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Patients with advanced liver disease challenge anesthesiologists, especially those providing regional anesthesia for postoperative pain management. Coagulopathy, encephalopathy, sepsis and other comorbidities complicate care. Liver failure lowers albumin and α1-acid glycoprotein and slows hepatic clearance, increasing the unbound fraction and effective exposure to amide local anesthetics. Risks are magnified by acidosis, low cardiac output, low body mass index, sepsis, and concurrent renal dysfunction. Neuraxial options are often limited by coagulopathy and the risk of catastrophic neurologic complications while superficial, compressible peripheral blocks are generally considered safer than deep plexus targets. Safe practice includes the use of ultrasound guidance, incremental injection with frequent aspirations, avoidance of unnecessary high-dose multiple-site injections, and conservative dosing and infusion strategies. Regional anesthesia is feasible in patients with hepatic failure when dose and technique are adjusted to disease biology and when local anesthetic systemic toxicity (LAST) preparedness is routine. Catheters should run at lower concentrations and rates with scheduled reassessment and clearly communicated stop times. Teams should keep 20% lipid emulsion immediately available for treatment of neurologic or cardiovascular signs of LAST. We provide a practical pathway to select the block, choose the agent, and set doses that keep a reasonable safety margin for local anesthetics.

Purpose Mycobacterium avium complex lung disease (MAC-LD) represents the most common form of nontuberculous mycobacterial lung infection, particularly affecting women and older adults. Clinical management remains challenging, including prediction and differentiation between progressive and non-progressive disease. Overexpression of PD-1 pathways have been reported in progressive disease, and we hypothesize that PD-1 inhibition can restore antigen-specific immune responses detectable by FluoroSpot assay. Methods Peripheral blood mononuclear cells from 22 participants, including progressive and non-progressive MAC-LD patients, healthy controls, and individuals with latent tuberculosis infection (LTBI) were stimulated with nontuberculous mycobacteria and Mycobacterium tuberculosis antigens. Cytokine secretion of interferon-gamma (IFN-γ) and interleukin-2 (IL-2) were quantified using dual FluoroSpot assay, with and without PD-1 blockade. Results Progressive MAC-LD cases demonstrated significant increases in glycopeptidolipid (GPL)- and PPD-stimulated IFN-γ responses following PD-1 blockade, which was not seen in healthy controls, LTBI, or non-progressive MAC-LD patients. After GPL stimulation and in the presence of anti-PD-1, the number of IFN-γ responses increased from 25% to 75% in samples from progressive MAC-LD patients. This supports an association between PD-1–mediated T-cell dysfunction and disease progression. Mycobacterial MTB300 peptide pool antigen failed to discriminate MAC-LD from healthy controls, underscoring antigen specificity. Conclusions Our pilot study demonstrates that IFN-γ FluoroSpot assays, particularly when combining GPL or PPD stimulation and PD-1 inhibition, may help identify progressive MAC-LD. These findings also support other studies reporting that immune checkpoint dysregulation can be present in some patients with progressive and severe MAC-LD patients. Additional studies are warranted to determine its pathogenic role.

Expert consensus recommendations from 21 academic centers were established for appropriate radiography utilization at 12 potentially low-yield anatomic sites through a multidisciplinary process endorsed by six major American medical societies.

