IMPORTANCE Extracorporeal cardiopulmonary resuscitation (ECPR) is expected to improve the neurological outcomes of patients with refractory cardiac arrest; however, it is invasive, expensive, and requires substantial human resources. The ability to predict neurological outcomes would assist in patient selection for ECPR. OBJECTIVE To develop and validate a prediction model for neurological outcomes of patients with out-of-hospital cardiac arrest with shockable rhythm treated with ECPR. DESIGN, SETTING, AND PARTICIPANTS This prognostic study analyzed data from the Japanese Association for Acute Medicine Out-of-Hospital Cardiac Arrest registry, a multi-institutional nationwide cohort study that included 87 emergency departments in Japan. All adult patients with out-of-hospital cardiac arrest and shockable rhythm who were treated with ECPR between June 2014 and December 2017 were included. Patients were randomly assigned to the development and validation cohorts based on the institutions. The analysis was conducted between November 2019 and August 2020. EXPOSURES Age (<65 years), time from call to hospital arrival (Յ25 minutes), initial cardiac rhythm on hospital arrival (shockable), and initial pH value (Ն7.0). MAIN OUTCOMES AND MEASURES The primary outcome was 1-month survival with favorable neurological outcome, defined by Cerebral Performance Category 1 or 2. In the development cohort, a simple scoring system was developed to predict this outcome using a logistic regression model. The diagnostic ability and calibration of the scoring system were assessed in the validation cohort. RESULTS A total of 916 patients were included, 458 in the development cohort (median [interquartile range {IQR}] age, 61 [47-69] years, 377 [82.3%] men) and 458 in the validation cohort (median [IQR] age, 60 [49-68] years; 393 [85.8%] men). The cohorts had the same proportion of favorable neurological outcome (57 patients [12.4%]). The prediction scoring system was developed, attributing a score of 1 for each clinical predictor. Patients were divided into 4 groups, corresponding to their scores on the prediction model, as follows: very low probability (score 0), low probability (score 1), middle probability (score 2), and high probability (score 3-4) of good neurological outcome. The mean predicted probabilities in the groups stratified by score were as follows: very low, 1.6% (95% CI, 1.6%-1.6%); low, 4.4% (95% CI, 4.2%-4.6%); middle, 12.5% (95% CI, 12.1%-12.8%); and high, 30.8% (95% CI, 29.1%-32.5%). In the validation cohort, the C statistic of the scoring system was (continued) Key Points Question Can the neurological outcome of patients with out-ofhospital cardiac arrest and shockable rhythm who are treated with extracorporeal cardiopulmonary resuscitation (ECPR) be predicted using accessible information? Findings In this prognostic study of 916 patients, a model using time to hospital arrival, pH in initial blood gas assessment, shockable rhythm on hospital arrival, and being younger than 65 years was developed to predict survival ...

Remdesivir, a prodrug of the nucleoside analog GS‐441524, plays a key role in the treatment of coronavirus disease 2019 (COVID‐19). However, owing to limited information on clinical trials and inexperienced clinical use, there is a lack of pharmacokinetic (PK) data in patients with COVID‐19 with special characteristics. In this study, we aimed to measure serum GS‐441524 concentrations and develop a population PK (PopPK) model. Remdesivir was administered at a 200 mg loading dose on the first day followed by 100 mg from day 2, based on the package insert, in patients with an estimated glomerular filtration rate (eGFR) greater than or equal to 30 ml/min. In total, 190 concentrations from 37 Japanese patients were used in the analysis. The GS‐441524 trough concentrations were significantly higher in the eGFR less than 60 ml/min group than in the eGFR greater than or equal to 60 ml/min group. Extracorporeal membrane oxygenation in four patients hardly affected the total body clearance (CL) and volume of distribution ( V d ) of GS‐441524. A one‐compartment model described serum GS‐441524 concentration data. The CL and V d of GS‐441524 were significantly affected by eGFR readjusted by individual body surface area and age, respectively. Simulations proposed a dose regimen of 200 mg on day 1 followed by 100 mg once every 2 days from day 2 in patients with an eGFR of 30 ml/min or less. In conclusion, we successfully established a PopPK model of GS‐441524 using retrospectively obtained serum GS‐441524 concentrations in Japanese patients with COVID‐19, which would be helpful for optimal individualized therapy of remdesivir.

While direct-acting antivirals (DAAs) for hepatitis c virus (HcV) have dramatically progressed, patients still suffer from treatment failures. For the radical eradication of HCV, a deeper understanding of multiple resistance-associated substitutions (RASs) at the single-clone level is essential. To understand HcV quasispecies and their dynamics during DAA treatment, we applied single-molecule real-time (SMRT) deep sequencing on sera from 12 patients with genotype-1b HCV infections with DAA treatment failures, both pre-and post-treatment. We identified >3.2 kbp sequences between NS3 and NS5A genes of 187,539 clones in total, classifying into haplotype codes based on the linkage of seven RAS loci. The number of haplotype codes during the treatment, per sample, significantly decreased from 14.67 ± 9.12 to 6.58 ± 7.1, while the number of nonsynonymous codons on the seven RAS loci, per clone, significantly increased from 1.50 ± 0.92 to 3.64 ± 0.75. In five cases, the minority multi-drug resistant haplotypes at pre-treatment were identical to the major haplotypes at relapse. Moreover, various structural variations (SVs) were detected and their dynamics analysed. These results suggest that SMRt deep sequencing is useful for detecting minority haplotypes and SVs, and to evaluate the dynamics of viral genomes at the single-clone level. The hepatitis C virus (HCV) has approximately 9.6 kb of a single-stranded RNA genome. After the approval of oral direct-acting antivirals (DAAs), after drastic HCV treatment, levels of HCV-RNA remain undetectable (sustained virological response; SVR) in most patients chronically infected by HCV or suffering from HCV-related diseases 1-5. In some patients, however, DAAs cannot completely eradicate HCV 1-4. One of the major causes of HCV survival during DAA treatment is thought to be a mutation of its genome. Mutations are likely to occur in the HCV genome due to the fact that RNA-dependent RNA polymerase lacks a proofreading function. Therefore, during HCV infection, the population of HCV includes similar but slightly different clones, and HCV is therefore known as a quasispecies 6,7. Some quasispecies have resistance-associated substitutions (RASs) and make the DAAs ineffective. For example, Y93H on the NS5A gene is associated with the resistance of NS5A inhibitors 8-11 , while the inframe deletion of the NS5A-P32 codon leads to the failure of glecaprevir and pibrentasvir treatments 12-15. Besides these resistance mutations, Q80/D168 on the NS3 gene and R30/ L31/Q54 on the NS5A gene are associated with RASs in HCV 16,17. The antiviral treatment of patients after liver transplantation, or of those with liver cirrhosis, is still challenging, and to achieve SVR in some of these cases,

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