Publications by authors named "Didier Raoult"

1,978 Publications

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Spreading of a new SARS-CoV-2 N501Y spike variant in a new lineage.

Clin Microbiol Infect 2021 May 12. Epub 2021 May 12.

IHU Méditerranée Infection, 19-21 boulevard Jean Moulin, 13005 Marseille, France; Aix-Marseille Univ., Institut de Recherche pour le Développement (IRD), Assistance Publique - Hôpitaux de Marseille (AP-HM), MEPHI, 27 boulevard Jean Moulin, 13005 Marseille, France. Electronic address:

Objectives: Our surveillance of the SARS-CoV-2 genomic epidemiology led us to detect several variants since summer 2020. We report the recent spread of a new SARS-CoV-2 spike 501Y variant.

Methods: SARS-CoV-2 sequences obtained from human nasopharyngeal samples by Illumina next-generation sequencing were analyzed using Nextclade and an in-house Python script and compared using BLASTn to the GISAID database. Phylogeny was performed using the IQ-TREE software.

Results: We identified that SARS-CoV-2 genomes from four patients diagnosed in our institute harbored a new set of amino acid substitutions including L18F;L452R;N501Y;A653V;H655Y;D796Y;G1219V±Q677H. These spike N501Y genomes are the first of Nextstrain clade 19B. We obtained partial spike gene sequences of this genotype for an additional 43 patients. All patients infected with this genotype were diagnosed since mid-January 2021. We detected 42 other genomes of this genotype in GISAID, which were obtained from samples collected in December 2020 in four cases and in 2021 in 38 cases. The 89 sequences obtained in our institute or other laboratories originated from the Comoros archipelago, Western European countries (mostly metropolitan France), Turkey and Nigeria.

Conclusion: These findings warrant further studies to investigate the spread, epidemiological and clinical features, and sensitivity to immune responses of this variant.
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http://dx.doi.org/10.1016/j.cmi.2021.05.006DOI Listing
May 2021

A metallo-β-lactamase enzyme for internal detoxification of the antibiotic thienamycin.

Sci Rep 2021 May 12;11(1):10062. Epub 2021 May 12.

IRD, APHM, MEPHI, IHU-Méditerranée Infection, Aix Marseille Univ, 19-21 Boulevard Jean Moulin, 13005, Marseille, France.

Thienamycin, the first representative of carbapenem antibiotics was discovered in the mid-1970s from soil microorganism, Streptomyces cattleya, during the race to discover inhibitors of bacterial peptidoglycan synthesis. Chemically modified into imipenem (N-formimidoyl thienamycin), now one of the most clinically important antibiotics, thienamycin is encoded by a thienamycin gene cluster composed of 22 genes (thnA to thnV) from S. cattleya NRRL 8057 genome. Interestingly, the role of all thn-genes has been experimentally demonstrated in the thienamycin biosynthesis, except thnS, despite its annotation as putative β-lactamase. Here, we expressed thnS gene and investigated its activities against various substrates. Our analyses revealed that ThnS belonged to the superfamily of metallo-β-lactamase fold proteins. Compared to known β-lactamases such as OXA-48 and NDM-1, ThnS exhibited a lower affinity and less efficiency toward penicillin G and cefotaxime, while imipenem is more actively hydrolysed. Moreover, like most MBL fold enzymes, additional enzymatic activities of ThnS were detected such as hydrolysis of ascorbic acid, single strand DNA, and ribosomal RNA. ThnS appears as a MBL enzyme with multiple activities including a specialised β-lactamase activity toward imipenem. Thus, like toxin/antitoxin systems, the role of thnS gene within the thienamycin gene cluster appears as an antidote against the produced thienamycin.
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http://dx.doi.org/10.1038/s41598-021-89600-xDOI Listing
May 2021

Multifaceted modes of action of the anticancer probiotic Enterococcus hirae.

Cell Death Differ 2021 May 11. Epub 2021 May 11.

Gustave Roussy Cancer Campus (GRCC), Villejuif, France.

A deviated repertoire of the gut microbiome predicts resistance to cancer immunotherapy. Enterococcus hirae compensated cancer-associated dysbiosis in various tumor models. However, the mechanisms by which E. hirae restored the efficacy of cyclophosphamide administered with concomitant antibiotics remain ill defined. Here, we analyzed the multifaceted modes of action of this anticancer probiotic. Firstly, E. hirae elicited emigration of thymocytes and triggered systemic and intratumoral IFNγ-producing and CD137-expressing effector memory T cell responses. Secondly, E. hirae activated the autophagy machinery in enterocytes and mediated ATG4B-dependent anticancer effects, likely as a consequence of its ability to increase local delivery of polyamines. Thirdly, E. hirae shifted the host microbiome toward a Bifidobacteria-enriched ecosystem. In contrast to the live bacterium, its pasteurized cells or membrane vesicles were devoid of anticancer properties. These pleiotropic functions allow the design of optimal immunotherapies combining E. hirae with CD137 agonistic antibodies, spermidine, or Bifidobacterium animalis. We surmise that immunological, metabolic, epithelial, and microbial modes of action of the live E. hirae cooperate to circumvent primary resistance to therapy.
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http://dx.doi.org/10.1038/s41418-021-00753-8DOI Listing
May 2021

Is minor surgery safe during the COVID-19 pandemic? A multi-disciplinary study.

PLoS One 2021 11;16(5):e0251122. Epub 2021 May 11.

Department of Urology and Kidney Transplantation, Aix-Marseille University, APHM, Conception University Hospital, Marseilles, France.

Background: To assess the risk of postoperative SARS-CoV-2 infection during the COVID-19 pandemic.