Introduction Lynch syndrome (LS) is a hereditary cancer syndrome that increases risk for colorectal and other cancers. We hypothesize that vaccines against tumor-associated antigens CEA, MUC1, and brachyury, simultaneously delivered in an adenovirus serotype-5 vector (Tri-Ad5) combined with the immune-enhancing IL-15 receptor superagonist nogapendekin-alfa-inbakicept (NAI) will reduce the incidence of colorectal neoplasms in LS carriers. Methods In this ongoing phase IIB double-blind placebo-controlled trial, two open-label safety phases (SPs) assessed safety of Tri-Ad5 alone (SP1, n=10) and with added NAI (SP2, n=10). A randomized controlled trial (RCT) follows the SPs. After baseline colonoscopy, vaccine dosing occurs at weeks 0, 4 and 8; Tri-Ad5 alone in SP1 and Tri-Ad5 plus NAI in SP2, with identical boosters at Week 52. The RCT phase participants (n=138) were randomized to receive Tri-Ad5 plus NAI or placebo. All participants complete colonoscopy at Weeks 52 and 104 for assessment of the primary endpoint: cumulative colorectal neoplasm incidence. Secondary endpoints include safety, tolerability, and immunogenicity. Results All 20 SP participants (median age 57.5 (range 42–75), 70% female, 15% minority) received all prime and booster series. SP1 participants reported 139 adverse events (AEs) and SP2 participants reported 178. AEs were predominantly grade 1; no treatment-related serious adverse events (SAEs) occurred. The most common treatment-related AEs were reactogenic events including grade 3 rash (without skin necrosis or breakdown) at NAI injection site (100% of SP2 participants). The RCT phase (n=138) recently completed accrual. Discussion In LS carriers without active cancer, the combination of Tri-Ad5 + NAI was well-tolerated; the RCT phase is ongoing. Clinical Trial Registration https://clinicaltrials.gov/study/ , identifier NCT05419011.

Abstract Rationale Fungal infections remain a major cause of morbidity and mortality post lung transplant due to unique exposure of the allograft to the external environment and the intensity of immunosuppression. Single-center studies have described variable rates of fungal infections. Contemporary population-level data with temporal trends, pathogen distribution, and associated outcomes are limited. Leveraging a large multicenter real-world dataset, we aimed to characterize incidence, prevalence and clinical outcomes of fungal infections among adult lung-transplant recipients. Methods Data were obtained from the TriNetX Global Collaborative Network (160 HCOs). Adult lung-transplant recipients (≥18 years) were identified between 2005 and 2024, using ICD and CPT procedure codes. Patients with solid organ transplants other than lung, combined-organ transplant or stem-cell transplant and HIV patients were excluded. Patients with pre transplant fungal infections were also excluded. Pre-transplant characteristics included demographics, comorbidities within a year, laboratory values within seven days, and medication within 90 days before transplantation. Post-transplant fungal infections were identified using ICD-10 codes for Aspergillus, Candida, Cryptococcus, Mucorales, Histoplasma, Blastomyces, Coccidioides, and Pneumocystis. TriNetX platform was utilized for statistical analysis. Incidence and prevalence of infections, all-cause mortality and transplant rejection were analyzed. Results A total of 12,857 adult lung-transplant recipients were identified. The mean age at transplantation was 57.6 ± 13.4 years, with a male predominance of (57%) and majority were white (65%). Average BMI was 26.8 ± 5.7 kg/m². The most common pulmonary conditions were COPD (15%), pulmonary fibrosis (17%), pulmonary hypertension (9%), bronchiectasis (3%), and cystic fibrosis (3%). Pre-transplant fungal and viral screening assays were rarely available (<1%). Medication exposure within 90 days prior to transplant demonstrated prednisone prescription (17%) methylprednisolone (7%), tacrolimus (6%), and mycophenolate mofetil (7%). Azathioprine and basiliximab were used in 2% each. Systemic antifungals (voriconazole, posaconazole, or fluconazole) in approximately 1% each.The overall incidence of post-transplant fungal infection was 3 % across full study period, rising to 7% in the modern era (2015-2024). Most frequently identified pathogens were Candida spp. (4.8%) and Aspergillus spp. (2.9%), followed by Pneumocystis Jirovecii (0.5%). Infection rates increased from 22 per 1,000 (2005-2014) to 75 per 1,000 (2015-2024) suggestive of improved diagnostic sensitivity and data capture, and longer post-transplant survival. All-cause mortality 5-year post transplant was 22.1%, and rejection rate was 22.5%. Conclusion Our study highlights a rising burden of fungal infections among lung-transplant recipients with potential implications for early post-transplant surveillance and antifungal prophylaxis strategies. This abstract is funded by: None

