Management of donations of personal protective equipment in response to the massive shortage during the COVID-19 health crisis: providing quality equipment to health care workers.

BACKGROUND: In the COVID-19 pandemic context, a massive shortage of personal protective equipment occurred. To increase the available stocks, several countries appealed for donations from individuals or industries. While national and international standards to evaluate personal protective equipment exist, none of the previous research studied how to evaluate personal protective equipment coming from donations to healthcare establishments. Our aim was to evaluate the quality and possible use of the personal protective equipment donations delivered to our health care establishment in order to avoid a shortage and to protect health care workers throughout the COVID-19 crisis. METHODS: Our intervention focused on evaluation of the quality of donations for medical use through creation of a set of assessment criteria and analysis of the economic impact of these donations. RESULTS: Between 20th March 2020 and 11th May 2020, we received 239 donations including respirators, gloves, coveralls, face masks, gowns, hats, overshoes, alcohol-based hand rubs, face shields, goggles and aprons. A total of 448,666 (86.3%) products out of the 519,618 initially received were validated and distributed in health care units, equivalent to 126 (52.7%) donations out of the 239 received. The budgetary value of the validated donations was 32,872 euros according to the pre COVID-19 prices and 122,178 euros according to the current COVID-19 prices, representing an increase of 371.7%. CONCLUSIONS: By ensuring a constant influx of personal protective equipment and proper stock management, shortages were avoided. Procurement and distribution of controlled and validated personal protective equipment is the key to providing quality care while guaranteeing health care worker safety.

Pyrosequencing analysis of bacterial diversity in dental unit waterlines.

Some infections cases due to exposure to output water from dental unit waterlines (DUWL) have been reported in the literature. However, this type of healthcare-associated risk has remained unclear and up until now the overall bacterial composition of DUWL has been poorly documented. In this study, 454 high-throughput pyrosequencing was used to investigate the bacterial community in seven dental offices (N = 7) and to identify potential bacterial pathogenic sequences. Dental unit waters (DUW) were collected from the tap water supplying units (Incoming Water; IW) to the output exposure point of the turbine handpiece (Output water; OW) following a stagnation period (OWS), and immediately after the last patient of the sampling day (OWA). A high bacterial diversity was revealed in DUW with 394 operational taxonomic units detected at the genus level. In addition to the inter-unit variability observed, results showed increased total bacterial cell concentration and shifts in bacterial community composition and abundance at the genus level, mainly within the Gamma- and Alpha-Proteobacteria class, as water circulated in the dental unit (DU). Results showed that 96.7%, 96.8% and 97.4% of the total sequences from IW, OWS and OWA respectively were common to the 3 defined water groups, thereby highlighting a common core microbiome. Results also suggested that stagnation and DU maintenance practices were critical to composition of the bacterial community. The presence of potentially pathogenic genera was detected, including Pseudomonas and Legionella spp. Emerging and opportunistic pathogenic genera such as Mycobacterium, Propionibacterium and Stenotrophomonas were likewise recovered in DUW. For the first time, an exhaustive evaluation of the bacterial communities present in DUW was performed taking into account the circulation of water within the DU. This study highlights an ignored diversity of the DUWL bacterial community. Our findings also contribute to a better appreciation of the potential infectious risk associated with dental care and suggest the importance of better managing microbial quality in DUW.

Are dentists enough aware of infectious risk associated with dental unit waterlines ?

Environmental conditions in DU encourage biofilm development. This biofilm may represent a risk for patients and dental staff exposed to water and aerosols generated during dental cares, particularly for immunocompromised persons. A survey was conducted on the 175 dental surgeons of the department of Vienne (France) to investigate the motivations of dental practitioners to renew their DU, their awareness levels with respect to infectious risks related to water circulating within DU, and methods used for the maintenance of DU waterlines. These dentists were only partially aware of the need for maintaining DU waterlines. For this maintaining, chemical treatments and purges of pipes were carried out by 88% and 91.5% of dentists respectively ; chemical treatments were usually on a continous mode and dentists seemed to have complete confidence in their DU supplier regarding the choice and the use of chemical treatments. Flushes were performed only once per day in most cases (63%). This survey also highlighted that dentists were not enough aware of water related infectous risk, even though 68% estimated that the development of a biofilm within DU waterlines was an actual risk. Finally, very positively, dentists strongly indicated their wish to be more informed regarding all these risks. Although these results are based on a relatively small sample, corresponding to dentists of a French department, they clearly suggest that awareness of dental surgeons is still insufficient and must be performed to permit an effective prevention of infectious risk related to DU waterlines.