Methods: The CONCEPTION study was a cohort, multidisciplinary study conducted at Conception University Hospital, in France, from March 17th to May 11th, 2020. Our study included all adult patients who underwent minor surgery in one of the seven surgical departments of our hospital: urology, digestive, plastic, gynecological, otolaryngology, gynecology or maxillofacial surgery. Preoperative self-isolation, clinical assessment using a standardized questionnaire, physical examination, nasopharyngeal RT-PCR and chest CT scan performed the day before surgery were part of our active prevention strategy. The main outcome was the occurrence of a SARS-CoV-2 infection within 21 days following surgery. The COVID-19 status of patients after discharge was updated during the postoperative consultation and to ensure the accuracy of data, all patients were contacted again by telephone.

Results: A total of 551 patients from six different specialized surgical Departments in our tertiary care center were enrolled in our study. More than 99% (546/551) of included patients underwent a complete preoperative Covid-19 screening including RT-PCR testing and chest CT scan upon admission to the Hospital. All RT-PCR tests were negative and in 12 cases (2.2%), preoperative chest CT scans detected pulmonary lesions consistent with the diagnosis criteria for COVID-19. No scheduled surgery was postponed. One patient (0.2%) developed a SARS-CoV-2 infection 20 days after a renal transplantation. No readmission or COVID-19 -related death within 30 days from surgery was recorded.

Conclusions: Minor surgery remained safe in the COVID-19 Era, as long as all appropriate protective measures were implemented. These data could be useful to public Health Authorities in order to improve surgical patient flow during a pandemic.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251122PLOS
May 2021

Infective endocarditis with neurological complications: Delaying cardiac surgery is associated with worse outcome.

Arch Cardiovasc Dis 2021 Apr 29. Epub 2021 Apr 29.

AP-HM, La Timone Hospital, Cardiology Department, 13005 Marseille, France; Aix Marseille Univ, IRD, AP-HM, MEPHI, IHU-Méditerranée Infection, 13005 Marseille, France. Electronic address:

Background: Infective endocarditis (IE) is associated with a high mortality rate, related in part to neurological complications. Studies suggest that valvular surgery should be performed early when indicated, but is often delayed by the presence of neurological complications.

Aim: To assess the effect of delaying surgery in patients with IE and neurological complications and to identify factors predictive of death.

Methods: In a prospective, single-centre study in a referral centre for IE, all patients with IE underwent systematic screening for neurological complications. The primary outcome was 6-month death. In patients presenting with neurological complications, the prognosis according to surgical status was analysed and a Cox regression model used to identify variables predictive of death.

Results: Between April 2014 and January 2018, 351 patients with a definite diagnosis of left-sided IE were included. Ninety-four patients (26.8%) presented with at least one neurological complication. Fifty-nine patients (17.7%) died during 6-month follow-up. Six-month mortality rates did not differ significantly between patients with and without neurological complications (P=0.60). Forty patients had a temporary surgical contraindication because of neurological complications. During the period of surgical contraindication, seven of these patients (17.5%) died, six (15.0%) presented a new embolic event, and 12 (30.0%) presented cardiac or septic deterioration. In multivariable analysis, predictive factors of death in patients presenting with neurological complications were temporary surgical contraindication (hazard ratio 7.36, 95% confidence interval 1.61-33.67; P=0.010) and presence of a mechanical prosthetic valve (hazard ratio 16.40, 95% confidence interval 2.22-121.17; P=0.006).

Conclusions: Patients with a temporary surgical contraindication due to neurological complications had a higher risk of death and frequent major complications while waiting for surgery. When indicated, the decision to postpone surgery in the early phase should be weighed against the risk of infectious or cardiac deterioration.
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http://dx.doi.org/10.1016/j.acvd.2021.01.004DOI Listing
April 2021

Global Discrepancies between Numbers of Available SARS-CoV-2 Genomes and Human Development Indexes at Country Scales.

Viruses 2021 04 28;13(5). Epub 2021 Apr 28.

IHU Méditerranée Infection, 19-21 Boulevard Jean Moulin, 13005 Marseille, France.

It has now been over a year since SARS-CoV-2 first emerged in China, in December 2019, and it has spread rapidly around the world. Some variants are currently considered of great concern. We aimed to analyze the numbers of SARS-CoV-2 genome sequences obtained in different countries worldwide until January 2021. On 28 January 2021, we downloaded the deposited genome sequence origin from the GISAID database, and from the "Our world in data" website we downloaded numbers of SARS-CoV-2-diagnosed cases, numbers of SARS-CoV-2-associated deaths, population size, life expectancy, gross domestic product (GDP) per capita, and human development index per country. Files were merged and data were analyzed using Microsoft Excel software. A total of 450,968 SARS-CoV-2 genomes originating from 135 countries on the 5 continents were available. When considering the 19 countries for which the number of genomes per 100 deaths was >100, six were in Europe, while eight were in Asia, three were in Oceania and two were in Africa. Six (30%) of these countries are beyond rank 75, regarding the human development index and four (20%) are beyond rank 80 regarding GDP per capita. Moreover, the comparisons of the number of genomes sequenced per 100 deaths to the human development index by country show that some Western European countries have released similar or lower numbers of genomes than many African or Asian countries with a lower human development index. Previous data highlight great discrepancies between the numbers of available SARS-CoV-2 genomes per 100 cases and deaths and the ranking of countries regarding wealth and development.
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http://dx.doi.org/10.3390/v13050775DOI Listing
April 2021

Stool Serology: Development of a Non-Invasive Immunological Method for the Detection of Enterovirus-Specific Antibodies in Congo Gorilla Faeces.

Microorganisms 2021 Apr 12;9(4). Epub 2021 Apr 12.

Institut Hospitalo-Universitaire Méditerranée-Infection, 19-21 Boulevard Jean Moulin, CEDEX 05, 13005 Marseille, France.

