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Metastatic castration-resistant prostate cancer (mCRPC) is a genetically heterogeneous disease with a poor prognosis. The prevalence of mutations in homologous recombination repair (HRR) pathway genes, including BRCA1/2, as well as treatment patterns and clinical outcomes, are not well characterized among Japanese men with mCRPC.This multicenter, noninterventional cohort study enrolled Japanese men with mCRPC from 24 institutions between 2014 and 2018. Mutations in the 15 HRR-related genes were assessed using archival primary or metastatic tumor samples. Patterns of sequential therapies for mCRPC were investigated. Patients were followed up for survival evaluation including prostate-specific antigen progression-free survival (PSA-PFS) and overall survival (OS).Of the 143 patients analyzed, HRR-related mutations were detected in 51 patients (35.7%). The most frequently mutated genes were CDK12 (N = 19, 13.3%), followed by BRCA2 (N = 18, 12.6%), ATM (N = 8, 5.6%), and CHEK2 (N = 3, 2.1%). The most common type of first-line therapy for mCRPC was next-generation hormonal agents (NHA, 44.4%), followed by first-generation antiandrogens (FGA, 30.3%), and taxanes (22.5%). Commonly prescribed first-/second-line sequential regimens included FGA/NHA (17.6%), NHA/NHA (15.5%), and NHA/taxanes (14.1%). The median PSA-PFS and OS for the entire cohort were 5.6 and 26.1 months, respectively. Patients carrying BRCA1/2 mutations had numerically shorter PSA-PFS (median 3.3 vs. 5.9 months) and OS (median 20.7 vs. 27.3 months) than those without mutations.In conclusion, approximately one-third of Japanese patients with mCRPC carried mutations in HRR-related genes in this study. The real-world outcomes of mCRPC are poor with conventional therapy, warranting an expansion of treatment options based on genetic abnormalities of the disease.

Immune checkpoint inhibitors (ICIs) have become central to lung cancer drug therapy, and establishing biomarkers that can predict effects and adverse events is awaited. We prospectively analyzed the association between the immune-related molecular expression in peripheral blood mononuclear cells (PBMCs) and lung cancer tissues, and the effects of ICI monotherapy. Twenty-one patients with advanced non-small cell lung cancer who received ICI monotherapy were included. Changes in the expression of immune-related molecules in PBMCs before and after the administration of ICI were analyzed by flow cytometry. The MHC class I and PD-L1 expression of cancer cells, and the PD-L1, CD8 and CD103 expression of tumor-infiltrating immune cells in lung cancer tissue were confirmed by immunohistochemistry. Among immune-related molecules expressed in PBMCs, the CD103 + CD39 + CD8 + T cell change after administration correlated with the clinical response. In the univariate analyses of the factors associated with progression-free survival (PFS), CD103 + CD39 + CD8 + cell change after administration was identified as a significant prognostic factor, while the CD103 + CD39 + CD8 + cell change after administration and Brinkman index were independent prognostic factors in a multivariate analysis of the factors associated with PFS. The CD103 + CD39 + CD8 + cell change after administration may predict the efficacy of ICIs.

Famotidine has been considered to be a potential treatment for COVID-19 but the current data is conflicting. This retrospective study was conducted by utilizing data of 9,565 COVID-19 hospitalized patients. Patients treated with and without famotidine were matched by propensity score using 1:1 matching scheme. 1,593 patients (16.7%) received famotidine. In-hospital mortality was similar in patients treated with and without famotidine in the propensity matched cohorts (28.3% versus 28.2%, P=0.97), which remains similar irrespective of severity or concomitant treatment by steroids. Famotidine treatment was not associated with a lower risk of in-hospital mortality of COVID-19 patients. This article is protected by copyright. All rights reserved.

We aimed to investigate whether hospitalizations of patients who tested positive for coronavirus disease 2019 (COVID‐19) antibodies are associated with reduced in‐hospital mortality. Of the 2459 patients admitted due to COVID‐19 and tested for antibodies, 937 (38.1%) had positive tests. After adjustment for patient characteristics and treatments, patients with positive COVID‐19 antibody test had lower in‐hospital mortality compared with those with negative test results (odds ratio [OR]: 0.62; 95% confidential interval [95% CI] 0.46–0.83, p = 0.001). In conclusion, positive COVID‐19 antibody test results were associated with the reduced risk of in‐hospital mortality for COVID‐19 patients.

Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection., 「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.

Background Statins are frequently prescribed for patients with dyslipidemia and diabetes mellitus. These comorbidities are highly prevalent in coronavirus disease 2019 (COVID-19) patients. Statin's beneficial effect on mortality in COVID-19 infection has been reported in several studies. However, these findings are still inconclusive. Methods We conducted a retrospective observational study among 6,095 patients with laboratory confirmed COVID-19 hospitalized in Mount Sinai Health System between March 1st 2020 and May 7th 2020. Patients were stratified into two groups: statin use prior to or during hospitalization (N=2,423) versus no statins (N=3,672). We evaluated in-hospital mortality as a primary outcome using propensity score matching and inverse probability treatment weighted (IPTW) analysis. In additional analysis, we compared continuous use of statins (N=1,108) with no statins, continuous use of statins with discontinuation of statins (N=644), and discontinuation of statins with no statins. Results Among 6,095 COVID-19 patients, statin use prior to or during hospitalization group were older (70.8±12.7 years versus 59.2±18.2 years, p, Graphical Abstract In hospital mortality for patients who used statins prior to or during hospitalization group versus no statins group, antecedent use of statins group versus no statins group, continuous use of statins group versus no statins group, discontinuation of statins group versus no statins group, and discontinuation of statins group versus continuation of statins groupImage, graphical abstract

Introduction: Obesity is one of the most frequent comorbidities among COVID-19 patients. Although previous studies have shown higher body mass index (BMI) is associated with higher mortality, steroids as the current standard treatment for moderate to severe COVID-19 infection were not applied in most patients in these studies. Hypothesis: We hypothesized that patients with higher BMI still have higher mortality even on steroids. Methods: We conducted a retrospective study of 4,587 hospitalized patients with COVID-19 who received corticosteroids between March 1 st , 2020, and March 30 th , 2021. We divided patients into 6 groups by BMI[MOU1] (less 18.5, 18.5-25, 25-30, 30-35, 35-40, 40 or greater, kg/m 2 ) and investigated in-hospital mortality as the primary outcome, in-hospital mortality among severe COVID-19 patients which was defined as requiring intensive care unit or endotracheal intubation as a subgroup analysis, and acute kidney injury (AKI) incidence rate as the secondary outcome. Results: Patients with higher BMI were younger and more likely to have a history of asthma, obstructive sleep apnea, diabetes, and less likely to have malignancies. The smooth spline curve showed J curve association of BMI with risk adjusted in-hospital mortality with flexion point at BMI between 25 and 30 kg/m 2 (Figure 1). Compared to overweight (25≤BMI2 ) patients, class III obesity (BMI>40 kg/m 2 ) was associated with higher risk adjusted in-hospital mortality overall (Table 1) as well as among patients with severe COVID-19 (OR [95% CI]: 3.21 [1.86-5.66], P Conclusions: Class III obesity was associated with higher in-hospital mortality and AKI incidence rate in COVID-19 patients with steroids treatment.

Introduction: Statins are frequently prescribed for patients with hypertension, dyslipidemia and diabetes mellitus. These comorbidities are highly prevalent in COVID-19 patients. Statin’s beneficial effect on mortalities in COVID-19 infection has been reported in several studies, but still inconclusive. Hypothesis: The inconclusive study results in association of satin use and COVID-19 can be resulted from variable timing of statins used among the studies. Our aim was to investigate whether consistent use of statins before and during hospitalization was effective to decrease the mortality due to COVID-19. Methods: We conducted a retrospective study among 6,095 patients with COVID-19 hospitalized in New York City between March 1st 2020 and May 7th 2021. Patients were stratified into two groups: statins use prior or during hospitalization (N=2,423) versus no statins (N=3,672). We evaluated in-hospital mortality as a primary outcome using propensity score matching and inverse probability treatment weighted (IPTW) analysis. In addition, we compared continuous use of statins (N=1,108) versus no statins. Results: Statins use prior or during hospitalization group were older (70.8±12.7 versus 59.2±18.2, P Conclusions: Use of statins prior or during hospitalization was not associated with a decreased risk of in-hospital mortality, however, continuous use of statins might have potential benefit of a decreased risk of in-hospital mortality due to COVID-19.

