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Abstract Background and Aims Although many studies revealed transcriptomic subtypes of HCC, concordance of the subtypes are not fully examined. We aim to examine a consensus of transcriptomic subtypes and correlate them with clinical outcomes. Approach and Results By integrating 16 previously established genomic signatures for HCC subtypes, we identified five clinically and molecularly distinct consensus subtypes. STM (STeM) is characterized by high stem cell features, vascular invasion, and poor prognosis. CIN (Chromosomal INstability) has moderate stem cell features, but high genomic instability and low immune activity. IMH (IMmune High) is characterized by high immune activity. BCM (Beta‐Catenin with high Male predominance) is characterized by prominent β‐catenin activation, low miRNA expression, hypomethylation, and high sensitivity to sorafenib. DLP (Differentiated and Low Proliferation) is differentiated with high hepatocyte nuclear factor 4A activity. We also developed and validated a robust predictor of consensus subtype with 100 genes and demonstrated that five subtypes were well conserved in patient‐derived xenograft models and cell lines. By analyzing serum proteomic data from the same patients, we further identified potential serum biomarkers that can stratify patients into subtypes. Conclusions Five HCC subtypes are correlated with genomic phenotypes and clinical outcomes and highly conserved in preclinical models, providing a framework for selecting the most appropriate models for preclinical studies.

BACKGROUND: Opioid-induced respiratory depression (OIRD) is common on the medical and surgical wards and is associated with increased morbidity and health care costs. While previous studies have investigated risk factors for OIRD, the role of race remains unclear. We aim to investigate the association between race and OIRD occurrence on the medical/surgical ward. METHODS: This is a post hoc analysis of the PRediction of Opioid-induced respiratory Depression In patients monitored by capnoGraphY (PRODIGY) trial; a prospective multinational observational blinded study of 1335 general ward patients who received parenteral opioids and underwent blinded capnography and oximetry monitoring to identify OIRD episodes. For this study, demographic and perioperative data, including race and comorbidities, were analyzed and assessed for potential associations with OIRD. Univariable χ 2 and Mann-Whitney U tests were used. Stepwise selection of all baseline and demographic characteristics was used in the multivariable logistic regression analysis. RESULTS: A total of 1253 patients had sufficient racial data (317 Asian, 158 Black, 736 White, and 42 other races) for inclusion. The incidence of OIRD was 60% in Asians (N = 190/317), 25% in Blacks (N = 40/158), 43% in Whites (N = 316/736), and 45% (N = 19/42) in other races. Baseline characteristics varied significantly: Asians were older, more opioid naïve, and had higher opioid requirements, while Blacks had higher incidences of heart failure, obesity, and smoking. Stepwise multivariable logistic regression revealed that Asians had increased risk of OIRD compared to Blacks (odds ratio [OR], 2.49; 95% confidence interval [CI], 1.54–4.04; P = .0002) and Whites (OR, 1.38; 95% CI, 1.01–1.87; P = .0432). Whites had a higher risk of OIRD compared to Blacks (OR, 1.81; 95% CI, 1.18–2.78; P = .0067). The model’s area under the curve was 0.760 (95% CI, 0.733–0.787), with a Hosmer-Lemeshow goodness-of-fit test P value of .23. CONCLUSIONS: This post hoc analysis of PRODIGY found a novel association between Asian race and increased OIRD incidence. Further study is required to elucidate its underlying mechanisms and develop targeted care pathways to reduce OIRD in susceptible populations.