SAR3419: an anti-CD19-Maytansinoid Immunoconjugate for the treatment of B-cell malignancies.

SAR3419 is a novel anti-CD19 humanized monoclonal antibody conjugated to a maytansine derivate through a cleavable linker for the treatment of B-cell malignancies. SAR3419 combines the strengths of a high-potency tubulin inhibitor and the exquisite B-cell selectivity of an anti-CD19 antibody. The internalization and processing of SAR3419, following its binding at the surface of CD19-positive human lymphoma cell lines and xenograft models, release active metabolites that trigger cell-cycle arrest and apoptosis, leading to cell death and tumor regression. SAR3419 has also been shown to be active in different lymphoma xenograft models, including aggressive diffuse large B-cell lymphoma, resulting in complete regressions and tumor-free survival. In these models, the activity of SAR3419 compared favorably with rituximab and lymphoma standard of care chemotherapy. Two phase I trials with 2 different schedules of SAR3419 as a single agent were conducted in refractory/relapsed B-cell non-Hodgkin lymphoma. Activity was reported in both schedules, in heavily pretreated patients of both follicular and diffuse large B-cell lymphoma subtypes, with a notable lack of significant hematological toxicity, validating SAR3419 as an effective antibody-drug conjugate and opening opportunities in the future. Numerous B-cell-specific anti-CD19 biologics are available to treat B-cell non-Hodgkin lymphoma, and early phase I results obtained with SAR3419 suggest that it is a promising candidate for further development in this disease. In addition, thanks to the broad expression of CD19, SAR3419 may provide treatment options for B-cell leukemias that are often CD20-negative.

[Prevention of fungal infections related to the water supply in French hospitals: proposal for standardization of methods]. / Surveillance mycologique de l'eau pour la prévention des mycoses invasives dans les établissements de santé: propositions de standardisation des méthodologies.

OBJECTIVES: The aims of this study were to assess the risk of fungal infections related to the water supply in several hospitals and to clarify the appropriate methodology in order to standardize the technical conditions of the controls and develop guidelines. It was conducted in 10 university hospital centers across the country from February 2004 through March 2005. METHOD: A preliminary study allowed us to optimize the mycological analysis. The study was conducted under the same conditions as for bacteriological controls: water filtration through a cellulose acetate membrane cultured on agar. Departments with the highest patient risk were selected, including hematology, organ transplantation, and burn units. We selected 98 sites and sampled both water and water-related surfaces at each: three one-liter water samples (the first flow, cold and hot water) and two or three surface samples (inside the tap, pommel of the shower and siphon). At each site, a form was filled to specify its location in the unit, any water treatment (chlorine or other), filtering, and temperature. Water from taps equipped with sterilized filtration was sampled without the filter. RESULTS: There was a significant difference (p=0.039) in the number of positive cultures between the three types of water sampled: hot water (>50 degrees C) was colonized less often than first flow or cold water. Only 4% of the hot-water samples had positive cultures, compared to the 52% of the cold-water samples. Except in two hospitals with generalized contamination of the water pipes (one with Exophiala spp and the other with Fusarium spp), colonization was usually slight. Cold water was more colonized than hot water, but 79% of the samples yielded fewer than 5CFU/L. Dematiaceous hyphomycetes were isolated; Aspergillus spp were rare. The number of CFU in surface samples (that is, biofilms) was higher (mean=15 CFU per sample) but surfaces were positive less often than water (13% compared with 43% of all water samples). Sampling from siphons was productive more often than from taps (23%), but the molds isolated differed from those in the related water. Relations to bacterial flora and P. aeruginosa were also studied, together with the effects of chemical treatment. CONCLUSION: Current regulations require only bacteriological survey. The absence of knowledge about the threshold of contamination at which there is a risk of nosocomial invasive fungal infections makes it difficult to impose routine monitoring. Mycological surveys of water are required during hospital renovation, plumbing work, pipe maintenance and when air samples are negative during nosocomial infection investigations.

Potent, selective and cell-mediated inhibition of human herpesvirus 6 at an early stage of viral replication by the non-nucleoside compound CMV423.

