Background Hydroxychloroquine has been widely administered to patients with Covid-19 without robust evidence supporting its use. Methods We examined the association between hydroxychloroqu...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa2012410?articleTools=true

Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19.

Immunology of COVID-19: Current State of the Science.

Key Clinical Points Evaluation and Management of Severe Covid-19 Patients with severe coronavirus disease 2019 (Covid-19) may become critically ill with acute respiratory distress syndrome that typ...

https://www.nejm.org/doi/pdf/10.1056/NEJMcp2009575?articleTools=true

Severe Covid-19

Key Clinical Points Mild or Moderate Covid-19 Covid-19 (the illness caused by SARS-CoV-2) has a range of clinical manifestations, including cough, fever, malaise, myalgias, gastrointestinal symptom...

https://www.nejm.org/doi/pdf/10.1056/NEJMcp2009249

Mild or Moderate Covid-19.

Importance Hydroxychloroquine, with or without azithromycin, has been considered as a possible therapeutic agent for patients with coronavirus disease 2019 (COVID-19). However, there are limited data on efficacy and associated adverse events. Objective To describe the association between use of hydroxychloroquine, with or without azithromycin, and clinical outcomes among hospital inpatients diagnosed with COVID-19. Design, Setting, and Participants Retrospective multicenter cohort study of patients from a random sample of all admitted patients with laboratory-confirmed COVID-19 in 25 hospitals, representing 88.2% of patients with COVID-19 in the New York metropolitan region. Eligible patients were admitted for at least 24 hours between March 15 and 28, 2020. Medications, preexisting conditions, clinical measures on admission, outcomes, and adverse events were abstracted from medical records. The date of final follow-up was April 24, 2020. Exposures Receipt of both hydroxychloroquine and azithromycin, hydroxychloroquine alone, azithromycin alone, or neither. Main Outcomes and Measures Primary outcome was in-hospital mortality. Secondary outcomes were cardiac arrest and abnormal electrocardiogram findings (arrhythmia or QT prolongation). Results Among 1438 hospitalized patients with a diagnosis of COVID-19 (858 [59.7%] male, median age, 63 years), those receiving hydroxychloroquine, azithromycin, or both were more likely than those not receiving either drug to have diabetes, respiratory rate >22/min, abnormal chest imaging findings, O2saturation lower than 90%, and aspartate aminotransferase greater than 40 U/L. Overall in-hospital mortality was 20.3% (95% CI, 18.2%-22.4%). The probability of death for patients receiving hydroxychloroquine + azithromycin was 189/735 (25.7% [95% CI, 22.3%-28.9%]), hydroxychloroquine alone, 54/271 (19.9% [95% CI, 15.2%-24.7%]), azithromycin alone, 21/211 (10.0% [95% CI, 5.9%-14.0%]), and neither drug, 28/221 (12.7% [95% CI, 8.3%-17.1%]). In adjusted Cox proportional hazards models, compared with patients receiving neither drug, there were no significant differences in mortality for patients receiving hydroxychloroquine + azithromycin (HR, 1.35 [95% CI, 0.76-2.40]), hydroxychloroquine alone (HR, 1.08 [95% CI, 0.63-1.85]), or azithromycin alone (HR, 0.56 [95% CI, 0.26-1.21]). In logistic models, compared with patients receiving neither drug cardiac arrest was significantly more likely in patients receiving hydroxychloroquine + azithromycin (adjusted OR, 2.13 [95% CI, 1.12-4.05]), but not hydroxychloroquine alone (adjusted OR, 1.91 [95% CI, 0.96-3.81]) or azithromycin alone (adjusted OR, 0.64 [95% CI, 0.27-1.56]), . In adjusted logistic regression models, there were no significant differences in the relative likelihood of abnormal electrocardiogram findings. Conclusions and Relevance Among patients hospitalized in metropolitan New York with COVID-19, treatment with hydroxychloroquine, azithromycin, or both, compared with neither treatment, was not significantly associated with differences in in-hospital mortality. However, the interpretation of these findings may be limited by the observational design.

/pdf/association-of-treatment-with-hydroxychloroquine-or-3plfeejise.pdf

Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State.