Background: The incidence of poliovirus has been significantly reduced by as much as 99.9% globally. Alongside this, however, vaccine-associated paralytic poliomyelitis has emerged. Previously, our team reported in the Lésio-Louna-Léfini Nature Reserve (Republic of Congo) the presence of a new C () in a male gorilla that was put away because of clinical symptoms of facial paralysis. This new virus, isolated was from the stool samples of this gorilla but also from the excrement of an eco-guardian, is very similar to Coxsackievirus () as well as poliovirus 1 and 2. We hypothesised that these symptoms might be due to poliovirus infection. To test our hypothesis, we developed and optimised a non-invasive immunoassay for the detection of -specific antibodies in gorilla faeces that could be useful for routine serosurveillance in such cases.

Methods: In order to assess the potential role of poliovirus infection, we have developed and optimised a protocol, based on the lyophilisation and solubilisation of small volumes of stool extracts from 16 gorilla and 3 humans, to detect specific antibodies by western blot and ELISA.

Results: First, total immunoglobulins were detected in the concentrated stool extracts. Specific antibodies were then detected in 4/16 gorilla samples and 2/3 human samples by western blot using both the polio vaccine antigen and the Ibou002 antigen and by ELISA using the polio vaccine antigen. Humoral responses were greater with the Ibou002 antigen.

Conclusion: We therefore suggest that this recombinant virus could lead to a polio-like disease in the endangered western lowland gorilla. The development of a non-invasive approach to detect microorganism-specific immunoglobulins from faecal samples opens numerous prospects for application in zoonotic infectious diseases and could revolutionise the screening of animals for important emerging infections, such as Ebola fever, rabies and coronavirus infections.
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http://dx.doi.org/10.3390/microorganisms9040810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068960PMC
April 2021

Current Status of Putative Animal Sources of SARS-CoV-2 Infection in Humans: Wildlife, Domestic Animals and Pets.

Microorganisms 2021 Apr 17;9(4). Epub 2021 Apr 17.

IHU-Méditerranée Infection, 13005 Marseille, France.

SARS-CoV-2 is currently considered to have emerged from a bat coronavirus reservoir. However, the real natural cycle of this virus remains to be elucidated. Moreover, the COVID-19 pandemic has led to novel opportunities for SARS-CoV-2 transmission between humans and susceptible animal species. In silico and in vitro evaluation of the interactions between the SARS-CoV-2 spike protein and eucaryotic angiotensin-converting enzyme 2 (ACE2) receptor have tentatively predicted susceptibility to SARS-CoV-2 infection of several animal species. Although useful, these data do not always correlate with in vivo data obtained in experimental models or during natural infections. Other host biological properties may intervene such as the body temperature, level of receptor expression, co-receptor, restriction factors, and genetic background. The spread of SARS-CoV-2 also depends on the extent and duration of viral shedding in the infected host as well as population density and behaviour (group living and grooming). Overall, current data indicate that the most at-risk interactions between humans and animals for COVID-19 infection are those involving certain mustelids (such as minks and ferrets), rodents (such as hamsters), lagomorphs (especially rabbits), and felines (including cats). Therefore, special attention should be paid to the risk of SARS-CoV-2 infection associated with pets.
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http://dx.doi.org/10.3390/microorganisms9040868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072559PMC
April 2021

Role of glyphosate in the emergence of antimicrobial resistance in bacteria?

J Antimicrob Chemother 2021 Apr 24. Epub 2021 Apr 24.

Institut Hospitalo-universitaire Méditerranée Infection, Marseille, France.

There is a discrepancy between antibiotic use in medicine and agriculture in the intertropical zone and frequency of antibiotic resistance in clinical bacteria in these countries. We provide evidence that glyphosate (a herbicide but also an antibiotic drug) could be a possible driver of antibiotic resistance in countries where this herbicide is widely used because of modification of the microbial environment. Emergence of resistance in bacteria and fungi is correlated with glyphosate use in the world over the last 40 years.
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http://dx.doi.org/10.1093/jac/dkab102DOI Listing
April 2021

Tick-borne relapsing fever Borreliosis, a major public health problem overlooked in Senegal.

PLoS Negl Trop Dis 2021 Apr 22;15(4):e0009184. Epub 2021 Apr 22.

Aix Marseille Univ, IRD, APHM, SSA, VITROME, Marseille, France.

Background: Tick-borne relapsing fever (TBRF) is the most common vector-borne bacterial disease in humans in West Africa. It is frequently clinically confused with malaria. Our study aims to determine, on a micro-geographic scale, the conditions for the maintenance and spread of TBRF in the Niakhar district of Senegal.

Methodology/principal Findings: We conducted clinical, entomological and animal reservoir investigations. Field surveys were carried out in order to investigate the presence of Ornithodoros sonrai vector ticks and to detect Borrelia spp. by qPCR using the 16S rRNA and glpQ genes, respectively. Micromammal trapping series were carried out inside homes and Borrelia infection was detected using brain tissue qPCR. Capillary blood samples from febrile patients were also tested for Borrelia using qPCR. More than 97% (40/41) of the villages surveyed were infested with O. sonrai ticks. The prevalence of Borrelia spp. infections in ticks was 13% (116/910), and over 73% (85/116) were positively confirmed as being Borrelia crocidurae. Borreliosis cases accounted for 12% (94/800) of episodes of fever and all age groups were infected, with children and young people between the ages of 8-14 and 22-28 being the most infected by the disease (16% and 18.4%). TBRF cases occurred in all seasons, with a peak in August. In two species of small rodents that were found to be infected (Arvicanthis niloticus, Mus musculus), the proportion of Borrelia infection was 17.5% (10/57), and the highest prevalence of infection (40.9%, 9/22) was observed in A. niloticus.

