Citations

Objectives To understand the trade-offs between different statistical modeling approaches, using real world data with small sub-populations, with rare exposures and increasingly rare outcomes. In particular, to compare adjusted regression, inverse probability weighting, and matching. Methods Data for these analyses came from the RADAR (N=1,134) and combined CNICS/JHHCC (N=14,434) cohorts. We estimated prevalence ratios (PRs) for self-reported use of specific substances comparing subpopulations (SP), SP-1 vs SP-3 and SP-2 vs SP-3, where SP-1 was the largest proportion (92% in RADAR, 81% in CNICS/JHHCC), SP2 was moderate proportion (18% in CNICS/JHHCC) and SP-3 was the smallest proportion (8% in RADAR, 1% in CNICS/JHHCC) of the population. We calculated PRs using 1) unadjusted relative risk regression (RR); and adjusted estimates controlling for age, race/ethnicity, study site, and year of interview using: 2) standard adjustment in RR; 3) stabilized inverse probability of treatment weighting (IPTW); and 4) matching with up to 3 matches from SP-1 or SP-2 per SP-3 participant. Results For most substances, all methods yielded consistent estimates. There were large weights in some of the IPTW analyses and in three cases these resulted in substantially divergent estimates. For the comparison between SP-1 and SP-3, the estimate for smoking was 1.3-fold greater in the matched analysis (PR=1.33, 95% CI: 1.02-1.75) than in IPTW (PR=1.03, 95% CI: 0.78-1.37 ATE and PR=1.05, 95% CI: 0.88-1.26 ATT). Even more extreme divergence in estimates was observed for differences between SP-2 and SP-3 with respect to methamphetamine/amphetamine, (IPTW-ATE: PR=1.51, 95% CI: 0.79-2.89; IPTW-ATT: PR=2.36, 95% CI: 1.36-4.12); vs Matching: PR=2.71, 95%CI: 1.47-4.99) and cocaine (IPTW-ATE: PR=1.15, 95% CI: 0.55-2.38; IPTW-ATT: PR=1.81, 95% CI: 1.03-3.18); vs Matching: PR=1.38, 95%CI: 0.76-2.53). Conclusion The combination of a rare exposure and a rare outcome can produce challenges for commonly used confounding adjustment strategies, and it is often best to compare different modeling approaches to gain greater insight.

Abstract Objectives This study aimed to characterize susceptibility profiles of both currently approved and investigational β-lactam agents against difficult-to-treat resistant Pseudomonas aeruginosa (DTR P. aeruginosa) clinical isolates, including carbapenemase-producing strains. Patients and methods A total of 502 consecutive DTR P. aeruginosa clinical isolates were collected from unique hospitalized patients between 2022 and 2024 across three tertiary care centres. Isolates originated from bloodstream, respiratory, urinary and intra-abdominal infections. Minimum inhibitory concentrations (MICs) for seven β-lactam agents were determined using triplicate reference broth microdilution. Susceptibility interpretations were based on CLSI criteria or, where applicable, investigational breakpoints. Whole-genome sequencing was performed to detect β-lactamase genes. Results Among the 502 isolates, cefepime-zidebactam exhibited the highest in vitro activity (100% susceptibility), followed by cefiderocol-xeruborbactam (98%), cefiderocol (95%), ceftolozane-tazobactam (90%), cefepime-taniborbactam (86%), ceftazidime-avibactam (85%), and imipenem-relebactam (41%). Notably, only 35% of isolates were susceptible to all seven agents. Carbapenemase genes were identified in 4% of isolates, including blaGES (n = 13), blaVIM (n = 7), blaKPC (n = 1) and blaIMP (n = 1). Among carbapenemase-producing isolates, cefepime-zidebactam retained activity against all isolates (100%), exceeding that of other approved β-lactam/β-lactamase inhibitor combinations (0%–24% susceptible), cefiderocol (76%), cefiderocol-xeruborbactam (86%) and cefepime-taniborbactam (81%). Conclusions While currently approved β-lactam agents retained activity against many DTR P. aeruginosa isolates, their performance was markedly compromised in the presence of carbapenemases, with the notable exceptions of cefepime-zidebactam and cefiderocol. Investigational β-lactam/β-lactamase inhibitor combinations exhibited consistently robust activity across resistance phenotypes, including carbapenemase-producing isolates, representing promising options for DTR P. aeruginosa infections.

