Citations

Rationale: Neuromuscular blocking agents (NMBAs) show potential benefits on mortality and other complications of acute respiratory distress syndrome (ARDS) in adult patients. Evidence-based decisions and processes ensure appropriate use of neuromuscular blockade in adult patients with ARDS. Objectives: The objective of these guidelines was to develop evidence-based recommendations for the administration of NMBAs in critically ill adult patients with ARDS. Design: The American College of Critical Care Medicine Board convened a 21-member multidisciplinary panel of experts in critical care medicine, nursing, respiratory therapy, pharmacology, surgery, neurology, and anesthesiology. The panel included two expert methodologists specialized in developing evidence-based recommendations in alignment with the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Conflict-of-interest policies were strictly followed during all phases of guidelines development including task force selection and voting. Methods: The panel members identified and formulated five Population, Intervention, Comparison, and Outcome questions. We conducted a systematic review for each question to identify the best available evidence, statistically analyzed the evidence, and assessed the certainty of the evidence using the GRADE methodology. We used the GRADE evidence-to-decision framework to formulate the recommendations. Results: The panel generated two conditional recommendations. One recommendation is to use NMBAs in adults with ARDS with Pa o 2 /F io 2 less than 150. For the other recommendations, there was equipoise in the recommendation for and against using titratable vs. fixed-dose NMBA dosing, a monitoring-based strategy for assessing depth of sedation and analgesia in adults with ARDS before initiating or while receiving neuromuscular blockade, and administration of NMBAs for patients who are proned, due to overall lack of evidence in critically ill patients and due to considerations of patient safety and experience concerns. Conclusions: These guidelines provide additional perspectives on the use of NMBA in patients with ARDS, recognizing that institutional and patient-specific considerations must help to guide the decision-making process.

776 Background: There continues to be a significant unmet need for safe, effective, and bladder sparing treatment options for patients with non-muscle invasive bladder cancer (NMIBC). TARA-002 is a lyophilized biological preparation for intravesical instillation containing inactivated cells of Streptococcus pyogenes (Group A, type 3) Su strain. TARA-002 rapidly enters cancer cells, activating TLR2 and NOD2 to trigger innate immunity, inflammation, and potential immunogenic cell death. ADVANCED-2 (NCT05951179) is an ongoing Phase 2, open-label study to evaluate the safety and efficacy of intravesical TARA-002 in adults ≥ 18 years with high-grade (HG)-NMIBC CIS (± Ta/T1). Preliminary results showed promising complete response (CR) rates and durable responses in patients with HG NMIBC treated with TARA-002 (Jayram et al. AUA 2025). This abstract presents pooled safety data of TARA-002 from the BCG-naïve cohort and BCG-unresponsive cohort of the ADVANCED-2 study. Methods: The ADVANCED-2 study includes 2 cohorts of BCG-naïve (Cohort A) and BCG-unresponsive (Cohort B) participants. Key exclusion criteria include penicillin allergy; history of ≥ T2 bladder cancer, nodal, or metastatic disease; and concomitant prostatic or upper tract urothelial involvement. Each participant is treated with TARA-002 to receive induction (6 weekly doses), reinduction (if persistent disease at 3 months), and maintenance (through 24 months). Response is assessed every 3 months for 2 years. Long-term follow-up is conducted up to 60 months. Safety is monitored throughout the study. Results: As of 07-October-2025, 60 participants (median age: 74; range: 45 to 92), have been enrolled and exposed to TARA-002: 31 BCG-naïve (Cohort A) and 29 BCG-unresponsive (Cohort B). In both cohorts, 18/60 (30.0 %) participants reported drug-related treatment emergent adverse events (TEAEs). Related TEAEs were Grade 1 (18/60; 30.0%) and Grade 2 (3/60; 5.0%), with no reported Grade 3-5 related TEAEs. Commonly reported related TEAEs (≥ 5%) included bladder spasm (10.0%), dysuria (13.3%), fatigue (6.7%), and micturition urgency (6.7%). Most TEAEs were mild and transient. In both cohorts, 10/60 (16.7%) experienced serious AEs (SAEs); 4/60 (6.7%) were Grade 2 and 9/60 (15.0%) were Grade 3. No participants experienced drug-related SAEs or drug-related TEAEs leading to withdrawal or death. Conclusions: TARA-002 monotherapy was well tolerated, thus demonstrating a favorable tolerability profile to date for the treatment of BCG-naïve and BCG-unresponsive HG NMIBC with CIS (±Ta/T1). TARA-002 has a promising safety profile as a bladder-sparing treatment in HG NMIBC across BCG exposure status. Updated safety data will be provided based on evaluable time points at the time of the presentation. Clinical trial information: NCT05951179 .

