Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

The Middle East Respiratory Syndrome coronavirus (MERS-CoV) has been detected in a number of countries in the Middle East and Europe with an apparently high mortality rate. It is phylogenetically related to the SARS coronavirus and has also been associated with severe respiratory illness as well as nosocomial transmission in healthcare settings. Current international recommendations do not support any specific therapies; however, there are a number of agents, which were used during the SARS epidemic of 2003. It is possible that these might be active against the related MERS coronavirus. We have reviewed the literature on the safety and efficacy of therapies used in patients with SARS with a view to their potential use in patients with MERS-CoV infections.

Therapeutic Options for Middle East Respiratory Syndrome Coronavirus (MERS-CoV) – possible lessons from a systematic review of SARS-CoV therapy

Cardiac arrhythmias are associated with poorer outcomes in patients with heart failure (HF), diabetes mellitus (DM), and chronic kidney disease (CKD). Previous studies have shown inconsistent conclusions regarding the association between sodium-glucose cotransporter 2 inhibitors (SGLT2i) and the risk of developing arrhythmias. This study aims to investigate the association of SGLT2i treatment with arrhythmia outcomes in clinical trials of patients with HF, DM, or CKD. MEDLINE, EMBASE, and ClinicalTrials.gov were searched from inception up to 27 August 2020. Randomized controlled trials that randomized patients with DM, CKD, or HF to SGLT2i or placebo were included. The outcomes of interest include atrial fibrillation (AF), embolic stroke, atrial flutter (AFL), AF/AFL, ventricular tachycardia (VT), and cardiac arrest. Relative risks (RRs) and 95% confidence intervals (CI) were pooled using a random-effects model. Out of 4,532 citations, 22 trials with altogether 52,115 patients were included (mean age 63.2 years; 33,747 [64.8%] of participants were men). SGLT2i were associated with a lower risk of AF (RR 0.82, 95% CI 0.70–0.96), embolic stroke (RR 0.32, 95% CI 0.12–0.85), AF/AFL (RR 0.82, 95% CI 0.71–0.95), and VT (RR 0.73, 95% CI 0.53–0.99), while the risk reductions in AFL (RR 0.83, 95% CI 0.58–1.17) and cardiac arrest (RR 0.83, 95% CI 0.61–1.14) did not reach statistical significance. The associations appeared to be consistent across different baseline conditions (DM vs CKD vs HF; atherosclerotic cardiovascular disease [ASCVD] vs no ASCVD) and the SGLT2i used. SGLT2i reduced the risk of cardiac arrhythmias. Our study provides further evidence for recommending the use of SGLT2i in patients with DM, CKD, and HF. Further research is needed to fully elucidate the mechanism by which SGLT2i protect against arrhythmias.

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Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and cardiac arrhythmias: a systematic review and meta-analysis

The pandemic, due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has stimulated the search for antivirals to tackle COVID-19 infection Molecules with known pharmacokinetics and already approved for human use have been demonstrated or predicted to be suitable to be used either directly or as a base for a scaffold-based drug design Among these substances, quercetin is known to be a potent in vitro inhibitor of 3CLpro, the SARS-CoV-2 main protease However, its low in vivo bioavailability calls for modifications to its molecular structure In this work, this issue is addressed by using rutin, a natural flavonoid that is the most common glycosylated conjugate of quercetin, as a model Combining experimental (spectroscopy and calorimetry) and simulation techniques (docking and molecular dynamics simulations), we demonstrate that the sugar adduct does not hamper rutin binding to 3CLpro, and the conjugated compound preserves a high potency (inhibition constant in the low micromolar range, Ki = 11 μM) Although showing a disruption of the pseudo-symmetry in the chemical structure, a larger steric volume and molecular weight, and a higher solubility compared to quercetin, rutin is able to associate in the active site of 3CLpro, interacting with the catalytic dyad (His41/Cys145) The overall results have implications in the drug-design of quercetin analogs, and possibly other antivirals, to target the catalytic site of the SARS-CoV-2 3CLpro

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Rutin Is a Low Micromolar Inhibitor of SARS-CoV-2 Main Protease 3CLpro: Implications for Drug Design of Quercetin Analogs

The guanosine analog AT-527 represents a promising candidate against Severe Acute Respiratory Syndrome coronavirus type 2 (SARS-CoV-2). AT-527 recently entered phase III clinical trials for the treatment of COVID-19. Once in cells, AT-527 is converted into its triphosphate form, AT-9010, that presumably targets the viral RNA-dependent RNA polymerase (RdRp, nsp12), for incorporation into viral RNA. Here we report a 2.98 Å cryo-EM structure of the SARS-CoV-2 nsp12-nsp7-nsp82-RNA complex, showing AT-9010 bound at three sites of nsp12. In the RdRp active-site, one AT-9010 is incorporated at the 3' end of the RNA product strand. Its modified ribose group (2'-fluoro, 2'-methyl) prevents correct alignment of the incoming NTP, in this case a second AT-9010, causing immediate termination of RNA synthesis. The third AT-9010 is bound to the N-terminal domain of nsp12 - known as the NiRAN. In contrast to native NTPs, AT-9010 is in a flipped orientation in the active-site, with its guanine base unexpectedly occupying a previously unnoticed cavity. AT-9010 outcompetes all native nucleotides for NiRAN binding, inhibiting its nucleotidyltransferase activity. The dual mechanism of action of AT-527 at both RdRp and NiRAN active sites represents a promising research avenue against COVID-19. 