CMV423 (2-chloro-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxamide) is a new antiviral agent with potent and selective in vitro activity against the beta-herpesvirus human cytomegalovirus (HCMV), but not against alpha- or gamma-herpesviruses. Here we report that its activity also extends to human herpesvirus 6 (HHV-6) and 7 (HHV-7). When compared in vitro to ganciclovir and foscarnet (the standard drugs recommended for treatment of HHV-6 infections), CMV423 showed a superior selectivity, due to its high activity (antiviral IC(50): 53nM) and low cytotoxicity (CC(50): 144microM), both in continuous cell lines and in CBLCs infected with HHV-6. From mechanistic experiments at the level of viral mRNA and protein expression, we learned that CMV423 targets an event following viral entry but preceding viral DNA replication. Its antiviral action was dependent on the cell line used, implying involvement of a cellular component. When compared to a panel of known protein kinase inhibitors, CMV423 was found to share anti-HHV-6 characteristics with herbimycin A, which affects tyrosine kinase activity through heat shock protein 90 (Hsp90) inhibition. We demonstrated that high concentrations of CMV423 have an inhibitory effect on the total cellular protein tyrosine kinase activity, and that CMV423 and herbimycin A, when combined, act synergistically against HHV-6. The activities of cyclin-dependent kinases, protein kinases A and C, and the HHV-6-encoded pU69 kinase were not affected. We, therefore, conclude that CMV423 exerts its activity against HHV-6 through inhibition of a cellular process that is critical at early stages of viral replication and that may affect protein tyrosine kinase activity.

Synthesis of non-immunosuppressive cyclophilin-Binding cyclosporin A derivatives as potential anti-HIV-1 drugs.

Original cyclosporin A (CsA) derivatives bearing various alkylthio side chains at the sarcosine residue 3 (R configuration) and for the most potent and selective compounds a 4'-hydroxyl group at the Me-Leucine residue 4 were prepared in one or two steps from commercially available CsA. The [2-(dimethyl or diethylamino)-ethylthio-Sar](3)-[(4'-OH)MeLeu](4)-CsA derivatives 3k and 3l displayed potent in vitro anti-HIV-1 (IC(50) approximately 46 nM) and low immunosuppressive activities (IC(50)>or=1500 nM).

2-Chloro-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxamide (CMV423), a new lead compound for the treatment of human cytomegalovirus infections.

Human cytomegalovirus (HCMV) remains one of the major pathogens in immunocompromised patients (AIDS and transplants) and the main cause for congenital infections leading from slight cognitive defects up to severe mental retardation. The drugs that are currently available for the treatment of HCMV infections, i.e. ganciclovir, foscarnet and cidofovir, are all acting at the level of the viral DNA polymerase. Here we describe an entirely new molecule, the 2-chloro-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxamide (CMV423), that shows very potent in vitro activity against HCMV. CMV423 is highly active against HCMV reference strains and clinical isolates, but also against those strains, isolated from patients or emerging after in vitro selection, that are resistant to either ganciclovir, foscarnet or cidofovir. CMV423 also showed activity in two ex vivo models, that are both highly relevant for the pathophysiology of HCMV, the retinal pigment epithelial and the bone marrow stromal cell assays. Viral antigen expression analysis by flow cytometry, as well as time of addition experiments, confirmed that CMV423 acts on a step of the viral replicative cycle that precedes the DNA polymerase step and, most likely, coincides with the immediate early (IE) antigen synthesis. Finally, CMV423 combined with either ganciclovir, foscarnet or cidofovir in checkerboard experiments demonstrated a highly synergistic activity.

Amoeboid Microglial Cells and not Astrocytes Synthesize TNF-alpha in Swiss Mouse Brain Cell Cultures.

The role of tumour necrosis factor (TNF-alpha) in brain physiology and pathology has been the focus of several studies. However, the source of this lymphokine in the central nervous system and the regulation of its synthesis is still poorly understood. We have therefore used purified astrocytes and brain macrophages in culture to compare the abilities of these two cell types to synthesize TNF-alpha and its mRNA. We find that, in the Swiss mouse, no significant TNF activity or TNF-alpha mRNA are produced by astrocytes, even following activation with lipopolysaccharides (LPS). On the other hand, purified microglial cells express a cytotoxic activity able to kill TNF-sensitive LM cells. Part of this activity is released into the culture medium and part remains bound to the membrane after mild paraformaldehyde treatment, demonstrating the existence in the culture of the soluble and membrane-bound forms of TNF activity. The fact that amoeboid microglial cells, and not astrocytes, are the actual source of TNF in brain cultures was further demonstrated by Northern blot analysis and in situ hybridization using a TNF-alpha specific oligonucleotide probe. The definition of the cell type which, in the CNS, is responsible for TNF synthesis will allow the regulation of this lymphokine to be analysed and opens the way for a better understanding of the interactions between amoeboid microglial cells and the other cell types which make up the nervous system.