Aims Studies have indicated that chloroquine (CQ) shows antagonism against COVID-19 in vitro. However, evidence regarding its effects in patients is limited. This study aims to evaluate the efficacy of hydroxychloroquine (HCQ) in the treatment of patients with COVID-19. Main methods From February 4 to February 28, 2020, 62 patients suffering from COVID-19 were diagnosed and admitted to Renmin Hospital of Wuhan University. All participants were randomized in a parallel-group trial, 31 patients were assigned to receive an additional 5-day HCQ (400 mg/d) treatment, Time to clinical recovery (TTCR), clinical characteristics, and radiological results were assessed at baseline and 5 days after treatment to evaluate the effect of HCQ. Key findings For the 62 COVID-19 patients, 46.8% (29 of 62) were male and 53.2% (33 of 62) were female, the mean age was 44.7 (15.3) years. No difference in the age and sex distribution between the control group and the HCQ group. But for TTCR, the body temperature recovery time and the cough remission time were significantly shortened in the HCQ treatment group. Besides, a larger proportion of patients with improved pneumonia in the HCQ treatment group (80.6%, 25 of 31) compared with the control group (54.8%, 17 of 31). Notably, all 4 patients progressed to severe illness that occurred in the control group. However, there were 2 patients with mild adverse reactions in the HCQ treatment group. Significance Among patients with COVID-19, the use of HCQ could significantly shorten TTCR and promote the absorption of pneumonia. Trial registration URL: https://www.clinicaltrials.gov/. The unique identifier: ChiCTR2000029559.

/pdf/efficacy-of-hydroxychloroquine-in-patients-with-covid-19-1pe13rbmvp.pdf

Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial

Background With the emergence of 4rd generation transmission, the prevention and treatment of the novel coronavirus disease 2019 (COVID-19) has entered a new period. We aimed to report several changes in the clinical characteristics at admission of patients with COVID-19. Methods Clinical records and laboratory results of patients suffering from COVID-19 were retrospectively reviewed and matched with the admission dates to analyze the changes in characteristics at the onset of illness. Results Of the 89 affected patients, 31 [34.8%] patients were admitted from January 16 to 22, and 58 [65.2%] were admitted from January 23 to 29. Patients were admitted with more systemic symptoms, such as fever (21 [67.7%] of 31), fatigue (13 [41.9%] of 31), and myalgia (7 [22.6%] of 31), before January 23. More patients (10 [32.3%] of 31) admitted before January 23 had a small amount of sputum production compared with a smaller proportion (4 [6.9%] of 58) of the patients admitted after January 23. Other symptoms, such as cough, nausea, diarrhea, and chest tightness, were not significantly different between the two groups. In addition, the group admitted before January 23 had a larger proportion of patients with reduced lymphocyte (13 [54.2%] of 24), CD3 (11 [54.4%] of 21), and CD8 (9 [42.9%] of 21) counts and elevated serum amyloid A (SAA, 18 [75%] of 24). Conclusions The initial symptoms of recently infected patients seem more insidious, indicating that the new coronavirus may gradually evolve into a virus similar to influenza and latent in asymptomatic carriers for a long time. Summary Compared with the cases admitted earlier, more hidden initial symptoms and improved immune system disorders appeared in COVID-19 patients infected recently.

/pdf/caution-the-clinical-characteristics-of-covid-19-patients-at-47mr46r5eq.pdf

Caution: The clinical characteristics of COVID-19 patients at admission are changing

Background: With the emergence of the 4th generation transmission, the prevention and treatment of the novel coronavirus disease 2019 (COVID-19) has entered a new period. During the admission, we found several changes in the clinical characteristics of patients with COVID-19. 

Methods: Patients suffered from COVID-19 were diagnosed and admitted to Renmin Hospital of Wuhan University. Clinical records, laboratory results were retrospectively reviewed and matched with the admission date to analyze characteristic changes of patients at the onset of illness. 

Findings: From Jan. 16 to Jan. 29, 2020, 89 patients had been identified as confirmed COVID-19. Patients were assigned into two groups according to the admission date. 31 [34·8%] of the infected patients were admitted from Jan. 16 to 22, and 58 [65·2%] were admitted from Jan. 23 to 29. Most of the infected patients were women (45 [77·6%] of 58) during Jan. 23 to 29, but less female (14 [45·2%] of 31) before Jan. 23. Patients admitted with more systemic symptoms such as fever (21 [67·7%] of 31), fatigue (13 [41·9%] of 31), and myalgia (7 [22·6%] of 31) before Jan. 23. Greater proportion of patients (10 [32·3%] of 31) admitted before Jan. 23 had a small amount of sputum production compared with a small proportion (4 [6·9%] of 58) admitted after Jan. 23. Other symptoms such as cough, nausea, diarrhea, and chest tightness were not significantly different between two groups. In addition, the group admitted before Jan. 23 had a larger proportion of patients with reduced lymphocyte (13 [54·2%] of 24), CD3 (11[52·4%] of 21), CD8 (9 [42·9%] of 21) cells and elevated SAA (18 [75·0%] of 24). 

Interpretation: The clinical characteristics of COVID-19 patients at the onset became partially different as the novel coronavirus spreads over time and generations, positive infection even appeared in patients after discharge. Findings from this study suggest that initial symptoms of recently infected patients seem more insidious. All provide clues that the new coronavirus may gradually evolve into an influenza-like virus, or it may be latent in some asymptomatic carrier for a long time. 

Funding Statement: No funding supported this study.

Declaration of Interests: All the authors declare no competing interests.

