Anti-SARS-CoV-2 (COVID-19) vaccination efficacy in patients with severe neuromuscular diseases.

INTRODUCTION: Patients with severe neuromuscular disease (sNMD) are considered at high risk of severe COVID-19. Muscle tissue is often replaced by fibroadipose tissue in these diseases whereas the new mRNA-based vaccines are injected intramuscularly. We aimed at evaluating the efficacy of two injections associated with a booster injection of mRNA vaccine in these patients. METHODS: We performed an observational, prospective, single-centre study to investigate the level of anti-S antibodies (Abs) and their neutralization activity at weeks 6 (W6) and 24 (W24) after two injections of mRNA-1273 vaccine and at weeks 12 (BW12) and 29 (BW29) after a booster injection of BNT162b2 vaccine in patients with sNMD. RESULTS: Thirty-three patients with sNMD were included. At W6, 30 patients (90.1%) showed a protective serum level of specific anti-S Abs with a strong neutralization capacity. We observed a decline over time: only 12 patients (36.3%) retained anti-S Abs levels considered as protective at W24. The neutralization activity remained above the cut off in 23 (69.7%). The booster vaccination restored robust neutralization activity for all analysed 22 patients (100%) at BW12, which was maintained without any significant drop at BW29 (16). No severe adverse event was reported in this cohort and none of the 33 patients developed symptomatic COVID-19 over one year. CONCLUSIONS: This study provides evidence that most sNMD patients receiving two injections of COVID-19 mRNA-based vaccines develop a strong humoral response after vaccination. A decline over time was observed but a single booster injection restores a long-term immunity. Moreover, no safety issues were observed.

A Multiplex PCR and DNA-Sequencing Workflow on Serum for the Diagnosis and Species Identification for Invasive Aspergillosis and Mucormycosis.

There has been significant increase in the use of molecular tools for the diagnosis of invasive aspergillosis (IA) and mucormycosis. However, their range of detection may be too limited as species diversity and coinfections are increasing. Here, we aimed to evaluate a molecular workflow based on a new multiplex PCR assay detecting the whole Aspergillus genus and the Mucorales order followed by a species-specific PCR or a DNA-sequencing approach for IA and/or mucormycosis diagnosis and species identification on serum. Performances of the MycoGENIE Aspergillus spp./Mucorales spp. duplex PCR kit were analyzed on a broad range of fungal strains and on sera from high-risk patients prospectively over a 12-month period. The kit allowed the detection of nine Aspergillus species and 10 Mucorales (eight genera) strains assessed. No cross-reactions between the two targets were observed. Sera from 744 patients were prospectively analyzed, including 35 IA, 16 mucormycosis, and four coinfections. Sensitivity varies from 85.7% (18/21) in probable/proven IA to 28.6% (4/14) in COVID-19-associated pulmonary aspergillosis. PCR-positive samples corresponded to 21 A. fumigatus, one A. flavus, and one A. nidulans infections. All the disseminated mucormycosis were positive in serum (14/14), including the four Aspergillus coinfections, but sensitivity fell to 33.3% (2/6) in localized forms. DNA sequencing allowed Mucorales identification in serum in 15 patients. Remarkably, the most frequent species identified was Rhizomucor pusillus (eight cases), whereas it is barely found in fungal culture. This molecular workflow is a promising approach to improve IA and mucormycosis diagnosis and epidemiology.

The influenza virus, SARS-CoV-2, and the airways: Clarification for the otorhinolaryngologist.

The influenza virus and SARS-CoV-2 cause trivial upper and severe lower respiratory infections (Influenza virus 290,000 to 650,000 deaths/year). These viruses come into contact with the airways either by direct projection, by secondary inhalation of airborne droplets, or by handling (fomites). The objective of this article is to clarify the mechanisms of production and penetration of droplets of secretions emitted during all expiratory phenomena likely to transport these viruses and come into contact with the respiratory mucosa. The droplets>5µm follow the laws of ballistics, those<5µm follow Brownian motion and remain suspended in the air. The aerosols of droplets are very heterogeneous whether the subject is healthy or sick. During an infectious period, not all droplets contain viral RNA. If these RNAs are detectable around patients, on surfaces, and in the ambient air at variable distances according to the studies (from 0.5m to beyond the patient's room), this is without prejudice to the infectious nature (viability) of the virus and the minimum infectious dose. There is a time lag between the patient's infectious period and that of RNA detection for both viruses. Subsequently, the inhaled particles must meet the laws of fluid dynamics (filtration) to settle in the respiratory tree. All of this partly explains the contagiousness and the clinical expression of these two viruses from the olfactory cleft to the alveoli.