743 Background: Although patients with Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) have several emerging therapeutic options, there remains a clinical unmet need to improve efficacy, durability of response, and tolerability while obviating the need for radical cystectomy. TARA-002 is a lyophilized biological preparation for intravesical instillation containing inactivated cells of Streptococcus pyogenes (Group A, type 3) Su strain. TARA-002 rapidly enters cancer cells, activating TLR2 and NOD2 to trigger the innate immune response, inflammation, and potential immunogenic cell death. Herein we present interim safety and efficacy data of TARA-002 from the BCG-unresponsive cohort of the ongoing ADVANCED-2 study (NCT05951179). Methods: ADVANCED-2 (Cohort B) is a Phase 2, open-label study to evaluate the safety and efficacy of intravesical TARA-002 in BCG-unresponsive adults ≥ 18 years with high-grade NMIBC CIS (± Ta/T1). Key exclusion criteria include penicillin allergy; history of ≥ T2 bladder cancer, nodal, or metastatic disease; or concomitant prostatic or upper tract urothelial involvement. TARA-002 is delivered intravesically for 2 hours and includes induction (6 weekly doses), reinduction (if persistent disease at 3 months), and maintenance (through 24 months). Response is assessed every 3 months for 2 years. Biopsy is mandated at Month 3. Long-term follow-up is conducted up to 60 months. Safety is monitored throughout the study. The primary endpoint is complete response (CR) at any time defined by the absence of any high-grade recurrence. The key secondary endpoint is duration of response. Results: As of 07-October-2025, 32 BCG-unresponsive participants have been enrolled. Majority of participants were White (84.4%, 27 of 32), non-Hispanic (93.8%, 30 of 32), and male (68.8%, 22 of 32). The median age was 74 years (range: 47 to 92). The majority of participants had a baseline diagnosis of CIS only ie, without concomitant Ta/T1 (75.0%, 24 of 32). TARA-002 demonstrated a 68.4% (13 of 19) CR at any time in evaluable participants. The 6-month CR was 75.0% (9 of 12), the 9-month CR was 50.0% (4 of 8), and the 12-month CR was 37.5% (3 of 8). The salvage rate was 75.0% (6 of 8) with reinduction therapy. Most treatment-emergent adverse events (TEAEs) were mild (CTCAE Grades 1-2) and transient; no participants experienced higher than Grade 3 TEAEs. No participants experienced drug-related serious adverse events (SAEs) or drug-related TEAEs leading to withdrawal or death. Conclusions: In participants with BCG-unresponsive high-risk NMIBC with CIS ± Ta/T1, TARA-002 appears to be well tolerated and demonstrated encouraging efficacy, supporting ongoing accrual of the ADVANCED-2 study. Further follow-up will inform durability of response, and data will be updated based on evaluable time points at the time of the presentation. Clinical trial information: NCT05951179 .

