Repurposing of chloroquine and hydroxychloroquine for the management of COVID-19

The Coronavirus Disease-19 (COVID-19) pandemic has impacted adversely on the global health and socio-economic activities. There is currently no evidence-based anti-SARS-CoV-2 drug for COVID-19 therapy. This review highlights some pharmacological properties of chloroquine and hydroxychloroquine and prospects of repurposing them for the treatment of COVID-19. Google scholar was employed in searching relevant published journal articles (n=118) in English. The search was later narrowed down to SARS-CoV-2, pathophysiology of COVID-19, available drugs for the management of COVID-19, clinical trials on repurposing drugs for COVID-19 therapy, and the role of chloroquine and hydroxychloroquine in the treatment of COVID-19. Documented evidence revealed that chloroquine and hydroxychloroquine have antiviral and immune-modulatory properties. Their antiviral effect is due to inhibition of the spike proteins of SARS-CoV-2 from binding to the cellular transmembrane receptors, angiotensin converting enzyme-2 thereby preventing viral infections. Also, sequestration of these drugs into the lysosomes elevates lysosomal pH thus inhibiting lysosomal enzymatic functions vital for viral replication in those cells. Whereas, their immune-modulatory activity averts the inflammatory complications of COVID-19, particularly acute respiratory syndrome, by preventing cytokine storm through suppression of the production and putative release of pro-inflammatory cytokines. The adverse effects from these drugs, notably irreversible retinopathy and cardiac arrhythmia are rare but become life-threatening when they occur. These are minimal with hydroxychloroquine compared to chloroquine. Chloroquine and hydroxychloroquine could be repurposed for managing COVID-19 cases because they are already extensively used for treating acute nonresistant malaria and auto-immune diseases. Also, a viable vaccine cannot be available in the near future while there is a pressing need for treatments to lower the daily rise in morbidity and mortality associated with the disease. Nevertheless, we suggest that emphasis should be on hydroxychloroquine because of its superior antiviral effect and clinical safety

Coupled FEM-DBEM method to assess crack growth in magnet system of Wendelstein 7-X

The fivefold symmetric modular stellarator Wendelstein 7-X (W7-X) is currently under construction in Greifswald, Germany. The superconducting coils of the magnet system are bolted onto a central support ring and interconnected with five so-called lateral support elements (LSEs) per half module. After welding of the LSE hollow boxes to the coil cases, cracks were found in the vicinity of the welds that could potentially limit the allowed number N of electromagnetic (EM) load cycles of the machine. In response to the appearance of first cracks during assembly, the Stress Intensity Factors (SIFs) were calculated and corresponding crack growth rates of theoretical semi-circular cracks of measured sizes in potentially critical position and orientation were predicted using Paris’ law, whose parameters were calibrated in fatigue tests at cryogenic temperature. In this paper the Dual Boundary Element Method (DBEM) is applied in a coupled FEM-DBEM approach to analyze the propagation of multiple cracks with different shapes. For this purpose, the crack path is assessed with the Minimum Strain Energy density criterion and SIFs are calculated by the Jintegral approach. The Finite Element Method (FEM) is adopted to model, using the commercial codes Ansys or Abaqus;, the overall component whereas the submodel analysis, in the volume surrounding the cracked area, is performed by FEM (“FEM-FEM approach”) or alternatively by DBEM (“FEM-DBEM approach”). The “FEM-FEM approach” considers a FEM submodel, that is extracted from the FEM global model; the latter provide the boundary conditions for the submodel. Such approach is affected by some restrictions in the crack propagation phase, whereas, with the “FEM-DBEM approach”, the crack propagation simulation is straightforward. In this case the submodel is created in a DBEM environment with boundary conditions provided by the global FEM analysis; then the crack is introduced and a crack propagation analysis has been performed to evaluate the effects of the crack shape and of the presence of nearby cracks on the allowed number of EM load cycles

Economic Burden of Community-Acquired Pneumonia among Adults in the Philippines: Its Equity and Policy Implications in the Case Rate Payments of the Philippine Health Insurance Corporation

AbstractObjectivesTo determine 1) the cost of hospitalization, the 1-week postdischarge cost, the total cost, and the economic burden of community-acquired pneumonia among patients aged 19 years or older in the Philippines and 2) the difference between the estimated costs and the Philippine Health Insurance Corporation (PhilHealth) pneumonia case rate payments.MethodsThe study involved two tertiary private hospitals in the Philippines. Using the societal perspective, both health care and non–health care costs were determined. A base-case analysis and sensitivity analyses were performed, and the economic burden of pneumonia was determined using PhilHealth claims.ResultsThe estimated cost of hospitalization for community-acquired pneumonia-moderate risk (CAP-MR) ranged from Philippine peso (PHP) 36,153 to 113,633 (US $852–2678) and its 1-week postdischarge cost ranged from PHP1450 to 8800 (US$34–207). The cost of hospitalization for community-acquired pneumonia-high risk (CAP-HR) ranged from PHP104,544 to 249,695 (US $2464–5885) and PHP101,248 to 243, 495 (US$2386–5739) using invasive and noninvasive ventilation, respectively. The postdischarge cost for CAP-HR ranged from PHP1716 to 10,529 (US $40–248). If only health care cost was considered, the cost ranged from PHP24,403 to 89,433 for CAP-MR and PHP92,848 to 213,395 for CAP-HR. The present PhilHealth case rate payments are PHP15,000 (US$354) and PHP32,000 (US $754) for CAP-MR and CAP-HR, respectively. Based on the number of PhilHealth claims for 2012 and the estimated health care cost, the economic burden of pneumonia in 2012 was PHP8.48 billion for CAP-MR and PHP643.76 million for CAP-HR.ConclusionsThe estimated health care cost of hospitalization is markedly higher than the PhilHealth case rate payments. As per the study results, the economic burden of pneumonia is, thus, significantly higher than PhilHealth estimates