Clinical and biological features of enteroviral meningitis among adults and children and factors associated with severity and length of stay.

BACKGROUND: Enterovirus (EV) meningitis is the most common form of meningitis. Clinical and biological manifestations may be non-specific, leading to prolonged and costly investigations. OBJECTIVES: To determine the different aspects of EV meningitis and the variables associated with length of stay (LOS) in hospital independently of patients' age. STUDY DESIGN: Single center retrospective study of all EV PCR positive CSF samples during 3.5 years in Bordeaux University Hospital, France. RESULTS: 172 patients were included. 65 were under 3 years old and 49 over 18 years old. 10% of patients had severe forms of the disease. 47 patients (27.3%) had normal CSF count and in 63 patients (36.6%) polynuclear cells predominated in CSF. Procalcitonin, Hoens' score or PCR in stool samples appeared as good markers for enteroviral diagnosis. Time elapsed before PCR results was associated with LOS (p = .002) and should help in limiting investigations in case of aseptic meningitis. CONCLUSION: Rapid availability of EV PCR reduces LOS for patients and contributes to diminish unnecessary procedures and further tests.

Gigabar spherical shock generation on the OMEGA laser.

This Letter presents the first experimental demonstration of the capability to launch shocks of several-hundred Mbar in spherical targets--a milestone for shock ignition [R. Betti et al., Phys. Rev. Lett. 98, 155001 (2007)]. Using the temporal delay between the launching of the strong shock at the outer surface of the spherical target and the time when the shock converges at the center, the shock-launching pressure can be inferred using radiation-hydrodynamic simulations. Peak ablation pressures exceeding 300 Mbar are inferred at absorbed laser intensities of ∼3×10(15) W/cm2. The shock strength is shown to be significantly enhanced by the coupling of suprathermal electrons with a total converted energy of up to 8% of the incident laser energy. At the end of the laser pulse, the shock pressure is estimated to exceed ∼1 Gbar because of convergence effects.

Epidemic of complicated mumps in previously vaccinated young adults in the South-West of France.

OBJECTIVE: We report the features and diagnosis of complicated mumps in previously vaccinated young adults. PATIENTS AND METHODS: We retrospectively studied 7 cases of complicated mumps managed during 1 year at the Bordeaux University Hospital. The diagnosis was suggested by the clinical presentation and confirmed using specific RT-PCR. RESULTS: Five cases of meningitis, 1 of orchitis, and 1 of unilateral hearing impairment were identified. Each of the 7 patients had been previously vaccinated with MMR, 4 had received 2 doses of this vaccine. Blood tests revealed high rates of IgG antibodies, usually considered as sufficient for immunological protection, and every patient had at least 1 positive RT-PCR test for mumps. CONCLUSION: Outbreaks of complicated mumps may still occur despite a broad coverage of MMR vaccination. The clinical presentation suggested mumps but the final diagnosis could only be confirmed by genomic detection of the virus. Unusual viral strains with increased neurovirulence, insufficient population coverage associated with immunity decrease over time may explain outbreaks of complicated mumps. A full vaccine scheme of contact people or a third injection of vaccine for previously vaccinated people who are at risk of developing mumps are required to prevent further spreading of the disease during the outbreak.

PDZ domain-mediated protein interactions: therapeutic targets in neurological disorders.

Protein-protein interactions are critical for cellular functioning, and their deregulation is involved in several diseases. Targeting these protein interacting domains could be a promising approach in drug designing. One such domain, the PDZ domain is encoded by several proteins of the nervous system in particular at the postsynaptic density site of neurons where they contribute to signal transduction pathways and neurotransmission. Since PDZ domains have well-defined binding sites, often corresponding to short amino acid motifs at the C-termini of target partner proteins, they provide promising targets for drug discovery. Viruses are art master in manipulating the signaling machinery of the cell they infect. Some of them such as rabies virus which promotes neuron survival by disrupting peculiar PDZ complexes can serve as a source of inspiration for the design of new neuroprotective drugs. This review highlights PDZ-mediated protein interactions in nervous system and their therapeutic potential.

The Alabama Coalition for a Healthier Black belt: a proof of concept project.

