Characteristics of patients discharged and readmitted after COVID-19 hospitalisation within a large integrated health system in the United States.

BACKGROUND: Limited studies have explored post-discharge outcomes following Coronavirus Disease 2019 (COVID-19) hospitalisation. We sought to characterise patients discharged following a COVID-19 hospitalisation within a large integrated health system in the United States. METHODS: We performed a retrospective study of 2180 COVID-19 patients discharged between 1 April 2020 and 31 July 2020. The primary endpoint was all-cause observation stay or inpatient readmission within 30 days from discharge. Bivariate and multivariable logistic regression analyses were performed to estimate the association between key socio-demographic and clinical characteristics with risk of 30-day readmission. RESULTS: The 30-day readmission rate was 7.6% (n = 166); 30-day mortality rate was 1% (n = 19). Most readmissions were respiratory-related (58%) and occurred at a median time of 5 days post discharge. Adjusted models showed that prior hospitalisations (Odds Ratio = 2.36, [95% Confidence Interval: 1.59-3.50]), chronic pulmonary disease (1.57 [1.09-2.28]), and discharge to home health (1.46 [1.01-2.11]) were significantly associated with 30-day readmission. Longer duration from diagnosis to index admission was borderline associated with lower odds of readmission (0.95 [0.91-1.00]). CONCLUSION: Readmission and mortality rates for COVID-19 following discharge are low. Most readmissions occur early and are due to respiratory causes and may reflect the prolonged acute disease course.

Pharmacological characterization of different fractions of Calotropis procera (Asclepiadaceae) in streptozotocin induced experimental model of diabetic neuropathy.

ETHNOPHARMACOLOGICAL RELEVANCE: Calotropis procera (Ait.) R.Br. is one of an ancient traditional shrub, which has been used for the treatment of diabetes, pain and inflammation for thousands of years in India. The root extract of Calotropis procera has been widely used by the tribal׳s of district Udaipur, Rajasthan (India) for treatment of diabetes mellitus and its associated complications like diabetic neuropathy. The present study was performed to explore the protective effect of root, stem and leaf extracts of Calotropis procera in diabetes and diabetic neuropathy against tactile allodynia, mechanical hyperalgesia and thermal hyperalgesia in streptozotocin induced diabetic rats. MATERIALS AND METHODS: Diabetes and peripheral neuropathy were induced in Wistar rats by injection of streptozotocin (45 mg/kg/intraperitoneally). The roots, stem and leaves of Calotropis procera were sequentially extracted with petroleum ether, chloroform, ethyl acetate and methanol. All the extracts were assessed by oral administration at 100 and 250 mg/kg in streptozotocin diabetic rats. The following compounds were used as positive controls: insulin NPH (1 IU/kg/day), metformin (500 mg/kg/day), glibenclamide (2.5 mg/kg/day) and a combination of acarbose (20 mg/kg/day) with methylcobalamine (500 µg/kg/day). In contrast, the streptozotocin induced untreated diabetic rats termed as negative control. Thermal hyperalgesia, mechanical hyperalgesia and tactile allodynia were evaluated in all groups of streptozotocin diabetic rats to assess the extent of neuropathy by Eddy׳s hot plate, tail immersion, Randall-Selitto and Von Frey hair tests. The basal nociceptive thresholds were assessed in week 4 of post streptozotocin injection. All groups received their treatment on a regular basis from 28 to 42 days following a confirmation of diabetic neuropathy. The nociceptive thresholds were assessed in all groups in week 5 and 6. The histopathology of pancreas and biochemical estimations of plasma insulin and glycosylated haemoglobin (HbA1C%) levels were also performed in week 6 of post streptozotocin injection. RESULTS: The negative control rats developed diabetes and diabetic neuropathy after 6 week of streptozotocin administration distinguished by significant (p<0.01) hyperalgesia and tactile allodynia with enhanced HbA1C% level compared to normoglycemic rats. Chronic administration of root methanol, stem methanol and leaf ethyl-acetate extracts of Calotropis procera for 2 weeks at 100 and 250 mg/kg doses significantly (p<0.01) attenuated the diabetes induced mechanical hyperalgesia, thermal hyperalgesia, tactile allodynia and HbA1C% level in streptozotocin diabetic rats as compared to negative control rats. Further, the root methanol extract of Calotropis procera in 100mg/kg dose showed the regeneration capability of ß cells in the histology of pancreas with significant (p<0.01) improvement in plasma insulin level in streptozotocin diabetic rats compared to negative control rats. CONCLUSION: Root methanol extract of Calotropis procera (100mg/kg) has shown ameliorative effect in diabetic neuropathy which may be attributed by its multiple actions including potent hypoglycemic and antioxidant.