Abstract Objective Leucocyte immunoglobulin-like receptor A3 (LILRA3) belongs to a family of leucocyte receptors. Our previous study reported LILRA3 transcripts were markedly upregulated in neutrophils from patients with APS. We undertook this study to investigate clinical implications of LILRA3 in APS and its potential role in APS-associated thrombosis. Methods Two independent cohorts were studied. The first consisted of 294 APS patients, 48 asymptomatic aPL carriers and 150 healthy controls (HCs) from Peking University People’s Hospital. The second included 99 APS patients, 25 aPL carriers and 40 HCs from United States APS centres. Serum or plasma concentrations of LILRA3 and MPO-DNA complexes were measured. Additionally, 35 patients with thrombotic APS (tAPS) were evaluated to determine potential effects of immunosuppressive therapy on serum concentrations of LILRA3 and MPO-DNA complexes. Results Both positivity and serum concentration of LILRA3 were significantly increased in APS patients, especially in those with tAPS. LILRA3-positive tAPS patients displayed more severe thrombotic manifestations. Serum LILRA3 was positively correlated with MPO-DNA complexes in LILRA3-positive tAPS. After immunosuppressive treatment, LILRA3 and MPO-DNA complexes were consistently decreased in tAPS patients. Key findings from the Peking cohort were confirmed in the United States cohort. Conclusion Our study provides first evidence that LILRA3 is aberrantly expressed in APS, especially in patients with tAPS. Serum LILRA3 correlated with MPO-DNA complexes, and the two indices were consistently decreased in tAPS patients after treatment. LILRA3 may play a role in thrombosis of APS and may serve as a biomarker and/or therapeutic target in tAPS.

Context.— Studies of lungs in patients with COVID-19 have focused on early findings. Objective.— To systematically study histopathologic and imaging features and presence of SARS-CoV-2 RNA in lung tissue from patients in later stages of COVID-19. Design.— Autopsies, explants, surgical lung biopsies, transbronchial biopsies, cryobiopsies, and needle biopsies from patients with COVID-19 whose onset of symptoms/confirmed diagnosis was more than 28 days before the procedure were studied. Available images were reviewed. Reverse transcription droplet digital polymerase chain reaction for SARS-CoV-2 RNA was performed on lung tissue. Results.— Of 44 specimens (43 patients; median age, 59.3 years; 26 [60.5%] male) features of acute lung injury (ALI) were seen in 39 (88.6%), predominantly organizing pneumonia and diffuse alveolar damage, up to 298 days after onset of COVID-19. Fibrotic changes were found in 33 specimens (75%), most commonly fibrotic diffuse alveolar damage (n = 22) and cicatricial organizing pneumonia (n = 12). Time between acquiring COVID-19 and specimen was shorter in patients with diffuse ALI (median, 61.5 days) compared with patients with focal (140 days) or no ALI (130 days) (P = .009). Sixteen (of 20; 80%) SARS-CoV-2 reverse transcription droplet digital polymerase chain reaction tests were positive, up to 174 days after COVID-19 onset. Time between COVID-19 onset and most recent computed tomography in patients with consolidation on imaging was shorter (median, 43.0 days) versus in patients without consolidation (87.5 days; P = .02). Reticulations were associated with longer time to computed tomography after COVID-19 onset (median, 82 versus 23.5 days; P = .006). Conclusions.— ALI and SARS-CoV-2 RNA can be detected in patients with COVID-19 for many months. ALI may evolve into fibrotic interstitial lung disease.

INTRODUCTION: Although an additional coronavirus disease 2019 vaccine dose for immunocompromised persons has been recommended in some countries, further data to guide vaccination strategies for patients with inflammatory bowel disease (IBD) are urgently needed. We sought to identify factors affecting initial humoral immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines among patients with IBD. METHODS: In this prospective cohort of SARS-CoV-2 immunized patients with IBD, we evaluated associations between participant age, sex, vaccine type, medication use, and the presence of a detectable antireceptor binding domain antibody and quantitative antibody level. RESULTS: In total, 1,909 participants were included (1,123, 692, and 94 received BNT162b2, mRNA-1273, and Ad26.COV2.S, respectively) of whom 96% achieved a positive antibody response. On multivariable analysis, factors associated with lack of antibody response were older age ( P = 0.043), BNT162b2 vs mRNA-1273 (odds ratio [OR] 2.1, 95% confidence interval [CI] 1.0–3.9), and combination therapy with anti-TNF and 6MP, azathioprine, or methotrexate (OR 4.2, 95% CI 2.4–7.3). The use of 5-aminosalicylate or sulfasalazine (OR 0.3, 95% CI 0.1–0.8) and ustekinumab (OR 0.2, 95% CI 0.05–0.8) was associated with decreased odds of lacking antibody response. DISCUSSION: Most patients with IBD mount an initial response to SARS-CoV-2 vaccination; however, older patients and those treated with anti-TNF and immunomodulator have blunted responses and may benefit the most from an additional vaccine dose. Patients treated with other classes of immunosuppressive medications have more robust initial immune responses to vaccination. These data should inform key decisions about patient selection for additional coronavirus disease 2019 vaccine doses in patients with IBD.