Background: Bleeding events can be critical in hospitalized patients with COVID-19, especially those with aggressive anticoagulation therapy. Objective: We aimed to investigate whether hemoglobin drop associated with increased risk of acute kidney injury (AKI) and in-hospital mortality among patients with COVID-19. Methods: This retrospective study was conducted by review of the medical records of 6,683 patients with laboratory confirmed COVID-19 hospitalized in the Mount Sinai Health system between March 1 st , 2020 and March 30 th 2021. We compared patients with and without hemoglobin drop >3g/dL during hospitalization within a week after admissions, using inverse probability treatment weighted analysis (IPTW). Outcomes of interest were in-hospital mortality and AKI which was defined as increased of creatine 1.5 times or 0.3mg/dL. Results: Of the 6,683 patients admitted due to COVID-19, 750 (11.2%) presented with a marked hemoglobin drop. Patients with hemoglobin drop were more likely to receive therapeutic anticoagulation within two days after admissions. Patients with hemoglobin drop had higher crude in-hospital mortality (40.8% versus 20.0%, P Conclusions: Hemoglobin drop during COVID-19 related hospitalizations was associated with a higher risk of AKI and in-hospital mortality. Figure Legends: Smooth spline curve of the association of hemoglobin drop and adjusted odds ratio of in-hospital mortality.

Introduction: Previous observational and randomized studies suggested potential benefit of therapeutic anticoagulation during hospitalization, but this treatment remains controversial Objective: We aimed to investigate the association of prophylactic and therapeutic anticoagulation with mortality for patients with COVID-19 who were treated with steroids and Remdesivir, which is the current standard treatments. Methods: This retrospective study was conducted by review of the electronic medical records for 9,565 patients with laboratory confirmed COVID-19 hospitalized in the Mount Sinai Health system between March 1 st 2020 and March 30 th 2021. The primary outcome of interest was the in-hospital mortality. Acute kidney injury was defined as any increase of creatinine by more than 0.3mg/dL or to more than 1.5 times baseline. A propensity score analysis (matching and weighting by inverse probability treatment weights) and multiple imputation was performed. Results: Of the 1,443 patients, 420 (29.1%) had therapeutic anticoagulation therapy. The 1,023 (70.9%) patients with prophylactic anticoagulation were older and had more comorbidities. After matching by propensity score (N=334 in each group), in-hospital mortality was not significantly different between patients with therapeutic anticoagulation and those with prophylactic anticoagulation (26.9% vs. 22.8%, P=0.24). Furthermore, IPTW and multiple imputation for missing data did not change the result (therapeutic versus prophylactic; odds ratio [95% confidential interval]: 1.14 [0.83-1.59], P=0.40]; 1.20 [0.84-1.73], P=0.31, respectively). Interestingly, patients with therapeutic anticoagulation had higher rate of acute kidney injury as compared to patients with prophylactic anticoagulation (26.6% vs. 16.8%, P=0.003). Conclusions: In conclusion, prophylactic versus therapeutic anticoagulation showed similar in-hospital mortality of COVID-19 patients treated with steroids and remdesivir, but therapeutic anticoagulation increased the risk of acute kidney injury compared to prophylactic anticoagulation.

We aimed to create the prediction model of in‐hospital mortality using machine learning methods for patients with coronavirus disease 2019 (COVID‐19) treated with steroid and remdesivir. We reviewed 1571 hospitalized patients with laboratory confirmed COVID‐19 from the Mount Sinai Health System treated with both steroids and remdesivir. The important variables associated with in‐hospital mortality were identified using LASSO (least absolute shrinkage and selection operator) and SHAP (SHapley Additive exPlanations) through the light gradient boosting model (GBM). The data before February 17th, 2021 (N = 769) was randomly split into training and testing datasets; 80% versus 20%, respectively. Light GBM models were created with train data and area under the curves (AUCs) were calculated. Additionally, we calculated AUC with the data between February 17th, 2021 and March 30th, 2021 (N = 802). Of the 1571 patients admitted due to COVID‐19, 331 (21.1%) died during hospitalization. Through LASSO and SHAP, we selected six important variables; age, hypertension, oxygen saturation, blood urea nitrogen, intensive care unit admission, and endotracheal intubation. AUCs using training and testing datasets derived from the data before February 17th, 2021 were 0.871/0.911. Additionally, the light GBM model has high predictability for the latest data (AUC: 0.881) (https://risk-model.herokuapp.com/covid). A high‐value prediction model was created to estimate in‐hospital mortality for COVID‐19 patients treated with steroid and remdesivir., HIGHLIGHTS •Through LASSO and SHAP techniques, we selected six important variables associated with death of patients infected with COVID‐19: age, hypertension, oxygen saturation, blood urea nitrogen, intensive care unit admission, and endotracheal intubation.•Area under the curves (AUCs) using training and testing datasets derived from the data before February 17th, 2021 were 0.871/0.911.•Additionally, the light gradient boosting model model has high predictability for the latest data (AUC: 0.881).