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A dual mechanism of action of AT-527 against SARS-CoV-2 polymerase

Rationale: Coronavirus disease 2019 (COVID-19) has spread worldwide and poses a threat to humanity. However, no specific therapy has been established for this disease yet. We conducted a systematic review to highlight therapeutic agents that might be effective in treating COVID-19. Methods: We searched Medline, Medrxiv.org, and reference lists of relevant publications to identify articles of in vitro, in vivo, and clinical studies on treatments for severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and COVID-19 published in English until the last update on October 11, 2020. Results: We included 36 studies on SARS, 30 studies on MERS, and 10 meta-analyses on SARS and MERS in this study. Through 12,200 title and 830 full-text screenings for COVID-19, eight in vitro studies, 46 randomized controlled trials (RCTs) on 6,886 patients, and 29 meta-analyses were obtained and investigated. There was no therapeutic agent that consistently resulted in positive outcomes across SARS, MERS, and COVID-19. Remdesivir showed a therapeutic effect for COVID-19 in two RCTs involving the largest number of total participants (n = 1,461). Other therapies that showed an effect in at least two RCTs for COVID-19 were sofosbuvir/daclatasvir (n = 114), colchicine (n = 140), IFN-s1b (n = 193), and convalescent plasma therapy (n = 126). Conclusions: This review provides information to help establish treatment and research directions for COVID-19 based on currently available evidence. Further RCTs are required.

https://ir.ymlib.yonsei.ac.kr/bitstream/22282913/181969/1/T202100076.pdf

Treatment of severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and coronavirus disease 2019 (COVID-19): a systematic review of in vitro , in vivo , and clinical trials.

Background Fluid overload is common in patients with diabetes and chronic kidney disease (DM and CKD; DMCKD) and can lead to structural and functional cardiac abnormalities including left ventricular hypertrophy (LVH) and left ventricular diastolic dysfunction (LVDD). Fluid overload represents a crucial step in the pathophysiological pathways to chronic heart failure in patients with end-stage renal disease. We evaluated the impact of fluid overload on cardiac alterations in patients with diabetes and non-dialysis-dependent CKD stage 5 (DMCKD5-ND) without intrinsic heart disease. Methods Bioimpedance spectroscopy, echocardiography, and N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) measurement were performed in 135 consecutive patients on the same day. Patients were divided into groups by tertiles of overhydration/extracellular water (OH/ECW) per bioimpedance spectroscopy. Results Fluid balance markers including OH/ECW and NT-proBNP were significantly higher in the LVDD+LVH group. OH/ECW and its exacerbation were positively associated with the ratio between early mitral inflow and annular early diastolic velocities (E/e' ratio) and left ventricular mass index (LVMI). The prevalence of LVH progressively increased across increasing tertiles of OH/ECW. In multiple regression analyses, OH/ECW as a continuous and categorical variable was independently associated with the E/e' ratio and LVMI after adjustment for multiple confounding factors. Conclusions Fluid overload was independently associated with LVDD and LVH in patients with DMCKD5-ND. Our study suggests that structural and functional cardiac abnormalities and volume status should be evaluated simultaneously in patients with early-stage DMCKD rather than only DMCKD5-ND, in addition to intensive blood pressure and glycemic control, regardless of evident cardiovascular disease.

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Fluid overload is a determinant for cardiac structural and functional impairments in type 2 diabetes mellitus and chronic kidney disease stage 5 not undergoing dialysis.

Background Diabetic nephropathy (DN) accounts for approximately half of all cases of chronic kidney disease (CKD) and end-stage kidney disease worldwide. The Renal Pathology Society (RPS) classification has been used to predict the renal prognosis in DN. In 2018, the Japanese Renal Pathology Society (JRPS) proposed a comprehensive classification system that included pathological changes in the kidney. The clinical significance of the JRPS classification system was comparatively evaluated in the present study. Methods A total of 93 cases diagnosed with DN from 2009 to 2019 were enrolled. JRPS scores (J-scores) were calculated by scoring the pathological factors in the JRPS classification system and comparing them with clinical parameters. Results Most pathological factors constituting the J-score were significantly correlated with clinical factors. Laminated nodules were inversely correlated with estimated glomerular filtration rate. After adjusting for age, sex, body mass index, hemoglobin A1c, diabetes duration, and hypertension, CKD stage was significantly correlated with JRPS grade, nodular lesions, and exudative lesions in the multivariate logistic regression analysis. However, receiver operating characteristic curve analysis revealed that the J-score (area under the curve [AUC] = 0.639) had lower clinical significance than the traditional RPS classification system (AUC = 0.675). Conclusion The JRPS classification can more comprehensively reflect renal changes than the RPS classification and is correlated with renal survival. When creating a new pathological classification, arteriolar hyalinosis should not be included, whereas laminated nodules should be included.

Pathological validation of the Japanese Renal Pathology Society classification and challenges in predicting renal prognosis in patients with diabetic nephropathy

Hanwul Shin

Papers

Treatment of severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and coronavirus disease 2019 (COVID-19): a systematic review of in vitro , in vivo , and clinical trials.

Fluid overload is a determinant for cardiac structural and functional impairments in type 2 diabetes mellitus and chronic kidney disease stage 5 not undergoing dialysis.

Pathological validation of the Japanese Renal Pathology Society classification and challenges in predicting renal prognosis in patients with diabetic nephropathy