INTRODUCTION: Despite the widespread use of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC), many patients remain at risk of progression. Emerging data suggest that normalization of alkaline phosphatase (ALP) and total bilirubin (TB)—particularly when TB < 0.6 times the upper limit of normal (× ULN)—is associated with improved outcomes compared with ALP reduction to < 1.5 × ULN. This study investigated the association between ALP normalization in response to UDCA and long-term clinical outcomes in a real-world cohort of patients with PBC. METHODS: We compared complication-free survival in patients achieving an ALP > ULN and < 1.5 × ULN (adequate response) with those with an ALP ≤ ULN on UDCA monotherapy. Complication-free survival was defined as the absence of serious liver-related clinical events. Restricted mean survival time was used to quantify survival time gained. RESULTS: Patients achieving normal ALP and/or TB ≤ 0.6 × ULN demonstrated significantly improved complication-free survival compared with those with an adequate ALP response. Event-free survival was extended by 1.34 years (95% CI: 0.56, 2.11; P = 0.001) for ALP normalization alone, 3.7 years (95% CI: 3.11, 4.29; P < 0.001) for TB ≤ 0.6 × ULN, and 4.51 years (95% CI: 4.13, 4.88; P < 0.001) for those meeting both criteria. The risk of severe clinical events was reduced in patients achieving ALP normalization (hazard ratio [HR] 0.34; 95% CI: 0.15, 0.80; P = 0.01), TB ≤ 0.6 × ULN (HR 0.23; 95% CI: 0.09, 0.55; P = 0.001), or both (HR 0.14; 95% CI: 0.05, 0.38; P < 0.001). High-risk patients, defined by liver stiffness measurement ≥ 10 kPa or clinical, histological, or laboratory evidence of cirrhosis or portal hypertension, derived the greatest benefit. DISCUSSION: Achieving normal ALP and TB ≤ 0.6 × ULN is associated with significantly improved complication-free survival, particularly in high-risk patients. These findings highlight the potential of biochemical thresholds as a meaningful therapeutic goal in PBC management.

BACKGROUND: Left ventricular (LV) dysfunction is a potential cardioembolic source of ischemic stroke, but its role in recurrent stroke risk and treatment response remains unclear. We explore whether LV injury associates with the risk of recurrent stroke and modifies the association between anticoagulation and stroke recurrence using real-world data. METHODS: We performed a multicenter, retrospective study of Cardiac Abnormalities in Stroke Prevention and Recurrence cohort across 27 US sites. Patients with LV ejection fraction ≥20% were included. LV injury, defined as LV ejection fraction 20% to 40% and wall motion abnormality, was the primary exposure and treatment effect modifier. The treatment of interest was anticoagulant versus antiplatelet therapy. The composite outcome included recurrent stroke, major bleeding, or death. Outcomes were evaluated using unadjusted and inverse probability weighting adjusted Cox proportional hazards models, with treatment effect modification tested by LV injury status. RESULTS: Among 2685 patients enrolled, 2328 with complete data were analyzed (median age, 65 years; 49.8% female; median follow-up, 1.6 years). LV injury was present in 310 patients (13.3%). Overall, 535 events occurred: 258 recurrent ischemic strokes, 28 hemorrhagic strokes, 67 major hemorrhages, and 256 deaths. LV injury was associated with a higher unadjusted risk of the primary outcome (hazard ratio [HR], 1.51 [95% CI, 1.21–1.87]), though nonsignificant after inverse probability weighting adjustment (adjusted HR, 1.29 [95% CI, 0.97–1.70]). In the LV injury subgroup, anticoagulation versus antiplatelet therapy was associated with a lower risk of the primary outcome (adjusted HR, 0.24 [95% CI, 0.10–0.59]), relative to the non-LV injury subgroup (adjusted HR, 1.28 [95% CI, 0.83–1.95]; p[LV-interaction], 0.001). Similar interactions were seen for EF 20% to 40% (versus >40%; adjusted HR, 0.19 [95% CI, 0.04–0.86]; p[LV-interaction], 0.001) and wall motion abnormality (versus no wall motion abnormality; adjusted HR, 0.33 [95% CI, 0.15–0.73]). CONCLUSIONS: After cryptogenic stroke, anticoagulation in those with LV injury was associated with lower rates of recurrent stroke, major bleeding, and death. These findings warrant confirmation in a dedicated randomized controlled trial. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06398366.