Abstract Rationale Fungal infections are common after lung transplantation and may adversely affect graft function and survival, but long-term outcomes remain incompletely defined. Using a large multicenter real-world dataset, we aimed to study the impact of post-transplant fungal infections on clinical outcomes of lung transplant recipients. Methods We conducted a retrospective, cohort study using the TriNetX Global Collaborative Network, which aggregates de-identified electronic health records from >160 healthcare organizations across North America, Europe, and Asia. Adult lung transplant recipients (≥18 years) between 2005 and 2024 were identified using ICD-10 and CPT codes. Patients with post-transplant fungal infection (aspergillosis, candidiasis, mucormycosis, histoplasmosis, coccidioidomycosis, blastomycosis) and matched controls without fungal infection within one year before or any time after transplant were identified. The index date was the date of transplantation. Propensity-score matching was performed on demographics, comorbidities, laboratory values, procedures and immunosuppressive medications. Outcomes included all-cause mortality (primary), allograft rejection, and chronic lung allograft dysfunction (CLAD) at 6 months, 1 year, 3 years, and 5 years. Kaplan-Meier and Cox proportional hazards models were used to estimate risk ratios (RRs), hazard ratios (HRs), and 95% confidence intervals (CIs). Analyses were conducted in TriNetX Analytics (v25.0, Cambridge, MA). Results A total of 3,083 patients with post-transplant fungal infection and 11,625 patients without infection were identified. Mean age was 58 ± 13 years, and 56% were male. The most common pulmonary comorbidities were chronic obstructive pulmonary disease, unspecified pulmonary fibrosis, idiopathic pulmonary fibrosis and bronchiectasis. Immunosuppression exposure was similar across groups. After propensity score matching across 56 clinical variables, both groups (1,790 per group) were well balanced. Mortality was higher in the fungal infection cohort at all follow-up points: 13.% vs 9% at 6 months (RR 1.45, 95% CI 1.2-1.75, p = 0.001), 17.8% vs 13% at 1 year (RR 1.36, p = 0.0001), 27.7% vs 21% at 3 years (RR 1.28, p < 0.0001), and 33 % vs 25% at 5 years (RR 1.32, p < 0.0001). Allograft rejection remained consistently higher (46-61% vs 22-34%), while CLAD occurred two- to three-fold more frequently (1.8-5.7% vs 0.7-2%). Conclusion Post-transplant fungal infection is independently associated with significantly increased mortality, acute rejection, and CLAD following lung transplantation. These findings underscore the need for early fungal surveillance, optimized antifungal prophylaxis, and individualized immunosuppression strategies to improve long-term patient outcomes. This abstract is funded by: None

Abstract Introduction Sedation is routinely administered to facilitate comfort and tolerance of life support for critically ill adults dependent on invasive mechanical ventilation. Isoflurane, a widely used anesthetic during surgery, has properties that may also benefit ICU patients requiring continuous sedation. However, efficacy as a sedative and safety in this population is not well established. Methods We conducted two identically designed multicenter randomized trials, INSPIRE ICU1 and INSPIRE ICU2, at hospitals across the US. Ventilator-dependent adults were randomly assigned in a 1.5:1 ratio to receive either inhaled isoflurane or intravenous propofol as the first-line sedative for up to 48 ± 6 hours, targeting a sedation depth between Richmond agitation-sedation scale (RASS) -1 (drowsy) to -4 (responsive only to physical stimuli). Isoflurane was administered via an anesthetic conserving device (Sedaconda ACD-S). In both arms, opioids were permitted at the lowest dose required to achieve freedom from pain. The primary outcome was the percentage of time at target sedation level, assessed as a noninferiority outcome with pre-specified margin of 15%. Secondary outcomes included opioid exposure, wake-up time after end of treatment, time to extubation, and proportion of time with spontaneous breathing effort. Results A total of 470 combined participants were included in the two trials. In each trial, 142 patients were randomly assigned to isoflurane and 93 to propofol. In INSPIRE ICU1, percentage of time within target sedation depth was 77.1 [53.2, 89.9] % with isoflurane and 80.9 [58.2, 96.4] % with propofol (difference -1.5 [-8.9, >99] %; p < 0.01 for noninferiority). In INSPIRE ICU2, percentage of time within target sedation depth was 72.6 [66.4, 78.9] % with isoflurane and 74.5 [67.5, 81.5] % with propofol (difference -1.9 [-9.4, >99] %; p < 0.01 for noninferiority). In both trials, patients assigned to isoflurane received significantly less opioid, measured as fentanyl equivalents, during the treatment period. In INSPIRE ICU2, participants receiving isoflurane were significantly likelier to exhibit spontaneous breathing efforts, but this finding was not replicated in INSPIRE ICU1. There were no significant differences in time to wake-up or time to extubation between groups in either trial. No episodes of malignant hyperthermia or propofol infusion syndrome were reported. Adverse events were comparable in type and frequency between groups. Conclusions In two US multicenter trials, isoflurane was noninferior to propofol for maintaining target sedation depth in adults undergoing invasive ventilation, and was associated with significantly lower opioid exposure. (NCT05327296, NCT05312385) This abstract is funded by: Sedana Medical

