PURPOSE: A causal biomarker for acute respiratory distress syndrome (ARDS) could fuel precision therapy options. Plasma angiopoietin-2 (ANG2), a vascular permeability marker, is a strong candidate based on experimental and observational evidence. We used genetic causal inference methods – Mendelian Randomization and mediation – to infer potential effects of plasma ANG2. METHODS: We genotyped 703 septic subjects, measured ICU admission plasma ANG2, and performed a quantitative trait loci (QTL) analysis to determine variants in the ANGPT2 gene associated with plasma ANG2 (p < 0.005). We then used linear regression and post-estimation analysis to genetically predict plasma ANG2 and tested genetically-predicted ANG2 for ARDS association using logistic regression. We estimated the proportion of the genetic effect explained by plasma ANG2 using mediation analysis. RESULTS: Plasma ANG2 was strongly associated with ARDS (OR 1.59 (95% CI 1.35, 1.88) per log). Five ANGPT2 variants were associated with ANG2 in European ancestry subjects (n=404). Rs2442608C, the most extreme cis QTL (coefficient 0.22, 95% CI 0.09 – 0.36, p=0.001), was associated with higher ARDS risk: adjusted OR 1.38 (95% CI 1.01, 1.87), p=0.042. No significant QTL were identified in African ancestry subjects. Genetically-predicted plasma ANG2 was associated with ARDS risk: adjusted OR 2.25 (95% CI 1.06 – 4.78), p=0.035. Plasma ANG2 mediated 34% of the rs2442608C - ARDS risk. CONCLUSIONS: In septic European ancestry subjects, the strongest ANG2-determining ANGPT2 genetic variant associates with higher ARDS risk. Plasma ANG2 may be a causal factor in ARDS development. Strategies to reduce plasma ANG2 warrant testing to prevent or treat sepsis-associated ARDS.

BackgroundEnrichment strategies improve therapeutic targeting and trial efficiency, but enrichment factors for sepsis trials are lacking. We determined whether concentrations of soluble tumor necrosis factor receptor-1 (sTNFR1), interleukin-8 (IL8), and angiopoietin-2 (Ang2) could identify sepsis patients at higher mortality risk and serve as prognostic enrichment factors.MethodsIn a multicenter prospective cohort study of 400 critically ill septic patients, we derived and validated thresholds for each marker and expressed prognostic enrichment using risk differences (RD) of 30-day mortality as predictive values. We then used decision curve analysis to simulate the prognostic enrichment of each marker and compare different prognostic enrichment strategies.Measurements and main resultsAn admission sTNFR1 concentration > 8861 pg/ml identified patients with increased mortality in both the derivation (RD 21.6%) and validation (RD 17.8%) populations. Among immunocompetent patients, an IL8 concentration > 94 pg/ml identified patients with increased mortality in both the derivation (RD 17.7%) and validation (RD 27.0%) populations. An Ang2 level > 9761 pg/ml identified patients at 21.3% and 12.3% increased risk of mortality in the derivation and validation populations, respectively. Using sTNFR1 or IL8 to select high-risk patients improved clinical trial power and efficiency compared to selecting patients with septic shock. Ang2 did not outperform septic shock as an enrichment factor.ConclusionsThresholds for sTNFR1 and IL8 consistently identified sepsis patients with higher mortality risk and may have utility for prognostic enrichment in sepsis trials.

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Objectives: Neck Imaging Reporting and Data System (NI-RADS) is a radiology reporting system for head and neck cancer surveillance. Imaging findings of high suspicion for recurrence are assigned Category 3 and recommended for "Biopsy, if clinically indicated." After implementing NI-RADS for surveillance neck computed tomography (CT), our objectives are to determine the incidence of squamous cell carcinoma (SCC) Category 3 lesions in the year post-implementation, the associated biopsy rate, and the positive predictive value of NI-RADS 3 for SCC recurrence.Study Design: Retrospective cohort study. Methods: Neck CTs reported with NI-RADS between February 2020 and February 2021 were reviewed to identify patients undergoing surveillance for SCC assigned NI-RADS 3. Cancer recurrence, defined as positive biopsy result or treatment of clinically determined recurrence, was determined by electronic medical record review.Results: During the study period, 580 neck CTs were reported with NI-RADS, of which 39 (7%) CTs obtained in 37 unique patients (28 male, 9 female, mean age 66.6 years) formed the study cohort. Biopsies were obtained in 23 lesions (45%), of which 17 (74%) were positive for recurrent SCC. One nondiagnostic biopsy was clinically determined to represent recurrence. Of 28 (55%) lesions not biopsied, 18 (64%) were ultimately treated as clinically determined recurrence. Thus, among 51 individual NI-RADS 3 lesions (32 primary, 19 neck), 36 (71%) represented recurrence. Conclusion:The incidence of NI-RADS 3 lesions in our cohort was 7%. The biopsy rate was 45%, and the overall positive predictive value of NI-RADS 3 for recurrent SCC was 71%. Category 3 lesions are associated with substantial SCC recurrence risk and should be managed accordingly.

We recognized a surge in acute hepatitis B at our institution and a link to the opioid epidemic since 2017. Among barriers to optimal management, we identified frequent deviations from national recommendations and patient noncompliance with follow-up.