Conclusion/significance: Our study indicates that TBRF is an endemic disease in the Niakhar district, where children and young people are the most infected. Arvicanthis niloticus and O. sonrai ticks are massively present and appear to be the main epidemiological reservoirs causing its extensive spread to humans.
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http://dx.doi.org/10.1371/journal.pntd.0009184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096072PMC
April 2021

Mink, SARS-CoV-2, and the Human-Animal Interface.

Front Microbiol 2021 1;12:663815. Epub 2021 Apr 1.

IHU-Méditerranée Infection, Marseille, France.

Mink are small carnivores of the Mustelidae family. The American mink is the most common and was imported to Europe, Asia, and Latin America for breeding, as its fur is very popular. Denmark, the Netherlands, and China are the biggest producers of mink. Mink farms with a high population density in very small areas and a low level of genetic heterogeneity are places conducive to contagion. The mink's receptor for SARS-CoV-2 is very similar to that of humans. Experimental models have shown the susceptibility of the ferret, another mustelid, to become infected with SARS-CoV-2 and to transmit it to other ferrets. On April 23, 2020, for the first time, an outbreak of SARS-CoV-2 in a mink farm was reported in the Netherlands. Since then, COVID-19 has reached numerous mink farms in the Netherlands, Denmark, United States, France, Greece, Italy, Spain, Sweden, Poland, Lithuania, and Canada. Not only do mink become infected from each other, but also they are capable of infecting humans, including with virus variants that have mutated in mink. Human infection with variant mink viruses with spike mutations led to the culling in Denmark of all mink in the country. Several animals can be infected with SARS-CoV-2. However, anthropo-zoonotic outbreaks have only been reported in mink farms. The rapid spread of SARS-CoV-2 in mink farms raises questions regarding their potential role at the onset of the pandemic and the impact of mutants on viral fitness, contagiousness, pathogenicity, re-infections with different mutants, immunotherapy, and vaccine efficacy.
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http://dx.doi.org/10.3389/fmicb.2021.663815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047314PMC
April 2021

Bartonella infections diagnosed in the French reference center, 2014-2019, and focus on infections in the immunocompromised.

Eur J Clin Microbiol Infect Dis 2021 Apr 12. Epub 2021 Apr 12.

Centre National de Référence des Rickettsies, Coxiella et Bartonella IHU-Méditerranée Infection, APHM, Marseille, France.

We studied retrospectively 651 PCR-confirmed Bartonella infections diagnosed at the French reference center for bartonellosis from 2014 to 2019. The most common form was cat-scratch disease (89%) followed by endocarditis (9%). Disseminated forms (2%) mainly presented as bacillary angiomatosis or peliosis hepatis in solid organ transplant recipients.
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http://dx.doi.org/10.1007/s10096-021-04244-zDOI Listing
April 2021

Implementation of an in-house real-time reverse transcription-PCR assay for the rapid detection of the SARS-CoV-2 Marseille-4 variant.

J Clin Virol 2021 Mar 31;139:104814. Epub 2021 Mar 31.

IHU Méditerranée Infection, 19-21 Boulevard Jean Moulin, 13005, Marseille, France; Aix-Marseille Univ., Institut de Recherche pour le Développement (IRD), Assistance Publique - Hôpitaux de Marseille (AP-HM), Microbes Evolution Phylogeny and Infections (MEPHI), 27 Boulevard Jean Moulin, 13005, Marseille, France. Electronic address:

Introduction: The SARS-CoV-2 pandemic has been associated with the occurrence since summer 2020 of several viral variants that overlapped or succeeded each other in time. Those of current concern harbor mutations within the spike receptor binding domain (RBD) that may be associated with viral escape to immune responses. In our geographical area a viral variant we named Marseille-4 harbors a S477 N substitution in this RBD.

Materials And Methods: We aimed to implement an in-house one-step real-time reverse transcription-PCR (qPCR) assay with a hydrolysis probe that specifically detects the SARS-CoV-2 Marseille-4 variant.

Results: All 6 cDNA samples from Marseille-4 variant strains identified in our institute by genome next-generation sequencing (NGS) tested positive using our Marseille-4 specific qPCR, whereas all 32 cDNA samples from other variants tested negative. In addition, 39/42 (93 %) respiratory samples identified by NGS as containing a Marseille-4 variant strain and 0/26 samples identified as containing non-Marseille-4 variant strains were positive. Finally, 2018/3960 (51%) patients SARS-CoV-2-diagnosed in our institute, 10/277 (3.6 %) respiratory samples collected in Algeria, and none of 207 respiratory samples collected in Senegal, Morocco, or Lebanon tested positive using our Marseille-4 specific qPCR.

Discussion: Our in-house qPCR system was found reliable to detect specifically the Marseille-4 variant and allowed estimating it is involved in about half of our SARS-CoV-2 diagnoses since December 2020. Such approach allows the real-time surveillance of SARS-CoV-2 variants, which is warranted to monitor and assess their epidemiological and clinical characterics based on comprehensive sets of data.
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http://dx.doi.org/10.1016/j.jcv.2021.104814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011323PMC
March 2021

High-flow oxygen therapy in elderly patients infected with SARS-CoV2 with a contraindication for transfer to an intensive care unit: a preliminary report.

Int J Infect Dis 2021 Apr 3. Epub 2021 Apr 3.

Aix-Marseille Université, IRD, MEPHI, APHM, IHU Méditerranée Infection, Marseille, France. Electronic address:

Objectives: In a conventional hospital ward, we used high-flow nasal oxygen (HFNO) to treat elderly COVID-19 patients non eligible for intensive care unit transfer.

Methods: This study was conducted in the Institut Hospitalo-Universitaire Méditerranée Infection, Assistance Publique-Hôpitaux de Marseille (AP-HM), France. We used high-flow nasal oxygen (HFNO) in our conventional infectious disease ward from 15 September 2020 for elderly patients non eligible for intensive care unit transfer.

