Predictive factors of clinical assays on hydroxychloroquine for COVID-19 mortality during the first year of the pandemic: A meta-synthesis

Background: The COVID-19 pandemic led to a violent debate about the efficacy of a repurposed drug hydroxychloroquine (HCQ) and a new broad-spectrum antiviral (remdesivir) and about randomized controlled trials (RCTs) and observational studies. To understand conflicting results in the literature, we performed a metasynthesis to determine whether intrinsic qualitative criteria within studies may predict apparent efficacy or ineffectiveness of HCQ and remdesivir. Methodology: Predictive criteria were identified through critical review of studies assessing HCQ and remdesivir for COVID-19 mortality from March to November 2020. Multiple correspondence analysis, comparative metaanalysis, and predictive value were used to explore and identify criteria associated with study outcomes. Results: Among the 61 included studies, potential conflict of interest, detailed therapeutic protocol, toxic treatment (overdose or use in contraindicated patients), known centers and doctors, and private data computing company were the most predictive criteria of the direction of effect of the studies. All 18 observational studies evaluating HCQ and reporting detailed therapeutic protocol without conflict of interest were Pro. Potential conflict of interest was a perfect predictor for remdesivir efficacy. RCTs were associated with HCQ inefficacy and potential conflict of interest. The most predictive criteria were validated and allowed perfect classification of 10 additional studies.Conclusion: In therapeutic trials on COVID-19, the major biases predicting the conclusions are not methodology nor data analysis, but conflict of interest and absence of medical expertise. The thorough search for declared or undeclared and direct or indirect conflict of interest, and medical expertise should be included in the quality criteria for the evaluation of future therapeutic studies in COVID-19 and beyond. A new checklist evaluating not only methodology but also conflict of interest and medical expertise is proposed

An Anaerobic-Type α-Ketoglutarate Ferredoxin Oxidoreductase Completes the Oxidative Tricarboxylic Acid Cycle of Mycobacterium tuberculosis

Aerobic organisms have a tricarboxylic acid (TCA) cycle that is functionally distinct from those found in anaerobic organisms. Previous reports indicate that the aerobic pathogen Mycobacterium tuberculosis lacks detectable α-ketoglutarate (KG) dehydrogenase activity and drives a variant TCA cycle in which succinyl-CoA is replaced by succinic semialdehyde. Here, we show that M. tuberculosis expresses a CoA-dependent KG dehydrogenase activity, albeit one that is typically found in anaerobic bacteria. Unlike most enzymes of this family, the M. tuberculosis KG: ferredoxin oxidoreductase (KOR) is extremely stable under aerobic conditions. This activity is absent in a mutant strain deleted for genes encoding a previously uncharacterized oxidoreductase, and this strain is impaired for aerobic growth in the absence of sufficient amounts of CO2. Interestingly, inhibition of the glyoxylate shunt or exclusion of exogenous fatty acids alleviates this growth defect, indicating the presence of an alternate pathway that operates in the absence of β-oxidation. Simultaneous disruption of KOR and the first enzyme of the succinic semialdehyde pathway (KG decarboxylase; KGD) results in strict dependence upon the glyoxylate shunt for growth, demonstrating that KG decarboxylase is also functional in M. tuberculosis intermediary metabolism. These observations demonstrate that unlike most organisms M. tuberculosis utilizes two distinct TCA pathways from KG, one that functions concurrently with β-oxidation (KOR-dependent), and one that functions in the absence of β-oxidation (KGD-dependent). As these pathways are regulated by metabolic cues, we predict that their differential utilization provides an advantage for growth in different environments within the host

The Level of DING Proteins Is Increased in HIV-Infected Patients: In Vitro and In Vivo Studies

DING proteins constitute an interesting family, owing to their intriguing and important activities. However, after a decade of research, little is known about these proteins. In humans, at least five different DING proteins have been identified, which were implicated in important biological processes and diseases, including HIV. Indeed, recent data from different research groups have highlighted the anti-HIV activity of some DING representatives. These proteins share the ability to inhibit the transcriptional step of HIV-1, a key step of the viral cycle that is not yet targeted by the current therapies. Since such proteins have been isolated from humans, we undertook a comprehensive study that focuses on the relationship between these proteins and HIV-infection in an infectious context. Hence, we developed a home-made ELISA for the quantification of the concentration of DING proteins in human serum. Using this method, we were able to determine the concentration of DING proteins in healthy and HIV-infected patients. Interestingly, we observed a significant increase of the concentration of DING proteins in non treated and treated HIV-infected patients compared to controls. In addition, cell cultures infected with HIV also show an increased expression of DING proteins, ruling out the possible role of antiretroviral treatment in the increase of the expression of DING proteins. In conclusion, results from this study show that the organism reacts to HIV-infection by an overexpression of DING proteins

Human paraoxonase: A promising approach for pre-treatment and therapy of organophosphorus poisoning

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Institut Hospitalier Universitaire Méditerranée Infection : leading research in medical microbiology and infectious diseases in the Mediterranean basin

We review reviewing our experience of point-of-care and mass spectrometry in Senegal as two disruptive technologies promoting the rapid diagnosis of infection, permitting better medical management of patients

Intoxication aux organophosphorés : vers des traitements enzymatiques

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Recombinant expression of Mimivirus L725 ORFan gene product

International audienceMimivirus was the first discovered amoebal giant virus. The Mimivirus virions are covered by a dense layer of approximately 130 nm-long fibers, the length and shape of which diverge from those of other viruses. Here, we aimed at expressing the L725 protein to further confirm and study its role as a fiber-associated protein. We report Escherichia coli expression of the L725 protein, which is encoded by a Mimivirus ORFan, was previously identified by proteomics in purified viral fibers and demonstrated to be a fiber-associated protein by RNA-silencing experiments. The expressed protein was recognized by anti-Mimivirus fiber or anti-Mimivirus L725 polyclonal antibodies. This study is the only expression, to our knowledge, of a product from a Mimiviral ORFan gene

Tandem purification of two HDL-associated partner proteins in human plasma, paraoxonase (PON1) and phosphate binding protein (HPBP) using hydroxyapatite chromatography

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