Abstract Purpose: Pancreatic ductal adenocarcinoma (PDAC) frequently recurs after neoadjuvant therapy (NT) and curative-intent resection. Although major pathologic response predicts favorable outcomes, most patients achieve only minor response with a heterogeneous recurrence risk. We asked whether the spatial organization of residual PDAC encodes clinically relevant biology beyond residual tumor burden. Experimental Design: In a retrospective cohort of 203 patients with resected PDAC treated with NT and restricted to minor pathologic response, routine hematoxylin and eosin (H&E) whole-slide images were segmented into cancer and stroma using an artificial intelligence–enabled pipeline. Spatial composition (patch density, edge density) and configuration (compactness/complexity, intermixing) were quantified and tested for associations with disease-free survival (DFS) using multivariable models adjusted for standard clinicopathologic factors. Results: Shorter DFS was associated with a fragmented, interface-rich tumor–stroma ecology featuring higher edge density and diversity and reduced homotypic aggregation, independent of clinicopathologic variables. Two spatial risk models were independently prognostic: (i) cancer mean shape index plus stromal shape index variability [adjusted hazard ratio (HR), 1.71; P = 0.003] and (ii) mean stromal patch area plus edge density (adjusted HR, 2.19; P = 0.002). Both models stratified outcomes in which pathologic response grading and residual cancer area did not. High-risk configurations were further associated with reduced intratumoral tumor-infiltrating lymphocyte (TIL) density and infiltration ratio, with relative TIL accumulation at the cancer periphery and within the stroma, consistent with an immune-excluded phenotype. Conclusions: Residual cancer–stroma topology quantified from standard H&E slides yields independent prognostic signals after NT in PDAC, provides a cellular immune correlate for spatial risk, and motivates prospective validation and spatially informed adjuvant strategies.

Importance As the use of robotic cholecystectomy increases, its value remains poorly defined for complex elective cholecystectomy (CEC), where complex gallbladder pathology results in increased technical difficulty. Objective To determine whether a robotic approach is associated with improved clinical outcomes and altered total hospital cost as compared with a laparoscopic approach for patients undergoing CEC. Design, Setting, and Participants This cohort study analyzed data from an academic hepatobiliary referral center for patients who underwent cholecystectomy from August 2018 to August 2024. CEC was defined by preoperative criteria: prior aborted or partial cholecystectomy, presence of a cholecystostomy tube, and/or history of gallbladder perforation or fistula. Exposure Robotic-assisted vs laparoscopic cholecystectomy. Main Outcomes and Measures The primary outcome was a composite of an unplanned postoperative endoscopic retrograde cholangiopancreatography or interventional radiology procedure. Secondary outcomes included operative time, postoperative complications, and operative and total hospital costs. Results A total of 863 patients underwent cholecystectomy and met inclusion criteria; 525 (60.8%) were female and 338 (39.2%) were male, and their median (IQR) age was 61 (45-71) years. Among patients undergoing CEC, the laparoscopic approach was independently associated with an increased need for unplanned endoscopic or percutaneous intervention compared with the robotic group (odds ratio, 4.24; 95% CI, 1.24-14.52; P = .02). There were no significant differences in postoperative outcomes between the laparoscopic and robotic groups in patients undergoing non-CEC. Patients undergoing the laparoscopic approach had significantly reduced operating room costs when compared with patients undergoing a robotic approach in both the CEC ($7720 vs $8936, respectively) and non-CEC groups ($6368 vs $ 8351, respectively). However, there was no difference in the overall total cost of care between laparoscopic CEC and robotic CEC groups ($14 309 vs $14 476, respectively). The overall total cost of care was significantly higher for patients undergoing robotic non-CEC as compared with laparoscopic non-CEC ($11 416 vs $9925, respectively). Conclusions and Relevance This study found that for complex gallbladder disease, robotic cholecystectomy offers a clinical advantage, reducing complications and downstream interventions without increasing the overall costs of care. These findings suggest strategic application of the robotic platform may offer clinical advantages in high-complexity gallbladder surgery, maximizing patient benefit and resource efficiency.