Results: Of the 44 patients (median age 83 years (57-94), mean: 80.25), 61.4% (27/44) were men. The median Charlson score was 7 (1-15). The median of the NEWS-2 score upon admission was 8 (3-11) and was 10 at the time of initiation of HFNO. The median PaO2/FiO2 ratio was 103 (71-151) prior to HNFO initiation. Among the 44 patients, 16 patients (36.4%) had been weaned from HFNO, and 28 patients had died (63.6%).

Conclusions: In this preliminary report, we observed that HFNO saved the lives of one-third of elderly COVID-19 patients who would have systematically died.
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http://dx.doi.org/10.1016/j.ijid.2021.03.087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019243PMC
April 2021

Occurrence of Ten Protozoan Enteric Pathogens in Three Non-Human Primate Populations.

Pathogens 2021 Mar 2;10(3). Epub 2021 Mar 2.

IHU Méditerranée infection, 13005 Marseille, France.

Non-human primate populations act as potential reservoirs for human pathogens, including viruses, bacteria and parasites, which can lead to zoonotic infections. Furthermore, intestinal microorganisms may be pathogenic organisms to both non-human primates and humans. It is, therefore, essential to study the prevalence of these infectious agents in captive and wild non-human primates. This study aimed at showing the prevalence of the most frequently encountered human enteric protozoa in non-human primate populations based on qPCR detection. The three populations studied were common chimpanzees () in Senegal and gorillas () in the Republic of the Congo and in the Beauval Zoo (France). spp. were mainly found, with an occurrence close to 100%, followed by (23.7%), (7.9%), (1.3%) and (0.2%). None of the following protozoa were detected: , , , . , or . As chimpanzees and gorillas are genetically close to humans, it is important to monitor them frequently against different pathogens to protect these endangered species and to assess potential zoonotic transmissions to humans.
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http://dx.doi.org/10.3390/pathogens10030280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001678PMC
March 2021

Emergence and outcomes of the SARS-CoV-2 'Marseille-4' variant.

Int J Infect Dis 2021 Mar 27;106:228-236. Epub 2021 Mar 27.

IHU Méditerranée Infection, Marseille, France; Microbes Evolution Phylogeny and Infections (MEPHI), Aix-Marseille Université, Marseille, France. Electronic address:

Background: In Marseille, France, following a first severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak in March-May 2020, a second epidemic phase occurred from June, involving 10 new variants. The Marseille-4 variant caused an epidemic that started in August and is still ongoing.

Methods: The 1038 SARS-CoV-2 whole genome sequences obtained in our laboratory by next-generation sequencing with Illumina technology were analysed using Nextclade and nextstrain/ncov pipelines and IQ-TREE. A Marseille-4-specific qPCR assay was implemented. Demographic and clinical features were compared between patients with the Marseille-4 variant and those with earlier strains.

Results: Marseille-4 harbours 13 hallmark mutations. One leads to an S477N substitution in the receptor binding domain of the spike protein targeted by current vaccines. Using a specific qPCR, it was observed that Marseille-4 caused 12-100% of SARS-CoV-2 infections in Marseille from September 2020, being involved in 2106 diagnoses. This variant was more frequently associated with hypoxemia than were clade 20A strains before May 2020. It caused a re-infection in 11 patients diagnosed with different SARS-CoV-2 strains before June 2020, suggesting either short-term protective immunity or a lack of cross-immunity.

Conclusions: Marseille-4 should be considered as a major SARS-CoV-2 variant. Its sudden appearance points towards an animal reservoir, possibly mink. The protective role of past exposure and current vaccines against this variant should be evaluated.
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http://dx.doi.org/10.1016/j.ijid.2021.03.068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997945PMC
March 2021

Running after ghosts: are dead bacteria the dark matter of the human gut microbiota?

Gut Microbes 2021 Jan-Dec;13(1):1-12

IHU Méditerranée Infection, Marseille, France.

The human gut microbiota has been explored by a wide range of culture-dependent and culture-independent methods, revealing that many microbes remain uncharacterized and uncultured. In this work, we aimed to confirm the hypothesis that some of the species present in the human gut microbiota remain uncultured not because of culture limitations, but because all members of such species are dead before reaching the end of the gastro-intestinal tract.We evaluate this phenomenon by studying the microbial viability and culturability of the human gut microbiota from the fresh fecal materials of eight healthy adults. For the first time, we applied fluorescence-activated cell sorting (FACS) combined with 16S metagenomics analysis and microbial culturomics.We identified a total of 1,020 bacterial OTUs and 495 bacterial isolates through metagenomics and culturomics, respectively. Among the FACS metagenomics results, only 735 bacterial OTUs were alive, comprising on average 42% of known species and 87% of relative abundance per individual. The remaining uncultured bacteria were rare, dead, or injured.Our strategy allowed us to shed light on the dark matter of the human gut microbiota and revealed that both metagenomics and culturomics approaches are needed for greater insight into the diversity and richness of bacteria in the human gut microbiota. Further work on culture is needed to enhance the repertoire of cultured gut bacteria by targeting low abundance bacteria and optimizing anaerobic sample conditioning and processing to preserve the viability of bacteria.
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http://dx.doi.org/10.1080/19490976.2021.1897208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993147PMC
March 2021

Potential zoonotic pathogens hosted by endangered bonobos.

Sci Rep 2021 Mar 18;11(1):6331. Epub 2021 Mar 18.

Aix Marseille Univ, IRD, AP-HM, MEPHI, IHU-Méditerranée Infection, Marseille, France.