ABSTRACT Background Critically ill patients with severe acute kidney injury (AKI) requiring kidney replacement therapy (KRT) have a grim prognosis. Recently, multiple studies focused on the impact of KRT initiation time [i.e., accelerated versus watchful waiting KRT initiation (WWS-KRT)] on patient outcomes. We aim to review the results of all related clinical trials. Methods In this systematic review, we searched all relevant randomized clinical trials from January 2000 to April 2021. We assessed the impacts of accelerated versus WWS-KRT on KRT dependence, KRT-free days, mortality and adverse events, including hypotension, infection, arrhythmia and bleeding. We rated the certainty of evidence according to Cochrane methods and the GRADE approach. Results A total of 4932 critically ill patients with AKI from 10 randomized clinical trials were included in this analysis. The overall 28-day mortality rate was 38.5%. The 28-day KRT-dependence rate was 13.0%. The overall incident of KRT in the accelerated group was 97.4% and 62.8% in the WWS-KRT group. KRT in the accelerated group started 36.7 h earlier than the WWS-KRT group. The two groups had similar risks of 28-day [pooled log odds ratio (OR) 1.001, P = 0.982] and 90-day (OR 0.999, P = 0.991) mortality rates. The accelerated group had a significantly higher risk of 90-day KRT dependence (OR 1.589, P = 0.007), hypotension (OR 1.687, P < 0.001) and infection (OR 1.38, P = 0.04) compared with the WWS-KRT group. Conclusions This meta-analysis revealed that accelerated KRT leads to a higher probability of 90-day KRT dependence and dialysis-related complications without any impact on mortality rate when compared with WWS-KRT. Therefore, we suggest the WWS-KRT strategy for critically ill patients.

Objective: This study determined the incidence rates for obesity among adult patients ages 20 and older empaneled in primary care practice in Midwest United States to potentially identify an optimum timeframe for initiating intervention. Background: Primary care practice patients are likely to reflect underlying community trends in overweight and obesity; however, data on overweight and obesity in primary care patients is limited. While childhood incidence rates of obesity have been well reported, there is still a paucity of data on the incidence of obesity among adult population; literature has mainly focused on its prevalence. Methods: Medical record review of identified cohort with BMI data was conducted. Population was stratified by age and sex and overweight category was subdivided into tertiles. Results: Majority of 40 390 individuals who comprised the final population and had follow-up data, consisted of adults ages 40 to 69 years (47.5%), female (59.8%) of non-Hispanic ethnicity (95.9%) with 21 379 (52.8%) falling in weight category of overweight. Incidence of obesity was 7% at 1 year and 16% at 3 years follow-up. Highest percentages of individuals who became obese at 1 and 3 years were in age category of 40 to 69 years among men and 20 to 39 years among women. In Cox regression analysis, there was statistically significant association to developing obesity among all tertile groups in the overweight category. Age and particularly gender appeared to be modifying factors to likelihood of developing obesity. Conclusion: Study results suggest that while obesity incidence is higher among certain age groups in both genders, middle-aged women, and men in all tertiles of overweight category are at highest risk and may be the optimum population to target for weight loss interventions. Findings support the initiation of population-based interventions before onset of obesity.

Significance The mechanisms underlying inflammatory disorders are poorly understood. In this study, we show that inappropriate cell death may cause uncontrolled inflammation. We found that CYLD, an enzyme that removes K63-linked polyubiquitination, is normally inhibited. But in the cpdm mouse strain that has a loss-of-function in the Sharpin gene, the brake on CYLD is no longer present. When CYLD is no longer inhibited, it turns on death signaling in cells exposed to the cytokine TNF, and the ensuing inappropriate cell death causes skin inflammation and other immune disorders in the cpdm mouse. Removing CYLD from the cpdm mouse prevents cell death and reverses the inflammation. We conclude that excessive CYLD activity leads to inappropriate cell death and inflammation.