Inhibitors of SARS-3CLpro: virtual screening, biological evaluation, and molecular dynamics simulation studies.

SARS-CoV from the coronaviridae family has been identified as the etiological agent of Severe Acute Respiratory Syndrome (SARS), a highly contagious upper respiratory disease that reached epidemic status in 2002. SARS-3CL(pro), a cysteine protease indispensible to the viral life cycle, has been identified as one of the key therapeutic targets against SARS. A combined ligand and structure-based virtual screening was carried out against the Asinex Platinum collection. Multiple low micromolar inhibitors of the enzyme were identified through this search, one of which also showed activity against SARS-CoV in a whole cell CPE assay. Furthermore, multinanosecond explicit solvent simulations were carried out using the docking poses of the identified hits to study the overall stability of the binding site interactions as well as identify important changes in the interaction profile that were not apparent from the docking study. Cumulative analysis of the evaluated compounds and the simulation studies led to the identification of certain protein-ligand interaction patterns which would be useful in further structure based design efforts.

Probing the structures of leishmanial farnesyl pyrophosphate synthases: homology modeling and docking studies.

Leishmania donovani and Leishmania major farnesyl pyrophosphate synthase ( LdFPPS and LmFPPS) are potential targets for the development of antileishmanial therapy. The protein sequence for LdFPPS was recently elucidated in our laboratory. Highly refined homology models were generated using the protein sequences of LdFPPS and the closely related LmFPPS enzyme. A ligand-refined model of LmFPPS with a bound bisphosphonate ligand was generated using restraint-guided molecular mechanics followed by quantum mechanics/molecular mechanics refinement. The ligand-refined model of LmFPPS was further validated through extensive pose validation, enrichment, and other docking studies involving known bisphosphonate inhibitors. The model was able to explain the critical binding site interactions and site-directed mutagenesis data obtained from experimental studies on related FPPS enzymes. The ligand-refined model in conjunction with the validated docking protocol could be utilized in the future for structure-based virtual screening and rational drug design studies against these targets.

Structure-based virtual screening against SARS-3CL(pro) to identify novel non-peptidic hits.

Severe acute respiratory syndrome is a highly infectious upper respiratory tract disease caused by SARS-CoV, a previously unidentified human coronavirus. SARS-3CL(pro) is a viral cysteine protease critical to the pathogen's life cycle and hence a therapeutic target of importance. The recently elucidated crystal structures of this enzyme provide an opportunity for the discovery of inhibitors through rational drug design. In the current study, Gold docking program was utilized to conduct extensive docking studies against the target crystal structure to develop a robust and predictive docking protocol. The validated docking protocol was used to conduct a structure-based virtual screening of the Asinex Platinum collection. Biological evaluation of a screened selection of compounds was carried out to identify novel inhibitors of the viral protease.

Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity.

The metabolic syndrome is a common precursor of cardiovascular disease and type 2 diabetes that is characterized by the clustering of insulin resistance, dyslipidemia, and increased blood pressure. In humans, mutations in the peroxisome proliferator-activated receptor-gamma (PPARgamma) have been reported to cause the full-blown metabolic syndrome, and drugs that activate PPARgamma have proven to be effective agents for the prevention and treatment of insulin resistance and type 2 diabetes. Here we report that telmisartan, a structurally unique angiotensin II receptor antagonist used for the treatment of hypertension, can function as a partial agonist of PPARgamma; influence the expression of PPARgamma target genes involved in carbohydrate and lipid metabolism; and reduce glucose, insulin, and triglyceride levels in rats fed a high-fat, high-carbohydrate diet. None of the other commercially available angiotensin II receptor antagonists appeared to activate PPARgamma when tested at concentrations typically achieved in plasma with conventional oral dosing. In contrast to ordinary antihypertensive and antidiabetic agents, molecules that can simultaneously block the angiotensin II receptor and activate PPARgamma have the potential to treat both hemodynamic and biochemical features of the metabolic syndrome and could provide unique opportunities for the prevention and treatment of diabetes and cardiovascular disease in high-risk populations.