Background : Severe coronavirus disease 2019 (COVID-19) is associated with systematic coagulopathy which might result in fatality. We aimed to investigate whether systematic anticoagulation before admission with COVID infection was associated with patients’ survival. Methods : We reviewed medical records of 6,095 hospitalized patients with laboratory confirmed COVID-19 from the Mount Sinai Health System. Patients were stratified into two groups: patients with therapeutic anticoagulation before admission (7.9%, N=480), or those without (92.1%, N=5,615). Propensity score matched analysis was conducted to assess the association of anticoagulation before admission and in-hospital mortality (N=296 in each group). Multiple imputation for missing data was conducted. Results : A total of 480 patients (7.9%) received anticoagulation before admission. Patients with anticoagulation before admission were older (72.1±14.7 years vs. 63.1±17.2 years), and had more comorbidities including chronic pulmonary obstructive disease, hypertension, diabetes, chronic kidney disease, atrial fibrillation, and heart failure (all p< 0.05). Notably, patients with anticoagulation before admission had lower D-dimer [1.48 (IQR 0.75, 2.79) μg/mL vs 1.66 (0.89, 3.52) μg/mL, p=0.002]. In a propensity score matched analysis (N=296 in each group), in-hospital mortality was not significantly different in patients with anticoagulation before admission compared to those without (28.4% vs 31.1%, p=0.53). In addition, inverse probability weighted analysis and multiple imputation for missing data did not change the result. Furthermore, these differences were not significant after excluding endotracheal intubation from both groups. Conclusion : Anticoagulation before admission was not associated with lower risk of in-hospital mortality of COVID-19 patients. Further investigation is needed to confirm these findings., Graphical Abstract Image, graphical abstract

BackgroundRemdesivir has been shown to decrease SARS-CoV-2 viral loads and the duration of COVID-19 symptoms. However, current evidence regarding the association between remdesivir and in-hospital mortality for patients with COVID-19 steroid treatments is limited. We aimed to investigate whether remdesivir reduces in-hospital mortality among patients with COVID-19 treated with steroids.MethodsIn this retrospective multicentre study, we reviewed the medical records of 3372 patients discharged between 1 March 2020 and 30 March 2021, with laboratory confirmed COVID-19 in the Mount Sinai Health System and treated with steroids. We evaluated the effect of remdesivir on the outcomes using propensity score analyses. Subgroup analyses were conducted by stratification of patients by endotracheal intubation and COVID-19 antibody status. Acute kidney injury (AKI) was defined as an absolute serum creatinine increase of 0.3 mg/dL or a relative increase of 50%.ResultsOf the 3372 eligible patients, 1336 (39.6%) received remdesivir. After 1:1 propensity score matching (N = 999 pairs), in-hospital mortality was similar between those with and without remdesivir (21.4% versus 21.6%, respectively, P = 0.96). Remdesivir was not significantly associated with in-hospital mortality regardless of endotracheal intubation or COVID-19 antibody status. However, there was a signal that remdesivir was associated with a reduced risk of AKI in the propensity matched analysis (17.5% versus 23.4%, respectively, P = 0.001).ConclusionsRemdesivir was not associated with reduced risk of in-hospital mortality in patients with COVID-19 treated with steroids but potentially associated with decreased risk of AKI. These findings should be confirmed in prospective studies focusing on COVID-19 patients treated with steroids.