Few publications, often limited to one specific pathogen, have studied bonobos (Pan paniscus), our closest living relatives, as possible reservoirs of certain human infectious agents. Here, 91 stool samples from semicaptive bonobos and bonobos reintroduced in the wild, in the Democratic Republic of the Congo, were screened for different infectious agents: viruses, bacteria and parasites. We showed the presence of potentially zoonotic viral, bacterial or parasitic agents in stool samples, sometimes coinfecting the same individuals. A high prevalence of Human mastadenoviruses (HAdV-C, HAdV-B, HAdV-E) was observed. Encephalomyocarditis viruses were identified in semicaptive bonobos, although identified genotypes were different from those identified in the previous fatal myocarditis epidemic at the same site in 2009. Non-pallidum Treponema spp. including symbiotic T. succinifaciens, T. berlinense and several potential new species with unknown pathogenicity were identified. We detected DNA of non-tuberculosis Mycobacterium spp., Acinetobacter spp., Salmonella spp. as well as pathogenic Leptospira interrogans. Zoonotic parasites such as Taenia solium and Strongyloides stercoralis were predominantly present in wild bonobos, while Giardia lamblia was found only in bonobos in contact with humans, suggesting a possible exchange. One third of bonobos carried Oesophagostomum spp., particularly zoonotic O. stephanostomum and O. bifurcum-like species, as well as other uncharacterized Nematoda. Trypanosoma theileri has been identified in semicaptive bonobos. Pathogens typically known to be transmitted sexually were not identified. We present here the results of a reasonably-sized screening study detecting DNA/RNA sequence evidence of potentially pathogenic viruses and microorganisms in bonobo based on a noninvasive sampling method (feces) and focused PCR diagnostics.
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http://dx.doi.org/10.1038/s41598-021-85849-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973442PMC
March 2021

Planarians (Platyhelminthes)-An Emerging Model Organism for Investigating Innate Immune Mechanisms.

Front Cell Infect Microbiol 2021 1;11:619081. Epub 2021 Mar 1.

Institut Hospitalo-Universitaire-Méditerranée-Infection, Marseille, France.

An organism responds to the invading pathogens such as bacteria, viruses, protozoans, and fungi by engaging innate and adaptive immune system, which functions by activating various signal transduction pathways. As invertebrate organisms (such as sponges, worms, cnidarians, molluscs, crustaceans, insects, and echinoderms) are devoid of an adaptive immune system, and their defense mechanisms solely rely on innate immune system components. Investigating the immune response in such organisms helps to elucidate the immune mechanisms that vertebrates have inherited or evolved from invertebrates. Planarians are non-parasitic invertebrates from the phylum Platyhelminthes and are being investigated for several decades for understanding the whole-body regeneration process. However, recent findings have emerged planarians as a useful model for studying innate immunity as they are resistant to a broad spectrum of bacteria. This review intends to highlight the research findings on various antimicrobial resistance genes, signaling pathways involved in innate immune recognition, immune-related memory and immune cells in planarian flatworms.
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http://dx.doi.org/10.3389/fcimb.2021.619081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958881PMC
March 2021

Combination of Hydroxychloroquine Plus Azithromycin As Potential Treatment for COVID-19 Patients: Safety Profile, Drug Interactions, and Management of Toxicity.

Microb Drug Resist 2021 Mar;27(3):281-290

Service de Pharmacie, Hôpital de la Timone, APHM, Marseille, France.

The coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2, has recently emerged worldwide. In this context, there is an urgent need to identify safe and effective therapeutic strategies for treatment of such highly contagious disease. We recently reported promising results of combining hydroxychloroquine and azithromycin as an early treatment option. Although ongoing clinical trials are challenging the efficacy of this combination, many clinicians claim the authorization to or have already begun to use it to treat COVID-19 patients worldwide. The aim of this article is to share pharmacology considerations contributing to the rationale of this combination, and to provide safety information to prevent toxicity and drug-drug interactions, based on available evidence.
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http://dx.doi.org/10.1089/mdr.2020.0232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987362PMC
March 2021

Hydroxychloroquine + azithromycin treatment in elderly patients.

Int J Antimicrob Agents 2021 Apr 11;57(4):106313. Epub 2021 Mar 11.

IHU-Méditerranée Infection, Marseille, France; Aix-Marseille Univ., IRD, APHM, MEPHI, Marseille, France.

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http://dx.doi.org/10.1016/j.ijantimicag.2021.106313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948678PMC
April 2021

Sputum proteomic analysis for distinguishing between pulmonary tuberculosis and non-tuberculosis using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS): preliminary results.

Clin Microbiol Infect 2021 Mar 9. Epub 2021 Mar 9.

Aix Marseille Université, IRD, AP-HM, SSA, VITROME, Marseille, France; IHU-Méditerranée Infection, Marseille, France. Electronic address:

Objectives: The aim was to evaluate the feasibility and diagnostic contribution of protein profiling using matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) applied to sputum to diagnose pulmonary tuberculosis.

Methods: Sputum samples collected from patients suspected of having pulmonary tuberculosis were analysed using MALDI-TOF MS. Using the differentially expressed protein peaks, we compared three groups of patients, including those with confirmed pulmonary tuberculosis (PTB), those without tuberculosis but with a lower respiratory tract infection (non-TB LRTI) and those without tuberculosis and without an LRTI (non-TB controls).

Results: A total of 102 patients included 35 PTB, 36 non-TB LRTI and 31 non-TB controls. The model differentiated between the PTB patients and the non-TB controls using the 25 most differentially expressed protein peaks, with a sensitivity of 97%, 95% CI 85-100%, and a specificity of 77%, 95% CI 59-90%. The model distinguished the PTB patients from the non-TB LRTI patients using the ten most differentially expressed protein peaks, with a sensitivity of 80%, 95% CI 63-92%, and a specificity of 89%, 95% CI 74-97%. We observed that the negative predictive value of MALDI-TOF MS sputum analysis was higher (96%, 95% CI 80-100%) than that of direct sputum microscopic examination and sputum culture (78%, 95% CI 62-89%) for non-TB controls. When MALDI-TOF MS sputum analysis and direct microscopic examination were combined, the negative predictive value reached 94%, 95% CI 80-99%, for non-TB LRTI patients.