Objective Lennox–Gastaut syndrome (LGS) is a severe treatment‐resistant epilepsy. Although vagus nerve stimulation (VNS) and deep brain stimulation (DBS) are established therapies, comparative data and the impact of dual neuromodulation remain limited. We compared seizure outcomes across VNS, DBS, and combined DBS + VNS therapy in LGS. Methods This retrospective cohort study at Mayo Clinic (2005–2024) included LGS patients treated with VNS and/or DBS . Seizure frequency was assessed at 6, 12, and 24 months post‐stimulation. Responder was defined as 50% or more seizure reduction. Results Forty patients were included (42% female, median, 150 seizures/month). Eleven patients underwent sequential VNS followed by DBS and contributed data to 2 treatment epochs, yielding 3 treatment groups: VNS alone (n = 29), DBS alone (n = 12), and DBS + VNS (n = 10). At 24 months, median seizure reduction rate was comparable between VNS (50%; 95% confidence interval [ CI], 44–75%) and the overall DBS cohort (59%, 95% CI, 33–86%) ( p = 0.54). However, a significant difference emerged when comparing the 3 treatment arms ( p = 0.027). Specifically, DBS + VNS therapy yielded significantly greater median reduction rate (81%, 95% CI, 60–99%) than DBS alone (43%, 95% CI, 0–58%) ( p adj = 0.027) or VNS alone (50%, 95% CI, 44.4–75.0%) ( p adj = 0.048). Four patients attained sustained seizure freedom above 1 year at last follow‐up. Interpretation VNS and DBS provide comparable seizure reduction in LGS over a 2‐year follow‐up period. DBS + VNS was associated with further improvements in seizure reduction in this small, retrospective dataset. This possibility warrants further investigation. ANN NEUROL 2026

Conventional cigarette smoking remains a leading preventable cause of morbidity and mortality despite declining prevalence, yet evidence-based treatments remain underused. This narrative review examines guideline-supported therapies and emerging approaches, including digital tools, neuromodulation, and harm-reduction strategies. Standard care typically combines FDA-approved pharmacotherapy with behavioral counseling. Digital interventions can extend access and support adherence, particularly when integrated with pharmacotherapy and follow-up. Repetitive transcranial magnetic stimulation (rTMS) can be considered as an adjunctive option for patients who do not respond to pharmacotherapy and is FDA-approved. For patients unable to quit, structured harm-reduction strategies may help reduce risk while supporting progression toward eventual abstinence. These approaches should be used alongside, not in place of, guideline-recommended pharmacotherapy and behavioral counseling, which remain the gold standard for care. This review outlines a pragmatic, primary care–oriented model that integrates stepped-care with harm-reduction strategies.

Abstract Background and Aims EUS-guided gastroenterostomy (EUS-GE) is an effective option to palliate symptoms of gastric outlet obstruction (GOO). While the jejunum is conventionally targeted (EUS-GJ), targeting the duodenum (EUS-GD) may offer clinical advantages. Outcomes were compared for EUS-GJ and EUS-GD. Methods Adult patients who underwent EUS-GE for GOO between 2020 and 2024 were included and categorized as an EUS-GD if the stent entered the transverse or ascending duodenum or an EUS-GJ if the stent entered more distally. The primary outcome was clinical success (soft diet tolerance at 7 days). Secondary outcomes included adverse events (AEs), stent misdeployment, and unplanned endoscopic reintervention. Baseline demographic variables and outcomes were compared with statistical significance at p < 0.05. Results Of the 139 included patients (median age 67 years (IQR 61–74); 41% female), 105 underwent EUS-GJ and 34 underwent EUS-GD. Clinical success was 98% for EUS-GJ and 94% for EUS-GD (p = 0.25). The misdeployment rate was 7% for EUS-GJ and 0% for EUS-GD (p = 0.19). The AE rate was 22% for EUS-GJ and 12% for EUS-GD (p = 0.23). There were no significant differences for stent obstruction (EUS-GJ 12% vs. EUS-GD 6%), bleeding (2% vs. 6%), perforation (4% vs. 0%), stent migration (1% vs. 0%), infection (3% vs. 0%), and unplanned reintervention (14% vs. 9%). Conclusion Both EUS-GJ and EUS-GD demonstrate high clinical success with no significant differences in adverse event rates. These data can support intraprocedural decision-making for endoscopists performing EUS-GE.