Background Bleeding events can be critical in hospitalized patients with COVID-19, especially those with aggressive anticoagulation therapy. Aim We aimed to investigate whether hemoglobin drop was associated with increased risk of acute kidney injury (AKI) and in-hospital mortality among patients with COVID-19. Design Retrospective cohort study. Methods This retrospective study was conducted by review of the medical records of 6683 patients with laboratory-confirmed COVID-19 hospitalized in the Mount Sinai Health system between 1st March 2020 and 30th March 2021. We compared patients with and without hemoglobin drop >3 g/dl during hospitalization within a week after admissions, using inverse probability treatment weighted analysis (IPTW). Outcomes of interest were in-hospital mortality and AKI which was defined as serum creatine change of 0.3 mg/dl increase or 1.5 times baseline. Results Of the 6683 patients admitted due to COVID-19, 750 (11.2%) patients presented with a marked hemoglobin drop. Patients with hemoglobin drop were more likely to receive therapeutic anticoagulation within 2 days after admissions. Patients with hemoglobin drop had higher crude in-hospital mortality (40.8% vs. 20.0%, P Conclusions Hemoglobin drop during COVID-19 related hospitalizations was associated with a higher risk of AKI and in-hospital mortality.

Our hypothesis was that high hemoglobin (Hb) level might be associated with hypercoagulable state and death due to COVID-19. Of the 9467 hospitalized COVID-19 patients, patients were subdivided into 5 groups based on the level of Hb; Hb

To elucidate the host genetic loci affecting severity of SARS-CoV-2 infection, or Coronavirus disease 2019 (COVID-19), is an emerging issue in the face of the current devastating pandemic. Here, we report a genome-wide association study (GWAS) of COVID-19 in a Japanese population led by the Japan COVID-19 Task Force, as one of the initial discovery GWAS studies performed on a non-European population. Enrolling a total of 2,393 cases and 3,289 controls, we not only replicated previously reported COVID-19 risk variants (e.g., LZTFL1, FOXP4, ABO, and IFNAR2), but also found a variant on 5p35 (rs60200309-A at DOCK2) that was significantly associated with severe COVID-19 in younger (-8 (odds ratio = 2.01, 95% confidence interval = 1.58-2.55). This risk allele was prevalent in East Asians, including Japanese (minor allele frequency [MAF] = 0.097), but rarely found in Europeans. Cross-population Mendelian randomization analysis made a causal inference of a number of complex human traits on COVID-19. In particular, obesity had a significant impact on severe COVID-19. The presence of the population-specific risk allele underscores the need of non-European studies of COVID-19 host genetics.

Coronavirus disease 2019 (COVID-19) is associated with abnormal hemostasis, autopsy evidence of systemic microthrombosis, and a high prevalence of venous thromboembolic disease. Tissue plasminogen activator (tPA) has been used in patients with critically ill COVID-19 with high clinical suspicion of pulmonary embolism (PE). A retrospective cohort study of 6095 hospitalized COVID-19 patients at 5 acute care hospitals in New York was conducted. 57 patients received tPA for presumed PE during March 10th to April 27th. The mean age was 60.8 ± 10.8 years, and 71.9% (41/57) were male. We defined strongly suspected PE among 75.4% (43/57) of patients who had acute worsening of hypoxia and acute hypotension requiring pressors. The findings suggestive of PE included right ventricular (RV) strain in 15.8% (9/57), deep venous thrombosis (DVT) in 7.0% (4/57), increased dead space ventilation (Vd) in 31.6% (18/57) of patients, respectively. RV strain and RV thrombus were present in 3.5% (2/57), RV strain and DVT in 5.3% (3/57), RV strain and increased Vd in 8.8% (5/57), and DVT and increased Vd in 3.5% (2/57) of patients. Chest CT Angiography was not performed in any of the patients. Following tPA infusion, 49.1% (28/57) of patients demonstrated improvement. Six patients (10.5%) survived to discharge, of whom 2 received extracorporeal membrane oxygenation and were transferred to other facilities for lung transplant, 2 were discharged home, and 2 were discharged to a rehabilitation facility. However, overall mortality was 89.5%. The utility of tPA for critically ill patients with COVID-19 and presumed PE warrants further studies.