The Alabama Coalition for a Healthier Black was a demonstration of concept project. This paper is a descriptive and qualitative overview of this 2.5 year project. Limited key project results are reported here. Located in the rural Black Belt region of Alabama this coalition had several key aims: to develop a collaboration between primary care and mental health care through co-location of services; use of video-conferencing capability to provide mental health services more efficiently; enhanced training in rural healthcare; and development of stigma reduction campaigns along with other coalition partner specific initiatives. Co-location and telepsychiatry implementation produced the major challenges and resulting adaptations to original aims. Despite many challenges these new service patterns were put into place and appear to be sustainable.

Preemptive therapy versus valgancyclovir prophylaxis in cytomegalovirus-positive kidney transplant recipients receiving antithymocyte globulin induction.

International consensus guidelines on the management of cytomegalovirus (CMV) infections in kidney transplantation recommend the use of universal prophylaxis over preemptive therapy for the highest risk kidney transplant recipients (KTR), namely donor+/recipient - CMV serostatus. However, no universal recommendations have been made for R+ KTR undergoing antithymocyte globulin (ATG) induction. In this retrospective study, we compared 1-year outcomes among 24 R+ KTR who received 3 months of valgancyclovir prophylaxis with 72 R+ KTR who were subjected to a preemptive strategy. All subjects received ATG induction. The incidence of CMV infection was significantly higher among the preemptive subjects versus the prophylaxis group (78% versus 38%, respectively; P = .0003), whereas the incidence of CMV disease was low and did not differ significantly between the cohorts (8% versus 7% respectively, P = .8). Late-onset CMV infections were only observed in the prophylaxis group (25% versus 0%, P = .0001). Finally, the rate of opportunistic infections, acute rejection episodes, and graft/patient survivals at 1 year were also similar between the two groups. In light of this study, preemptive therapy and universal prophylaxis were almost equally effective to prevent CMV infection among R+ KTR receiving ATG induction.

Adenovirus infections in Bordeaux University Hospital 2008-2010: clinical and virological features.

BACKGROUND: Transversal epidemiological data on adenovirus infections in a hospital setting, including both immuno-competent and transplanted patients, are limited and rarely contain the application of molecular virology. OBJECTIVES: To describe the clinical characteristics and molecular epidemiology of adenovirus infections in Bordeaux University Hospital from 2008 to 2010 (clinical data, viral load and adenovirus species distribution). STUDY DESIGN: Adenovirus DNA quantification (qPCR) and typing (sequencing of hexon and protein VI genes and protein VI polymerase chain reaction (PCR) product analysis) were applied retrospectively to 215 clinical samples from 105 adenovirus-infected patients (2008-2010, Bordeaux University Hospital). Clinical data were recovered and analysed for 73 children and 25 adults. RESULTS: Viral loads were measured in stools, upper and lower respiratory fluids, blood, urine and digestive tract biopsies; the highest values were observed in stools and respiratory samples. Stool viral loads were comparable whatever the immune status. Adenovirus was typed in 57 patients: species Human adenovirus (HAdV) C dominated (n=36), followed by B (n=15), F (n=5) and D (n=1). We could demonstrate no association between HAdV species and load or clinical severity (observed in most patients). In the immuno-compromised, in contrast to immuno-competent patients, adenovirus infections presented no seasonal variation. Co-infections were frequent: mostly bacterial in immuno-competent children (33%) and viral in immuno-compromised people (34%). CONCLUSIONS: The species HAdV C dominates the local ecology, in both respiratory and digestive tract infections, independently of the patient's immune status. Adenovirus infections, often associated with co-infection of bacterial or viral agents, frequently lead to severe clinical consequences in hospital patients.

High incidence of anticytomegalovirus drug resistance among D+R- kidney transplant recipients receiving preemptive therapy.

Anti-cytomegalovirus (CMV) prophylaxis is recommended in D+R- kidney transplant recipients (KTR), but is associated with a theoretical increased risk of developing anti-CMV drug resistance. This hypothesis was retested in this study by comparing 32 D+R- KTR who received 3 months prophylaxis (valganciclovir) with 80 D+R- KTR who received preemptive treatment. The incidence of CMV infections was higher in the preemptive group than in the prophylactic group (60% vs. 34%, respectively; p = 0.02). Treatment failure (i.e. a positive DNAemia 8 weeks after the initiation of anti-CMV treatment) was more frequent in the preemptive group (31% vs. 3% in the prophylactic group; p = 0.001). Similarly, anti-CMV drug resistance (UL97 or UL54 mutations) was also more frequent in the preemptive group (16% vs. 3% in the prophylactic group; p = 0.05). Antiviral treatment failures were associated with anti-CMV drug resistance (p = 0.0001). Patients with a CMV load over 5.25 log(10) copies/mL displayed the highest risk of developing anti-CMV drug resistance (OR = 16.91, p = 0.0008). Finally, the 1-year estimated glomerular filtration rate was reduced in patients with anti-CMV drug resistance (p = 0.02). In summary, preemptive therapy in D+R- KTR with high CMV loads and antiviral treatment failure was associated with a high incidence of anti-CMV drug resistance.