Variability in novel inflammatory markers (HBP and SAA) post-surgery could indicate ongoing perioperative inflammation. This pilot cohort study collected blood from 99 patients undergoing elective cardiac surgery at baseline, 24 hours, 7 days, and 3 months post-surgery. Inflammatory markers (HBP, SAA, PCT, CRP, IL-6) were measured with a point-of-care device. Demographic and clinical data were extracted from health records. Serum SAA increased significantly in the acute postoperative phase (M e [IQR];SAA baseline =81.1[87] vs SAA 24hr= 232.65[88.02];U[72]=2343,p<0.0001), remained elevated at 7 days (Me 7d =252.6[88.56];U[57]=1484,p<0.0001) and were still more pronounced than baseline at t 3m (Me 3m =118.44[101.52];U[38]=448,p=0.0008). HBP showed a significant rise at seven days (HBP baseline =45[26;89] vs HBP 7d =121[69.75;224.5]; U[56]=805,p<0.0001) then returned to near baseline by t 3m (Me 3m =32.5[15.75;98.5]). Traditional inflammatory markers PCT, CRP, and IL-6 demonstrated a rapid increase at t 24h and plateaued at t 7d . None of the biomarkers showed variability at baseline or postoperatively with preoperative status or postoperative complications. Cluster analysis of the inflammatory markers at 24 hours (t 24h ) identified distinct subgroups. Cluster #1-patients with a modest increase in all markers; Cluster#2 characterized with a robust increase in IL-6; Cluster #3 showed increase in CRP and decline in HBP; Cluster #4 showed a modest increase in IL-6 and decline in HBP; Cluster #5 represented a decline in both CRP and SAA. Patients in these clusters differ with respect to age, pre-existing peripheral artery disease, and borderline differences in perioperative acetaminophen use. SAA and HBP remain elevated longer than IL-6, CRP, and PCT after surgery, suggesting that inflammation may persist beyond 3 months.

PURPOSE Deficient mismatch repair/microsatellite instability (dMMR, MSI-H) in biliary tract cancers (BTCs) is observed in 1%-5% of tumors. MSI-H across solid tumors has demonstrated durable response to immune checkpoint inhibitors (ICIs) regardless of the anatomic location. Here, we describe clinical outcomes and surgical conversion of MSI-H BTC treated with ICIs. Patients and Methods We conducted a multicenter, retrospective analysis of BTC patients with dMMR/MSI-H between 2017 and 2024 at Mayo Clinic, University of Michigan, and University Hospitals Seidman Cancer Center. Outcomes of interest were surgical resection rate, rate of pathologic response, 2-year overall survival (OS; time from initiation of treatment to death/last follow-up), and time to treatment discontinuation (TTD; time from initiation of treatment to cessation because of any cause). Analyses were descriptive. RESULTS Thirty patients with MSI-H BTC were identified: 19 with cholangiocarcinoma, three with gallbladder cancer, and 8 with BTC undefined. The median age at diagnosis was 61.5 years (range, 26-86). Twenty-six (86.7%) patients had advanced stage at diagnosis. Twenty-seven patients (90%) received first-line systemic therapy, and 13 (48.1%) continued onto second line. Six patients (23.1%) were restaged to resectable from advanced disease after ICI therapy and underwent resection; all remained recurrence-free at last follow-up. Of these six patients, 3 (50%) achieved a pathologic complete response. Among those receiving first-line therapy, the median TTD was 9.9 months (95% CI, 5.7 to 14.5 months) and the 2-year OS was 73% (95% CI, 56% to 94%). CONCLUSION ICI therapy in patients with MSI-H BTC demonstrated durable response and downstaged some BTC to a resectable stage. dMMR/MSI-H should be performed up-front to guide treatment decisions.