BACKGROUNDNo therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2. METHODSWe conducted a randomized, controlled, open-label trial involving hospitalized adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19, and an oxygen saturation (Sao 2 ) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao 2 ) to the fraction of inspired oxygen (Fio 2 ) of less than 300 mm Hg. Patients were randomly assigned in a 1:1 ratio to receive either lopinavir-ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone. The primary end point was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first. RESULTSA total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomization; 99 were assigned to the lopinavir-ritonavir group, and 100 to the standard-care group. Treatment with lopinavir-ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.24; 95% confidence interval [CI], 0.90 to 1.72). Mortality at 28 days was similar in the lopinavir-ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, −5.8 percentage points; 95% CI, −17.3 to 5.7). The percentages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir-ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were more common in the lopinavir-ritonavir group, but serious adverse events were more common in the standard-care group. Lopinavir-ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events. CONCLUSIONS

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The muscle myosins and hexomeric proteins consisting of two heavy chains and two pairs of light chains, the latter called essential (ELC) and regulatory (RLC). The light chains stabilize the long alpha helical neck of the myosin head. Their function in striated muscle, however, is only partially understood. We report here the identification of distinct missense mutations in a skeletal/ventricular ELC and RLC, each of which are associated with a rare variant of cardiac hypertrophy as well as abnormal skeletal muscle. We show that myosin containing the mutant ELC has abnormal function, map the mutant residues on the three-dimensional structure of myosin and suggest that the mutations disrupt the stretch activation response of the cardiac papillary muscles.

The aim of this study was to investigate the prevalence of sleep problems, depression and anxiety symptoms among conscripted frontline nurses fighting coronavirus disease 2019 (COVID-19) in Wuhan. This study was a cross-sectional study conducted with 100 frontline nurses. Sleep quality, depression, and anxiety symptoms were measured using the Pittsburgh sleep quality index (PSQI), the Generalized Anxiety Disorder 7-Item Scale (GAD-7) and the Patient Health Questionnaire-9 (PHQ-9), respectively. Mean sleep duration was 5.71 hours (SD = 1.09) and mean sleep latency was 33.49 minutes (SD = 28.87). A total of 76%, 81%, 45%, and 19% reported difficulty initiating sleep (DIS), difficulty maintaining sleep (DMS) or early morning awakening (EMA), nightmares and using hypnotics respectively. Among 100 participants in this study, 60 (60%) had poor sleep quality, 46 (46%) suffered depression symptoms and 40 (40%) reported anxiety symptoms. Sleep quality (OR = 3.16, 95% CI: 1.17–8.52) and anxiety symptoms (OR = 8.07, 95% CI: 2.92–22.33) were significantly associated with depression symptoms. Depression symptoms (OR = 7.92, 95% CI: 2.89–21.73) were related to anxiety symptoms. Similarly, depression symptoms (OR = 3.24, 95% CI: 1.19–8.79) were associated with poor sleep quality. Sleep disturbance, depression, and anxiety symptoms are very common among frontline nurses who treating patients with COVID-19 in Wuhan, China. Comprehensive measures that involve psychosocial and personal behaviors should be implemented to improve sleep quality and prevent depression and anxiety symptoms.

Arbidol, ethyl-6-bromo-4-[(dimethylamino)-methyl]-5-hydroxy-1-methyl-2-[(phenylthio)methyl]-in dole-3-carboxylate hydrochloride monohydrate, is an antiviral chemical agent. In this report, we studied the antiviral activity of arbidol against a panel of human respiratory viruses, namely influenza A virus (FLU-A, A/PR/8/34 H1N1), respiratory syncytial virus (RSV), human rhinovirus type 14 (HRV 14), coxsackie virus B3 (CVB3) and adenovirus type 7 (AdV-7) in vitro in cell culture. Arbidol was found to present potent inhibitory activity against enveloped and non-enveloped RNA viruses, including FLU-A, RSV, HRV 14 and CVB3 when added before, during, or after viral infection, with 50% inhibitory concentration (IC50) ranging from 2.7 to 13.8 microg/ml. However, arbidol showed selective antiviral activity against AdV-7, a DNA virus, only when added after infection (therapeutic index (TI) = 5.5). Orally administered arbidol at 50 or 100 mg/kg/day beginning 24 h pre-virus exposure for 6 days significantly reduced mean pulmonary virus yields and the rate of mortality in mice infected with FLU-A (A/PR/8/34 H1N1). Our results suggest that arbidol has the ability to elicit protective broad-spectrum antiviral activity against a number of human pathogenic respiratory viruses.

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Treatment with exogenous interferon (IFN)-a is not effective in the majority of patients with chronic hepatitis B virus (HBV) infection. Recent evidence suggests that HBV has evolved strategies to block the nuclear translocation of signal transducer and activator of transcription (STAT) 1 to limit IFN-a-induced cellular antiviral responses. However, it remains unclear whether STAT1 translocation is impaired in chronic hepatitis B patients and what mechanisms are involved. Here we report that the expression of HBV polymerase (Pol) in human hepatic cell lines inhibited induction of IFN-stimulated genes and resulted in a weakened antiviral activity of IFN-a. Ectopic expression of Pol suppressed IFN-a-induced STAT1 serine 727 phosphorylation and STAT1/2 nuclear accumulation, whereas STAT1 tyrosine 701 phosphorylation, and STAT1-STAT2 heterodimer formation were not affected. Further studies demonstrated that Pol interacted with the catalytic domain of protein kinase C-d (PKC-d) and perturbed PKC-d phosphorylation and its association with STAT1, which resulted in the suppression of STAT1 Ser727 phosphorylation. Moreover, Pol was found to interfere with nuclear transportation of STAT1/2 by competitively binding to the region of importin-a5 required for STAT1/2 recruitment. Truncation analysis suggested that the terminal protein and RNase H domains of Pol were able to bind to PKC-d and importin-a5, respectively, and were responsible for the inhibition of IFN-a signaling. More importantly, the inhibition of STAT1 and PKC-d phosphorylation were confirmed in a hydrodynamicbased HBV mouse model, and the blockage of IFN-a-induced STAT1/2 nuclear translocation was observed in HBV-infected cells from liver biopsies of chronic HBV patients.Conclusions: These results demonstrate a role for Pol in HBV-mediated antagonization of IFN-a signaling and provide a possible molecular mechanism by which HBV resists the IFN therapy and maintains its persistence. (HEPATOLOGY 2013;57:470-482) C hronic hepatitis B (CHB) caused by hepatitis B virus (HBV) is a serious health problem worldwide. The mechanism by which chronic infection is established and maintained is unknown but is thought to be due, in part, to a suppressed host immune response. One key component of the host antiviral responses is the interferon (IFN) system. Viral infection of the host initiates the synthesis of type I IFNs, which consist predominantly of IFN-a and IFN-b (IFN-a/b). By binding to type I IFN receptors,

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