Growth dynamics of plexiform neurofibromas: a retrospective cohort study of 201 patients with neurofibromatosis 1

BACKGROUND: To examine the natural growth dynamics of internal plexiform neurofibromas (PNs) in patients with neurofibromatosis 1 (NF1). METHODS: Two hundred and one NF1 patients underwent whole body MRI (WBMRI). Tumour burden was estimated volumetrically. Non-parametric Spearman’s rho correlation coefficients were used to analyse the relationship of growth rate to tumour volume and age. Chi-squared and Mann–Whitney U tests were used for analysing the association of tumour occurrence with sex or age. Chi-squared tests were used to analyse the association of tumour growth with age group. RESULTS: Seventy-one of 171 patients with serial WBMRI exams had internal PNs (median follow up 2.2 years [1.1 to 4.9 years]). Median whole body tumour volume was 86.4 mL [5.2 to 5878.5 mL]) with a median growth rate of 3.7%/year (−13.4 to 111%/year) that correlated with larger whole body tumour volume (P<0.001) and lower age (P=0.004). No new PNs developed in 273.0 patient-years among patients without tumours. Rate of new tumour development among patients with PNs was 0.6%/year (95% confidence interval 0.02 to 3.4%). Twenty-seven (13.5%) tumours increased significantly and were more frequent among children (P<0.001). Growth rate of tumours was inversely correlated with age (Spearman’s rho=−0.330, P<0.001). Seventy-one (35.5%) tumours had smaller volumes on follow up (median −3.4%/year [−0.07% to −35.9%/year]). CONCLUSION: Children with NF1 and internal PNs are at risk for tumour growth. Most PNs grow slowly or not at all, and some decrease in size. New tumours are infrequent in NF1 patients with PNs and unlikely in patients without PNs

Immediate postoperative high-sensitivity troponin T concentrations and long-term patient-reported

BACKGROUND: Myocardial injury after noncardiac surgery is associated with mortality and major adverse postoperative cardiovascular events. The effect of postoperative troponin concentrations on patient-reported health-related quality of life (HRQoL) is unknown. OBJECTIVE: The study examined the association between immediate postoperative troponin concentrations and self-reported HRQoL 1 year after surgery. DESIGN: Prospective cohort study. SETTING: Single-centre tertiary care hospital in the Netherlands between July 2012 and 2015. PATIENTS: Patients aged at least 60 years undergoing moderate and major noncardiac surgery.None. MAIN OUTCOME MEASURES: HRQoL total score was assessed with the EuroQol five-dimensional questionnaire. Tobit regression analysis was used to determine the association between postoperative troponin concentrations and 1-year HRQoL. Peak high-sensitivity troponin T values were divided into four categories: less than 14, 14 to 49, 50 to 149 and at least 150 ng l. RESULTS: A total of 3085 patients with troponin measurements were included. 2634 (85.4%) patients were alive at 1-year follow-up of whom 1297 (49.2%) returned a completed questionnaire. The median score for HRQoL was 0.82 (0.85, 0.81, 0.77 and 0.71 per increasing troponin category). Multivariable analysis revealed betas of -0.06 [95% confidence interval (CI) -0.09 to -0.02], -0.11 (95% CI -0.18 to -0.04) and -0.18 (95% CI -0.29 to -0.07) for troponin levels of 14 to 49, 50 to 149 and at least 150 ng l when compared with values less than 14 ng l. Other independent predictors for lower HRQoL were chronic obstructive pulmonary disease, female sex, peripheral arterial disease and increasing age. CONCLUSION: Higher levels of postoperative troponin measured immediately after surgery were independently associated with lower self-reported HRQoL total score at 1-year follow-up

Sacubitril/valsartan reduces serum uric acid concentration, an independent predictor of adverse outcomes in PARADIGM-HF