Abstract Respiratory viral infections such as influenza and SARS-CoV-2 can lead to the development of chronic lung disease and impaired pulmonary function long after the recovery from acute illness. However, the mechanisms underlying these post-acute sequelae remain poorly understood. Using human lung samples from patients with post-acute sequelae of COVID-19 with pulmonary fibrosis (PASC-PF) and an aged mouse model of chronic lung disease following acute viral infection, we found that CD4+ T cells were enriched near the dysplastic Krt8Hi epithelial regions of the lung. Similarly, in aged mice, CD4+ T cells localized to Krt8Hi areas, and their spatial distribution correlated positively with the extent of epithelial dysplasia. Further analysis of bronchoalveolar lavage (BAL) fluid from COVID-19 convalescent individuals revealed a distinct population of FoxP3−PD-1HiCD4+ T cells highly expressing ICOS, CD69, and CD103 - markers characteristic of both T follicular helper (TFH) and tissue-resident memory (TRM) cells, which we have defined as tissue-resident helper (TRH) cells previously. Notably, the frequency of these TRH-like cells correlated positively with the extent of reticulate or consolidated regions on chest CT scans, indicative of lung fibrosis. Furthermore, the frequency of these cells was negatively associated with lung functional parameters including forced vital capacity (FVC). These findings suggest that PD-1HiCD4+ TRH-like cells expand in PASC and may contribute to chronic lung sequelae. Given that Bcl6 is required for TRH differentiation, we employed an aged, CD4-specific, inducible Bcl6-deficient (Bcl6iΔCD4) mouse model to evaluate the functional contribution of these cells to post viral lung fibrosis. Bcl6 deficiency led to a marked reduction in total and antigen-specific PD-1HiCD4+ TRH cells, as confirmed by flow cytometry and immunofluorescence. Strikingly, Bcl6 iΔCD4 mice displayed significantly decreased inflammatory and fibrotic lesions in the lung compared to wild-type controls. Moreover, Bcl6 iΔCD4 mice exhibited enhanced lung regeneration, evidenced by increased AT1 and AT2 epithelial cells and improved pulmonary function. Together, these findings identify Bcl6-dependent CD4+ TRH responses as key drivers of post-viral chronic lung sequelae. This study reveals a novel immunopathogenic mechanism linking persistent tissue helper memory T-cell responses to impaired lung repair and fibrosis, providing new insight into the development of post-viral lung disease and potential therapeutic targets for conditions such as respiratory long COVID. This abstract is funded by: American Lung Association, NIH

