Research response to coronavirus disease 2019 needed better coordination and collaboration: a living mapping of registered trials.

OBJECTIVES: Researchers worldwide are actively engaging in research activities to search for preventive and therapeutic interventions against coronavirus disease 2019 (COVID-19). Our aim was to describe the planning of randomized controlled trials (RCTs) in terms of timing related to the course of the COVID-19 epidemic and research question evaluated. STUDY DESIGN AND SETTING: We performed a living mapping of RCTs registered in the WHO International Clinical Trials Registry Platform. We systematically search the platform every week for all RCTs evaluating preventive interventions and treatments for COVID-19 and created a publicly available interactive mapping tool at https://covid-nma.com to visualize all trials registered. RESULTS: By August 12, 2020, 1,568 trials for COVID-19 were registered worldwide. Overall, the median ([Q1-Q3]; range) delay between the first case recorded in each country and the first RCT registered was 47 days ([33-67]; 15-163). For the 9 countries with the highest number of trials registered, most trials were registered after the peak of the epidemic (from 100% trials in Italy to 38% in the United States). Most trials evaluated treatments (1,333 trials; 85%); only 223 (14%) evaluated preventive strategies and 12 postacute period intervention. A total of 254 trials were planned to assess different regimens of hydroxychloroquine with an expected sample size of 110,883 patients. CONCLUSION: This living mapping analysis showed that COVID-19 trials have relatively small sample size with certain redundancy in research questions. Most trials were registered when the first peak of the pandemic has passed.

Recombinant human plasma phospholipid transfer protein (PLTP) to prevent bacterial growth and to treat sepsis.

Although plasma phospholipid transfer protein (PLTP) has been mainly studied in the context of atherosclerosis, it shares homology with proteins involved in innate immunity. Here, we produced active recombinant human PLTP (rhPLTP) in the milk of new lines of transgenic rabbits. We successfully used rhPLTP as an exogenous therapeutic protein to treat endotoxemia and sepsis. In mouse models with injections of purified lipopolysaccharides or with polymicrobial infection, we demonstrated that rhPLTP prevented bacterial growth and detoxified LPS. In further support of the antimicrobial effect of PLTP, PLTP-knocked out mice were found to be less able than wild-type mice to fight against sepsis. To our knowledge, the production of rhPLTP to counter infection and to reduce endotoxemia and its harmful consequences is reported here for the first time. This paves the way for a novel strategy to satisfy long-felt, but unmet needs to prevent and treat sepsis.

Worsening of diet-induced atherosclerosis in a new model of transgenic rabbit expressing the human plasma phospholipid transfer protein.

OBJECTIVE: Plasma phospholipid transfer protein (PLTP) is involved in intravascular lipoprotein metabolism. PLTP is known to act through 2 main mechanisms: by remodeling high-density lipoproteins (HDL) and by increasing apolipoprotein (apo) B-containing lipoproteins. The aim of this study was to generate a new model of human PLTP transgenic (HuPLTPTg) rabbit and to determine whether PLTP expression modulates atherosclerosis in this species that, unlike humans and mice, displays naturally very low PLTP activity. METHODS AND RESULTS: In HuPLTPTg rabbits, the human PLTP cDNA was placed under the control of the human eF1-α gene promoter, resulting in a widespread tissue expression pattern and in increased plasma PLTP. The HuPLTPTg rabbits showed a significant increase in the cholesterol content of the plasma apoB-containing lipoprotein fractions, with a more severe trait when animals were fed a cholesterol-rich diet. In contrast, HDL cholesterol level was not modified in HuPLTPTg rabbits. Formation of aortic fatty streaks was increased in hypercholesterolemic HuPLTPTg animals as compared with nontransgenic littermates. CONCLUSIONS: Human PLTP expression in HuPLTPTg rabbit worsens atherosclerosis as a result of increased levels of atherogenic apoB-containing lipoproteins but not of alterations in their antioxidative protection or in cholesterol content of plasma HDL.

Isolation and characterisation of two multidrug resistance associated protein genes from maize.

Two genes encoding ATP-binding cassette (ABC) transporters were isolated from the crop plant Zea mays (maize). The clones, designated ZmMRP1 and ZmMRP2, were highly homologous to members of the multidrug resistance associated protein (MRP) subfamily. Genomic Southern analysis and characterisation of bacterial artificial chromosome (BAC) clones demonstrated that both genes are present in two copies in maize, which are located in proximity to each other, suggesting the occurrence of duplication events. The full-length genomic and cDNA sequences of ZmMRP1 and 2 were obtained, permitting analysis of the intron/exon structures and protein domains. Intron positions and phasing were conserved between ZmMRP1 and 2 and their closest Arabidopsis homologues. Both clones contained two copies each of the membrane spanning domains and nucleotide-binding folds diagnostic of the ABC superfamily, and ZmMRP1 contained an additional N-terminal membrane-spanning domain (MSD0) that is typical of MRP transporters but which is lacking in the most closely related Arabidopsis and rice MRPs. In contrast, ZmMRP2 and its closest rice but not Arabidopsis homologues lacked MSD0, suggesting the repeated loss of this domain in MRP family evolution. ZmMRP1 and 2 were expressed in all tissues examined but displayed distinct expression profiles in response to herbicide safeners and pro-oxidants. ZmMRP1 was induced by aminotriazole and to a lesser extent by menadione, whereas ZmMRP2 was expressed at a lower constitutive level and did not exhibit strong induction by any of the compounds tested. The characterisation of these clones represents an important step in the experimental analysis of the MRP subfamily in a monocotyledonous crop plant.