Aims: Elevated serum uric acid concentration (SUA) has been associated with an increased risk of cardiovascular disease, but this may be due to unmeasured confounders. We examined the association between SUA and outcomes as well as the effect of sacubitril/valsartan on SUA in patients with heart failure with reduced ejection fraction (HFrEF) in PARADIGM-HF. Methods and results: The association between SUA and the primary composite outcome of cardiovascular death or heart failure (HF) hospitalization, its components, and all-cause mortality was examined using Cox regression analyses among 8213 patients using quintiles (Q1–Q5) of SUA adjusted for baseline prognostic variables including estimated glomerular filtration rate (eGFR), diuretic dose, and log N-terminal pro-brain natriuretic peptide. Change in SUA from baseline over 12 months was also evaluated in each treatment group. Patients in Q5 (SUA ≥8.6 mg/dL) compared with Q1 (&lt;5.4 mg/dL) were younger (62.8 vs. 64.2 years), more often male (88.7% vs. 63.1%), had lower systolic blood pressure (119 vs. 123 mmHg), lower eGFR (57.4 vs. 76.6 mL/min/1.73 m2), and greater diuretic use. Higher SUA was associated with a higher risk of the primary outcome (adjusted hazard ratios) Q5 vs. Q1 = 1.28 [95% confidence intervals (1.09–1.50), P = 0.003], cardiovascular death [1.44 (1.11–1.77), P = 0.001], HF hospitalization [1.37 (1.11–1.70), P = 0.004], and all-cause mortality [1.36 (1.13–1.64), P = 0.001]. Compared with enalapril, sacubitril/valsartan reduced SUA by 0.24 (0.17–0.32) mg/dL over 12 months (P &lt; 0.0001). Sacubitril/valsartan improved outcomes, irrespective of SUA concentration. Conclusion: Serum uric acid concentration was an independent predictor of worse outcomes after multivariable adjustment in patients with HFrEF. Compared with enalapril, sacubitril/valsartan reduced SUA and improved outcomes irrespective of SUA

GeMInA, Genomic Metadata for Infectious Agents, a geospatial surveillance pathogen database

The Gemina system (http://gemina.igs.umaryland.edu) identifies, standardizes and integrates the outbreak metadata for the breadth of NIAID category A–C viral and bacterial pathogens, thereby providing an investigative and surveillance tool describing the Who [Host], What [Disease, Symptom], When [Date], Where [Location] and How [Pathogen, Environmental Source, Reservoir, Transmission Method] for each pathogen. The Gemina database will provide a greater understanding of the interactions of viral and bacterial pathogens with their hosts and infectious diseases through in-depth literature text-mining, integrated outbreak metadata, outbreak surveillance tools, extensive ontology development, metadata curation and representative genomic sequence identification and standards development. The Gemina web interface provides metadata selection and retrieval of a pathogen's; Infection Systems (Pathogen, Host, Disease, Transmission Method and Anatomy) and Incidents (Location and Date) along with a hosts Age and Gender. The Gemina system provides an integrated investigative and geospatial surveillance system connecting pathogens, pathogen products and disease anchored on the taxonomic ID of the pathogen and host to identify the breadth of hosts and diseases known for these pathogens, to identify the extent of outbreak locations, and to identify unique genomic regions with the DNA Signature Insignia Detection Tool

The Human Disease Ontology 2022 update.

The Human Disease Ontology (DO) (www.disease-ontology.org) database, has significantly expanded the disease content and enhanced our userbase and website since the DO\u27s 2018 Nucleic Acids Research DATABASE issue paper. Conservatively, based on available resource statistics, terms from the DO have been annotated to over 1.5 million biomedical data elements and citations, a 10× increase in the past 5 years. The DO, funded as a NHGRI Genomic Resource, plays a key role in disease knowledge organization, representation, and standardization, serving as a reference framework for multiscale biomedical data integration and analysis across thousands of clinical, biomedical and computational research projects and genomic resources around the world. This update reports on the addition of 1,793 new disease terms, a 14% increase of textual definitions and the integration of 22 137 new SubClassOf axioms defining disease to disease connections representing the DO\u27s complex disease classification. The DO\u27s updated website provides multifaceted etiology searching, enhanced documentation and educational resources

The DO-KB Knowledgebase: a 20-year journey developing the disease open science ecosystem.

In 2003, the Human Disease Ontology (DO, https://disease-ontology.org/) was established at Northwestern University. In the intervening 20 years, the DO has expanded to become a highly-utilized disease knowledge resource. Serving as the nomenclature and classification standard for human diseases, the DO provides a stable, etiology-based structure integrating mechanistic drivers of human disease. Over the past two decades the DO has grown from a collection of clinical vocabularies, into an expertly curated semantic resource of over 11300 common and rare diseases linking disease concepts through more than 37000 vocabulary cross mappings (v2023-08-08). Here, we introduce the recently launched DO Knowledgebase (DO-KB), which expands the DO\u27s representation of the diseaseome and enhances the findability, accessibility, interoperability and reusability (FAIR) of disease data through a new SPARQL service and new Faceted Search Interface. The DO-KB is an integrated data system, built upon the DO\u27s semantic disease knowledge backbone, with resources that expose and connect the DO\u27s semantic knowledge with disease-related data across Open Linked Data resources. This update includes descriptions of efforts to assess the DO\u27s global impact and improvements to data quality and content, with emphasis on changes in the last two years

Predicting Early Mortality Among Implantable Defibrillator Patients Treated With Cardiac Resynchronization Therapy

Background: The beneficial effects of a cardiac resynchronization defibrillator (CRT-D) in patients with heart failure, low left ventricular ejection fraction (LVEF), and wide QRS have clearly been established. Nevertheless, mortality r