Discussion: These results suggest that MALDI-TOF MS sputum analysis coupled with microscopic examination could be used as a screening tool for diagnosing pulmonary TB.
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http://dx.doi.org/10.1016/j.cmi.2021.02.031DOI Listing
March 2021

Sunbathing, a possible risk factor of murine typhus infection in Greece.

PLoS Negl Trop Dis 2021 Mar 12;15(3):e0009186. Epub 2021 Mar 12.

Laboratory of Medical Microbiology, Hellenic Pasteur Institute, Athens, Greece.

Background: There are few studies about the presence of murine typhus in Greece. Our objective was to conduct a large scale retrospective investigation to determine the clinical and epidemiological features of patients diagnosed with murine typhus in Greece.

Methodology/principal Findings: From 2012 to 2019 serum samples from hospitalized patients and outpatients throughout Greece suspected for murine typhus infection were tested by immunofluorescence assay for Rickettsia typhi. Immunofluorescence positive samples obtained since 2016 were also tested by qPCR targeting R. typhi. Clinical and epidemiological data were retrospectively collected for the patients with confirmed murine typhus. Overall, we tested 5,365 different patients and, in total, 174 patients from all geographic regions of Greece were diagnosed with murine typhus. The most frequently reported sign or symptom was fever (89%), followed by headache (84%) and rash (81%). The classical triad of fever, headache, and rash was present in 72% of patients during their illness. Severe infections with complications including acute renal failure or septic shock were not recorded. The majority of cases (81%) occurred during May-October and peaked in June and September. Most of patients (81%) infected in Athens, recalled that their only activity the last weeks before symptoms onset was swimming on the beach and 59% of them also reported an insect bite while sunbathing.

Conclusions/significance: Our results may reflect the reemergence of murine typhus in Greece and we highlight the importance of awareness of this difficult-to-recognize undifferentiated febrile illness.
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http://dx.doi.org/10.1371/journal.pntd.0009186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990230PMC
March 2021

Clinical evidence of the role of Methanobrevibacter smithii in severe acute malnutrition.

Sci Rep 2021 Mar 8;11(1):5426. Epub 2021 Mar 8.

Aix Marseille Univ, IRD, APHM, MEPHI, 19-21 Boulevard Jean Moulin, 13005, Marseille, France.

Gut microbial dysbiosis has been shown to be an instrumental factor in severe acute malnutrition (SAM) and particularly, the absence of Methanobrevibacter smithii, a key player in energy harvest. Nevertheless, it remains unknown whether this absence reflects an immaturity or a loss of the microbiota. In order to assess that, we performed a case-control study in Mali using a propensity score weighting approach. The presence of M. smithii was tested using quantitative PCR on faeces collected from SAM children at inclusion and at discharge when possible or at day 15 for controls. M. smithii was highly significantly associated with the absence of SAM, detected in 40.9% controls but only in 4.2% cases (p < 0.0001). The predictive positive value for detection of M. smithii gradually increased with age in controls while decreasing in cases. Among children providing two samples with a negative first sample, no SAM children became positive, while this proportion was 2/4 in controls (p = 0.0015). This data suggests that gut dysbiosis in SAM is not an immaturity but rather features a loss of M. smithii. The addition of M. smithii as a probiotic may thus represent an important addition to therapeutic approaches to restore gut symbiosis.
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http://dx.doi.org/10.1038/s41598-021-84641-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940396PMC
March 2021

New Insights Into the Physiopathology of COVID-19: SARS-CoV-2-Associated Gastrointestinal Illness.

Front Med (Lausanne) 2021 18;8:640073. Epub 2021 Feb 18.

Aix-Marseille University, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France.

Although SARS-CoV-2 is considered a lung-tropic virus that infects the respiratory tract through binding to the ACE2 cell-surface molecules present on alveolar lungs epithelial cells, gastrointestinal symptoms have been frequently reported in COVID-19 patients. What can be considered an apparent paradox is that these symptoms (e.g., diarrhea), sometimes precede the development of respiratory tract illness as if the breathing apparatus was not its first target during viral dissemination. Recently, evidence was reported that the gut is an active site of replication for SARS-CoV-2. This replication mainly occurs in mature enterocytes expressing the ACE2 viral receptor and TMPRSS4 protease. In this review we question how SARS-CoV-2 can cause intestinal disturbances, whether there are pneumocyte-tropic, enterocyte-tropic and/or dual tropic strains of SARS-CoV-2. We examine two major models: first, that of a virus directly causing damage locally (e.g., by inducing apoptosis of infected enterocytes); secondly, that of indirect effect of the virus (e.g., by inducing changes in the composition of the gut microbiota followed by the induction of an inflammatory process), and suggest that both situations probably occur simultaneously in COVID-19 patients. We eventually discuss the consequences of the virus replication in brush border of intestine on long-distance damages affecting other tissues/organs, particularly lungs.
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http://dx.doi.org/10.3389/fmed.2021.640073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930624PMC
February 2021

COVID-19 re-infection.

Eur J Clin Invest 2021 May 17;51(5):e13537. Epub 2021 Mar 17.

IRD, APHM, Aix-Marseille University, MEPHI, Marseille, France.

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http://dx.doi.org/10.1111/eci.13537DOI Listing
May 2021

Automated Western immunoblotting detection of anti-SARS-CoV-2 serum antibodies.

Eur J Clin Microbiol Infect Dis 2021 Mar 3. Epub 2021 Mar 3.

