.0%), NISs showed a mean (SD) change of 10.9 (14.7), and mean (SD) mBMI (calculated as weight in kilograms divided by height in meters squared times serum albumin in grams per liter) increased by 46.4 (120.7) over 5 years from baseline. Norfolk QOL-DN and R-ODS scores showed mean (SD) changes of 4.1 (16.7) and –3.7 (6.2), respectively. Adverse events (AEs) leading to study withdrawal occurred in 47 patients (22.3%). Infusion-related reactions were the most common treatment-related AE (n = 34 [16.1%]). Overall, 41 patients (19.4%) died during the study. Patisiran treatment in the parent study and low familial amyloid polyneuropathy score at parent study baseline were associated with significantly improved survival. Conclusions and Relevance In the longest study of an RNAi therapeutic for any disease, patisiran treatment resulted in modest changes for patients with hATTR-PN with an acceptable safety profile. These results highlight the importance of initiating early treatment for hATTR and the potential of RNAi therapeutics in medicine. Trial Registration ClinicalTrials.gov Identifier: NCT02510261