Background Acute respiratory distress syndrome (ARDS) is a life-threatening disease; however, its treatment has not yet been fully established. The progression of ARDS is considered to be mediated by altered intercellular communication between immune and structural cells in the lung. One of several factors involved in intercellular communication is the extracellular vesicle (EV). They act as carriers of functional content such as RNA molecules, proteins, and lipids and deliver cargo from donor to recipient cells. EVs have been reported to regulate the nucleotide-binding oligomerization like receptor 3 (NLRP3) inflammasome. This has been identified as the cellular machinery responsible for activating inflammatory processes, a key component responsible for the pathogenesis of ARDS. Methods Here, we provide comprehensive genetic analysis of microRNAs (miRNAs) in EVs, demonstrating increased expression of the miRNA-466 family in the bronchoalveolar lavage fluid of a mouse ARDS model. Results Transfection of bone marrow-derived macrophages (BMDMs) with miRNA-466 g and 466 m-5p resulted in increased interleukin-1 beta (IL-1β) release after LPS and ATP treatment, which is an established in vitro model of NLRP3 inflammasome activation. Moreover, LPS-induced pro-IL-1β expression was accelerated by miRNA-466 g and 466 m-5p in BMDMs. Conclusions These findings imply that miRNA-466 family molecules are secreted via EVs into the airways in an ARDS model, and this exacerbates inflammation through the NLRP3 inflammasome. Our results suggest that the NLRP3 inflammasome pathway, regulated by extracellular vesicle miRNA, could act as a therapeutic target for ARDS.

Although the pathogenesis of pulmonary fibrosis remains unclear, it is known to involve epithelial injury and epithelial-mesenchymal transformation (EMT) as a consequence of cigarette smoke (CS) exposure. Moreover, smoking deposits iron in the mitochondria of alveolar epithelial cells. Iron overload in mitochondria causes the Fenton reaction, leading to reactive oxygen species (ROS) production, and ROS leakage from the mitochondria induces cell injury and inflammation in the lungs. Nevertheless, the mechanisms underlying iron metabolism and pulmonary fibrosis are yet to be elucidated. In this study, we aimed to determine whether iron metabolism and mitochondrial dysfunction are involved in the pathogenesis of pulmonary fibrosis. We demonstrated that administration of the iron chelator deferoxamine (DFO) reduced CS-induced pulmonary epithelial cell death, mitochondrial ROS production, and mitochondrial DNA release. Notably, CS-induced cell death was reduced by the administration of an inhibitor targeting ferroptosis, a unique iron-dependent form of non-apoptotic cell death. Transforming growth factor-β-induced EMT of pulmonary epithelial cells was also reduced by DFO. The preservation of mitochondrial function reduced Transforming growth factor-β-induced EMT. Furthermore, transbronchial iron chelation ameliorated bleomycin-induced pulmonary fibrosis and leukocyte migration in a murine model. Our findings indicate that iron metabolism and mitochondrial dysfunction are involved in the pathogenesis of pulmonary fibrosis. Thus, they may be leveraged as new therapeutic targets for pulmonary fibrosis.

Background While the results of previous meta-analyses have shown beneficial effects of corticosteroid therapy on post-extubation stridor and extubation failure in adults, these results might not be generalizable to children because of the differences in anatomy and structure. We aimed to determine the benefits of corticosteroids on those outcomes in pediatric populations. Methods We searched PubMed, EMBASE, and reference lists of articles from inception until February 2019. Randomized controlled trials and observational studies on the efficacy of systemic corticosteroid administration given prior to elective extubation in mechanically ventilated pediatrics were eligible. Outcomes included post-extubation stridor indicating laryngeal edema and extubation failures. Results A total of ten randomized controlled trials with 591 pediatric patients were included: seven of the ten studies for post-extubation stridor/suspected upper airway obstruction and nine of the ten studies for extubation failure. The estimate of pooled odds ratios (ORs) for post-extubation stridor/suspected upper airway obstruction was 0.40 (95% CI: 0.21–0.79). When analysis was restricted to trials that had explicit data for infants and explicit data for pediatric patients under 5 years old excluding infants, the estimates of pooled ORs were 0.53 (95% CI: 0.20–1.40) and 0.68 (95% CI: 0.38–1.22), respectively. For pediatric patients who received corticosteroids, there was a 0.37-fold lower odds of extubation failure than that in pediatric patients who did not receive corticosteroids (OR, 0.37; 95% CI, 0.22–0.61). While three observational studies were included in this review, their estimates have a potential for bias and we did not perform a meta-analysis. Conclusions Despite a relatively small sample size in each randomized controlled trial and wide ranges of ages and steroid administration regimens, our results suggest that the use of corticosteroids for prevention of post-extubation stridor and extubation failure could be considered to be acceptable in pediatric patients.

Of the 6,079 patients admitted due to COVID-19 during March-May, 2020, 902 patients (14.8%) had influenza test. Among them, only 3 patients (0.33%) had positive test of influenza with concomitant infection of SARS-CoV-2. Our study demonstrated the very low rate of positive influenza test during COVID-19 pandemic. This article is protected by copyright. All rights reserved.