IHU-Méditerranée Infection, 19-21 Boulevard Jean Moulin, 13005, Marseille, France.

ELISA and chemiluminescence serological assays for COVID-19 are currently incorporating only one or two SARS-CoV-2 antigens. We developed an automated Western immunoblotting as a complementary serologic assay for COVID-19. The Jess Simple Western system, an automated capillary-based assay, was used, incorporating an inactivated SARS-CoV-2 lineage 20a strain as the source of antigen, and total immunoglobulins (IgG, IgM, IgA) detection. In total, 602 sera were tested including 223 from RT-PCR-confirmed COVID-19 patients, 76 from patients diagnosed with seasonal HCoVs and 303 from coronavirus-negative control sera. We also compared this assay with the EUROIMMUN® SARS-CoV-2 IgG ELISA kit. Among 223 sera obtained from RT-PCR-confirmed COVID-19 patients, 180/223 (81%) exhibited reactivity against the nucleocapsid and 70/223 (31%) against the spike protein. Nucleocapsid reactivity was further detected in 9/76 (14%) samples collected from patients diagnosed with seasonal HCoVs and in 15/303 (5%) coronavirus-negative control samples. In the subset of sera collected more than 2 weeks after the onset of symptoms, the sensitivity was 94% and the specificity 93%, the latter value probably reflecting cross-reactivity of SARS-CoV-2 with other coronaviruses. The automated Western immunoblotting presented a substantial agreement (90%) with the compared ELISA (Cohen's Kappa=0.64). Automated Western immunoblotting may be used as a second line test to monitor exposure of people to HCoVs including SARS-CoV-2.
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http://dx.doi.org/10.1007/s10096-021-04203-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928199PMC
March 2021

Can ACE2 Receptor Polymorphism Predict Species Susceptibility to SARS-CoV-2?

Front Public Health 2020;8:608765. Epub 2021 Feb 10.

Aix-Marseille Université, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France.

A novel severe acute respiratory syndrome coronavirus, SARS-CoV-2, emerged in China in December 2019 and spread worldwide, causing more than 1.3 million deaths in 11 months. Similar to the human SARS-CoV, SARS-CoV-2 shares strong sequence homologies with a sarbecovirus circulating in bats. Because bats are expected to be able to transmit their coronaviruses to intermediate animal hosts that in turn are a source of viruses able to cross species barriers and infect humans (so-called spillover model), the identification of an intermediate animal reservoir was the subject of intense researches. It was claimed that a reptile () was the intermediate host. This hypothesis was quickly ruled out and replaced by the pangolin () hypothesis. Yet, pangolin was also recently exonerated from SARS-CoV-2 transmission to humans, leaving other animal species as presumed guilty. Guided by the spillover model, several laboratories investigated the species polymorphism of the angiotensin I converting enzyme 2 (ACE2) to find the best fits with the SARS-CoV-2 spike receptor-binding site. Following the same strategy, we used multi-sequence alignment, 3-D structure analysis, and electrostatic potential surface generation of ACE2 variants to predict their binding capacity to SARS-CoV-2. We report evidence that such simple investigation is a powerful tool to quickly screen which species are potentially susceptible to SARS-CoV-2. However, possible receptor binding does not necessarily lead to successful replication in host. Therefore, we also discuss here the limitations of these approaches in our quest on the origins of COVID-19 pandemic.
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http://dx.doi.org/10.3389/fpubh.2020.608765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902720PMC
March 2021

Multispacer sequence typing of Coxiella burnetii from milk and hard tick samples from ruminant farms in Lebanon.

Vet Ital 2020 Dec 1;56(4):289-296. Epub 2020 Dec 1.

Lebanese University, Doctoral School of sciences and Technology, Beirut, Lebanon.

his study was carried out to detect and characterize Coxiella burnetii in ruminant milk samples and in different tick species from seropositive farms in four Lebanese regions. Milk and tick samples were screened for C. burnetii presence by quantitative real-time PCR (qPCR) targeting IS1111 region followed by multispacer sequence typing (MST). The overall positive percentages of 9.6% (27/282) and 95.45% (84/88) for C. burnetii were recorded in ruminant milk and tick samples, respectively. In detail, the C. burnetii DNA was recorded in 52/54 (96.3%) of Rhipicephalus annulatus, 20/21 (95.24%) of Rhipicephalus turanicus, 6/6 (100%) of Hyalomma anatolicum, 5/6 (83.3%) of Rhipicephalus sanguineus and 1/1 of Rhipicephalus bursa. After genotyping of some IS1111-positive samples (17/111), different MST genotypes were identified. Out of 15 positive ticks, 10 were infected with MST2 genotype, 4 were infected with MST7 genotype and 1 was infected with MST57. Moreover, genotypes MST20 and MST58 were found in one cow and one goat milk samples, respectively. The present study confirmed the high genetic diversity of C. burnetii in Lebanon.
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http://dx.doi.org/10.12834/VetIt.1799.13290.1DOI Listing
December 2020

Low blood zinc concentrations in patients with poor clinical outcome during SARS-CoV-2 infection: is there a need to supplement with zinc COVID-19 patients?

J Microbiol Immunol Infect 2021 Feb 13. Epub 2021 Feb 13.

IHU-Méditerranée Infection, Marseille, France; Aix Marseille Univ., IRD, AP-HM, MEPHI, Marseille, France. Electronic address:

Among 275 patients with COVID-19, we found that median blood zinc level was significantly lower in patients with poor clinical outcome (N = 75) as compared to patients with good clinical outcome (N = 200) (840 μg/L versus 970 μg/L; p < 0.0001), suggesting that zinc supplementation could be useful for patients with severe COVID-19.
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http://dx.doi.org/10.1016/j.jmii.2021.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881284PMC
February 2021