Ethics Approval Statement: The research protocol was reviewed and approved by the Ethics Committee in Renmin Hospital of Wuhan University (Wuhan, China). All research procedures adhered to the tenets of the Declaration of Helsinki.

Caution: Clinical Characteristics of COVID-19 Patients Are Changing at Admission

Diabetic nephropathy (DN) is a common microvascular complication that easily leads to end-stage renal disease. It is important to explore the key biomarkers and molecular mechanisms relevant to diabetic nephropathy (DN). We used highthroughput RNA sequencing to obtain the genes related to DN glomerular tissues and healthy glomerular tissues of mice. Then we used LIMMA to analyze differentially expressed genes (DEGs) between DN and non-diabetic glomerular samples. And we performed KEGG, gene ontology functional (GO) enrichment, and gene set enrichment analysis to reveal the signaling pathway of the disease. The CIBERSORT algorithm based on support vector machine was used to determine the immune infiltration score. Random forest algorithm and Cytoscape obtained hub genes. Finally, we applied co-staining, immunohistochemical staining, RT-qPCR and western blotting to validate the protein and mRNA expression of both hub genes. We obtained 913 DEGs mainly related to inflammatory factors and immunity. GSEA results showed that differential genes were mainly enriched in IL-17 signaling pathway, lipid and atherosclerosis, rheumatoid arthritis, TNF signaling pathway, neutrophil extracellular trap formation, Staphylococcus aureus infection and other pathways. The intersection of the random forest algorithm and Cytoscape revealed both hub genes of CD300A and CXCL1. Experiments have shown that the both key genes of CD300A and CXCL1 shown increased expression in glomerular podocytes, and are related to the inflammation of diabetic nephropathy. And immunohistochemical staining and RT-qPCR further confirmed that the protein and mRNA expression level of CD300A or CXCL1 in glomeruli tissue in DN mice were increased. The expression levels of CD300A and CXCL1 increased significantly under HG (high glucose) stimulation, further confirming that diabetes can lead to increased levels of CD300A and CXCL1 at the cellular level. Through bioinformatics analysis, machine learning algorithms, and experimental research, CD300A and CXCL1 are confirmed as both potential biomarkers in diabetic nephropathy. And we further revealed the main pathways of differential genes and the differentially distributed immune infiltrating cells in diabetic nephropathy. 

An integrated bioinformatics analysis and experimental study identified key biomarkers CD300A or CXCL1, pathways and immune infiltration in diabetic nephropathy mice

Compromised glycolysis in podocytes contributes to the initiation of diabetic kidney disease (DKD). Podocyte injury is characterized by cytoskeletal remodeling and foot process fusion. Compromised glycolysis in diabetes likely leads to switch of energy supply in podocyte. However, the underlying mechanism by which disturbed energy supply in podocytes affects the cytoskeletal structure of podocytes remains unclear.Metabolomic and transcriptomic analyses were performed on the glomeruli of db/db mice to examine the catabolism of glucose, fatty, and amino acids. Ornithine catabolism was targeted in db/db and podocyte-specific pyruvate kinase M2 knockout (PKM2-podoKO) mice. In vitro, expression of ornithine decarboxylase (ODC1) was modulated to investigate the effect of ornithine catabolism on mammalian target of rapamycin (mTOR) signaling and cytoskeletal remodeling in cultured podocytes.Multi-omic analyses of the glomeruli revealed that ornithine metabolism was enhanced in db/db mice compared with that in db/m mice under compromised glycolytic conditions. Additionally, ornithine catabolism was exaggerated in podocytes of diabetic PKM2-podoKO mice compared with that in diabetic PKM2flox/flox mice. In vivo, difluoromethylornithine (DFMO, inhibitor of ODC1) administration reduced urinary albumin excretion and alleviated podocyte foot process fusion in db/db mice. In vitro, 2-deoxy-d-glucose (2-DG) exposure induced mTOR signaling activation and cytoskeletal remodeling in podocytes, which was alleviated by ODC1-knockdown. Mechanistically, a small GTPase Ras homolog enriched in the brain (Rheb), a sensor of mTOR signaling, was activated by exposure to putrescine, a metabolic product of ornithine catabolism.These findings demonstrate that compromised glycolysis in podocytes under diabetic conditions enhances ornithine catabolism. The metabolites of ornithine catabolism contribute to mTOR signaling activation via Rheb and cytoskeletal remodeling in podocytes in DKD. 

Zongwei Zhang

Papers

Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial

Caution: The clinical characteristics of COVID-19 patients at admission are changing

Caution: Clinical Characteristics of COVID-19 Patients Are Changing at Admission

An integrated bioinformatics analysis and experimental study identified key biomarkers CD300A or CXCL1, pathways and immune infiltration in diabetic nephropathy mice

Compromised glycolysis contributes to foot process fusion of podocytes in diabetic kidney disease: Role of ornithine catabolism.