We read with interest the paper in the July issue of JACC: Cardiovascular Interventions by Tonino et al. ([1][1]) about the TIDES-ACS (Titanium-Nitride-Oxide-Coated Versus Everolimus-Eluting Stents in Acute Coronary Syndrome) trial ([2][2]). The investigators leveraged Cox proportional regression

Patients with short telomeres and interstitial lung disease may have decreased chronic lung allograft dysfunction (CLAD)-free survival following lung transplantation. The relationship between post-transplant telomere length and outcomes following lung transplantation has not been characterised among all recipients, regardless of native lung disease. This was a single-centre prospective cohort study. Consenting transplant recipients had their telomere length measured using quantitative real-time PCR assays on peripheral blood collected at the time of surveillance bronchoscopy. We assessed the association between early post-transplant telomere length (as measured in the first 100 days) and CLAD-free survival, time to clinically significant leukopenia, cytomegalovirus (CMV) viraemia, chronic kidney disease, and acute cellular rejection. We also assessed the association between rate of telomere shortening and CLAD-free survival. Telomere lengths were available for 98 out of 215 (45.6%) recipients who underwent lung transplant during the study period (median measurement per patient=2 (interquartile range, 1–3)). Shorter telomere length was associated with decreased CLAD-free survival (hazard ratio (HR)=1.24; 95% CI=1.03–1.48; p=0.02), leukopenia requiring granulocyte colony-stimulating factor (HR=1.17, 95% CI=1.01–1.35, p=0.03), and CMV viraemia among CMV-mismatch recipients (HR=4.04, 95% CI=1.05–15.5, p=0.04). Telomere length was not associated with acute cellular rejection or chronic kidney disease. Recipients with more rapid loss in telomere length (defined as the highest tertile of telomere shortening) did not have worse subsequent CLAD-free survival than those without rapid loss (HR=1.38, 95% CI=0.27–7.01, p=0.70). Shorter early post-transplant telomere length is associated with decreased CLAD-free survival and clinically significant leukopenia in lung transplant recipients, regardless of native lung disease., Shorter recipient telomere length following lung transplantation is associated with clinically significant leukopenia and decreased chronic lung allograft dysfunction-free survival https://bit.ly/2ytymXc

Using Mt. Sinai (New York City) EMR health system data, we retrospectively analyzed a cohort of 8438 COVID-19 patients seen between March 1st and April 22nd 2020. Risk of intubation and of death rose as a function of increasing age and as a function of greater cardiovascular comorbidity. Combining age and specific comorbidity markers showed patterns suggesting that cardiovascular comorbidities increased relative risks for adverse outcomes most substantially in the younger subjects with progressively diminishing relative effects at older ages.

Background and aimsObesity has been reported to be one of the most frequent comorbidities in COVID-19 patients and associated with higher rates of in-hospital mortality compared to non-obese patients. Acute kidney injury (AKI) is also known to be a complication associated with obesity in critically-ill COVID-19 patients. We aimed to investigate whether obesity was associated with increased risk of in-hospital mortality and AKI among patients with COVID-19 treated with corticosteroids.MethodsWe utilized 9965 hospitalized COVID-19 patient data and divided patients who were treated with corticosteroids into 6 groups by body mass index (BMI) (less than 18.5, 18.5-25, 25-30, 30-35, 35-40, 40kg/m2 or greater). The association between BMI and in-hospital mortality and between BMI and incidence rate of AKI during admission among COVID-19 patients receiving corticosteroids were retrospectively investigated.ResultsThere were 4587 study participants receiving corticosteroids (mean age 66.5±15.5 years, men 56.6%, mean BMI 29.0±7.2kg/m2). The smooth spline curve suggested a J-shape association between BMI and in-hospital mortality. Patients with BMI above 40kg/m2 exhibited a higher in-hospital mortality and higher incidence rate of AKI during admission compared to patients with BMI between 25 and 30kg/m2. The differences in in-hospital mortality and the rate of AKI were larger among patients with severe COVID-19.ConclusionsClass III obesity was associated with high in-hospital mortality and AKI in patients with COVID-19 treated by corticosteroids. Clinicians must stay vigilant on the impact of class III obesity and development of AKI to disease trajectory of COVID-19 patients.