Latent viral infections of the nervous system: role of the host immune response.

Viruses that infect the nervous system may cause acute, chronic or latent infections. Despite the so-called immunoprivileged status of the nervous system, immunosurveillance plays an important role in the fate of viral infection of the brain. Herpes simplex virus 1 (HSV-1) persists in the nervous system for the life of the host with periodic stress induced reactivation that produces progeny viruses. Prevention of reactivation requires a complex interplay between virus neurons, and immune response. New evidence supports the view that CD8+T cells employing both lytic granule- and IFN-gamma-dependent effectors are essential in setting up and maintaining HSV-1 latency. HSV-1 infection of the nervous system can be seen as a parasitic invasion which leaves the individual at risk for subsequent reactivation and disease. The recent observation that herpes virus latency may confer protection against experimental bacterial infection suggests that unexpected symbiosis may exist between latent viruses and the infected nervous system of its host.

Oseltamivir susceptibility in south-western France during the 2007-8 and 2008-9 influenza epidemics and the ongoing influenza pandemic 2009.

The recent emergence of seasonal influenza A(H1N1) strains resistant to oseltamivir makes it necessary to monitoring carefully the susceptibility of human influenza viruses to neuraminidase inhibitors. We report the prevalence of the oseltamivir resistance among influenza A viruses circulating in south-western France over the past three years: seasonal influenza A(H1N1), seasonal influenza A(H3N2), and the influenza A(H1N1)v viruses associated with the ongoing 2009 pandemic. The main result of the study is the absence of oseltamivir resistance in the pandemic H1N1 strains studied so far (n=129).

Immune evasion, a critical strategy for rabies virus.

It is intriguing to note that RABV progression is interrupted neither by destruction of the infected neuron nor by the immune response. Thus, it is likely that RABV has developed a subversive strategy to avoid functional neuron impairment, which compromises the infectious cycle. Rabies virus neuroinvasiveness results from two factors: not only does neurotropic rabies virus avoid inducing neuronal cell death, but also 'protective' T cells that migrate into the infected nervous system are killed by apoptosis or inactivated, as a result of the overexpression of immunosubversive molecules such as FasL, HLA-G or B7-H1 in the infected nervous system. This suggests that the preservation of the neuronal network and the destruction of T cells that invade the nervous system in response to the infection are crucial events for rabies virus neuroinvasion and for transmission of rabies virus to another animal. Implications of these findings for rabies treatment are discussed.

High CRMP2 expression in peripheral T lymphocytes is associated with recruitment to the brain during virus-induced neuroinflammation.

Collapsin Response Mediator Protein (CRMP)-2 is involved in T-cell polarization and migration. To address the role of CRMP2 in neuroinflammation, we analyzed its involvement in lymphocyte recruitment to the central nervous system in mouse infected with neurotropic and non-neurotropic virus strains (RABV, CDV). A sub-population of early-activated CD69+CD3+ T lymphocytes highly expressing CRMP2 (CRMP2hi) peaked in the blood, lymph nodes and brain of mice infected with neurotropic viruses, and correlated with severity of disease. They displayed high migratory properties reduced by CRMP2 blocking antibody. These data point out the potential use of CRMP2 as a peripheral indicator of neuroinflammation.

Improvement of progressive multifocal leukoencephalopathy after cidofovir therapy in a patient with a destructive polyarthritis.

The human neurotropic JC virus (JCV) is responsible for progressive multifocal leukoencephalopathy (PML), an infectious demyelinating brain disease with major morbidity and mortality, usually refractory to treatment. We describe a PML in a 67-year-old woman with a destructive polyarthritis associated with anti-JO1 antibodies treated with corticosteroids. Although glucocorticoid therapy was maintained, administration of cidofovir improved the neurological condition. Our observation demonstrates the expanding clinical importance of JCV in systemic rheumatic diseases, particularly when immunosuppressive agents are used, and neurological symptoms or white matter changes on central nervous system imaging should arouse the suspicion of PML.