Abstract Rationale Interstitial lung abnormalities (ILA) are abnormal findings on chest CT scans that may represent early-stages of interstitial lung disease. The presence of fibrosis (traction bronchiectasis and/or honeycombing) identifies those with ILA at an increased risk for mortality, however, determining who will progress remains a challenge, and the role of blood-based biomarkers in ILA risk-stratification is unknown. Methods Data from four prospective cohort studies were used to identify associations between plasma proteins measured with DNA aptamers (SomaScan) and ILA, fibrosis, and mortality. The Genetic Epidemiology of COPD Study (COPDGene) was used to identify protein associations, and findings were replicated by meta-analysis of the Age, Gene/Environment Susceptibility-Reykjavik study (AGES-Reykjavik), SubPopulations and InteRmediate Outcome Measures in COPD Study (SPIROMICS), and Framingham Heart Study (FHS). Protein associations with ILA and with fibrotic ILA compared to non-fibrotic ILA were performed using multivariable logistic regression; among those with ILA, Cox proportional hazards models were used to identify protein associations with mortality. Models were adjusted for age, gender, race, BMI, smoking status, pack-year smoking history, and for mortality, COPD. Benjamini-Hochberg false discovery rate p-values <0.05 were considered significant. Results 524 (10.7%) of 4,899 COPDGene participants had ILA, of whom 57 (10.9%) had fibrosis; of 8,146 AGES-Reykjavik, SPIROMICS and FHS participants included in the meta-analysis, 666 (8.2%) had ILA, of whom 198 (29.7%) had fibrosis. In COPDGene, 230 proteins were associated with ILA; the most significant of which were SFTPD (adjusted odds ratio per standard deviation [SD] of protein [OR]=2.21, p = 3.7E-41) and SFTPB (OR = 1.82, p = 7.9E-37). In the meta-analysis, 159 of the ILA-associated proteins were replicated. Of the 230 ILA-associated proteins in COPDGene, 9 were associated with fibrosis, and 5 of these 9 proteins were associated with mortality among those with ILA. The 5 proteins associated with all three outcomes were WFDC2 (ORILA=1.90, p = 2.6E-34; ORFibrosis=2.00, p = 0.0001; adjusted hazards of mortality per SD of protein [HR]=1.59, p = 3.4E-05), GDF15 (ORILA=1.67, p = 3.6E-23; ORFibrosis=1.78, p = 0.0006; HR = 1.63, p = 1.4E-06), SCGB3A1 (ORILA=1.52, p = 4.5e-14; ORFibrosis=1.80, p = 0.0002; HR = 1.25, p = 0.02), TREM1 (ORILA=1.44, p = 1.4e-14; ORFibrosis=1.62, p = 0.001; HR = 1.25, p = 0.02) ICAM5 (ORILA=1.42, p = 1.2e-11; ORFibrosis=1.79, p = 0.0001; HR = 1.31, p = 0.002). In the meta-analysis, 6 of the 9 fibrosis-associated proteins and all 5 ILA mortality-associated proteins replicated. Conclusion This represents the first plasma proteomic screen demonstrating reproducible biomarker associations not only with ILA presence, but also with measures of severity and adverse outcomes. These results provide compelling targets for further study, including their prospective evaluation as clinical biomarkers for early disease identification and prognostication. This abstract is funded by: Multiple Sources

Abstract Rationale To construct multi-trait polygenic scores (PRS) predicting chronic obstructive pulmonary disease (COPD) and exacerbations, validate their performance in diverse cohorts, and identify PRS-related proteins for potential therapeutic targeting. Methods PRSmix+, a multi-trait PRS framework, is used to train a composite PRS (PRSmulti) in COPDGene non-Hispanic white participants (n = 6,647). Associations of PRSmulti with COPD status (GOLD 2-4 vs. GOLD 0 or ICD) and exacerbation frequency were tested in COPDGene African American (n = 2,466), ECLIPSE (n = 1,858), MassGeneral Brigham Biobank (n = 15,152), and All of Us (n = 118,566). Protein prediction models were applied to GWAS summary statistics from traits contributing to PRSmulti and were validated with proteomic data in COPDGene (n = 5,173) and UK Biobank (n = 5,012). Results PRSmix+ selected 7 traits for PRSmulti. In multivariable models, PRSmulti was associated with COPD status (meta-analysis random effects (RE) OR 1.58 [95% CI: 1.28-1.94]) and exacerbation frequency (meta-analysis RE beta 0.21 [95% CI: 0.11-0.31]), with higher effect sizes observed in smoking-enriched cohorts. PRSmulti outperformed traditional single-trait PRS in all tested cohorts. Using protein prediction models, we identified 73 proteins associated with the PRS that were also validated with measured protein levels in COPDGene and UK biobank. Of these proteins, 25 were linked to approved or investigational drugs. Notable targets include AGER (RAGE), IL1RL1, and SCARF2, all implicated in COPD pathogenesis and exacerbations. Conclusions Multi-trait PRS improves prediction of COPD and exacerbation risk. Integration with proteomic data identifies druggable protein targets, offering a promising avenue for precision medicine in COPD management. Trial registration. COPDGene: NCT00608764; ECLIPSE: NCT00292552. This abstract is funded by: NIH and the COPD Foundation