GATA factors GATA1 and GATA2 and ETS factor PU.1 are known to function antagonistically during hematopoietic development. In mouse mast cells, however, these factors are coexpressed and activate the expression of the Ms4a2 gene encoding the β chain of the high-affinity IgE receptor (FceRI). The present study showed that these factors cooperatively regulate Ms4a2 gene expression through distinct mechanisms. Although GATA2 and PU.1 contributed almost equally to Ms4a2 gene expression, gene ablation experiments revealed that simultaneous knockdown of both factors showed neither a synergistic nor an additive effect. A chromatin immunoprecipitation analysis showed that they shared DNA binding to the +10.4-kbp region downstream of the Ms4a2 gene with chromatin looping factor LDB1, whereas the proximal -60-bp region was exclusively bound by GATA2 in a mast cell-specific manner. Ablation of PU.1 significantly reduced the level of GATA2 binding to both the +10.4-kbp and -60-bp regions. Surprisingly, the deletion of the +10.4-kbp region by genome editing completely abolished the Ms4a2 gene expression as well as the cell surface expression of FceRI. These results suggest that PU.1 and LDB1 play central roles in the formation of active chromatin structure whereas GATA2 directly activates the Ms4a2 promoter.

TOPIC: Chest Infections TYPE: Original Investigations PURPOSE: Inhaled corticosteroids (ICS) are widely used in patients with asthma and chronic obstructive pulmonary disease (COPD). The pooled epidemiological studies have shown that patients with asthma or COPD are at lower hospitalization risk, which could be related to the protective effect of ICS. However, some studies showed no protective effects of ICS on the prognosis of COVID-19. The very recent study suggested that the use of ICS, within 2 weeks of admission, improved survival only for patients aged 50 years and older with asthma, but not for those with chronic pulmonary disease. Herein, we are highly concerned about whether the use of ICS affects the prognosis of COVID-19. METHODS: We retrospectively analyzed over 6,095 hospitalized patients with laboratory confirmed COVID-19 at the Mount Sinai Health System in New York between March 1stand May 2nd, 2020. Patients were stratified into those with or without ICS before admission and were assessed for in-hospital mortality as a primary outcome. Patients were matched by propensity score using 1:1 matching scheme without replacement. We performed this analysis with and without multiple imputation for missing data and then performed an inverse probability weighted analysis. All statistical calculations and analyses were performed in R, with p-values

6062 Background: Human papillomavirus-positive oropharyngeal cancer (HPV OPC) portends a more favorable prognosis compared to HPV-negative cases. To prevent overtreatment, long-term morbidity and deterioration in functionality and quality of life (QoL), multiple studies have focused on de-intensification techniques for HPV OPC treatment. To this end, we prospectively assessed differences in patient reported QoL in locally advanced HPV OPC patients receiving rdCRTversus sdCRT)in a randomized trial using a sequential therapy plan. Methods: Patients were enrolled between December 2012 and February 2016; received 3 cycles of induction docetaxel, cisplatin, and 5-FU; and were randomized to sdCRT (70 Gy) or rdCRT (56 Gy) with weekly carboplatin. Patients were followed for Progression Free Survival (PFS), Overall Survival (OS), and changes in QoL as assessed by the MD Anderson Dysphagia Inventory (MDADI), MD Anderson Symptom Inventory (MDASI Head and Neck), Xerostomia Questionnaire (XQ), and the European Organization for Research and Treatment of Cancer Questionnaire (EORTC QLQ-C30) with the head and neck module (EORTC HN). A mixed model ANOVA was used to estimate changes from baseline QoL to that at each follow-up timepoint and to compare the difference in QoL changes between the treatment arms. Results: We randomized 20 HPV+ locally advanced (LA) patients (median age: 56.5 yrs) to rdCRT (12 subjects) or sdCRT (8 subjects). 70% had high risk features. At a median follow-up of 81.5 mos, PFS and OS were 87.5% and 83.3% for sdCRT and rdCRT, respectively with a median OS of 76 mos in both arms. One patient in the sdCRT arm developed an HPV negative retromolar trigone squamous cell cancer in the radiation field 7 yrs after therapy. Baseline QoL was identical in the 15 patients who completed the QoL modules. Patients receiving rdCRT hadsignificantly lower declines in QoL scores at 3-6 month follow-up. At 5 yrs, differences in QoL changes all favored the rdCRT arm (Table) and two QoL scales reached statistical significance (P