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Although uncommon, Epstein-Barr virus-related neurological disorders represent the seventh most frequent cause of infectious encephalitis in adults. The limited number of publications on EBV encephalitis mainly document isolated clinical cases. This study aimed to summarize published data on EBV encephalitis. A systematic literature search identified 97 EBV encephalitis cases. In the selected cases, EBV-related neurological disorders manifested as lymphocytic pleocytosis in the cerebrospinal fluid (CSF) with moderate hyperproteinorachia. The EBV PCR test was positive in 87% of the CSF samples, with wide-ranging viral loads. When encephalitis occurred in the context of past EBV infections, all of the EBV PCR tests on CSF samples were positive. On the contrary, negative EBV PCR tests on CSF samples occurred only in the context of primary infections. EBV PCR was rarely carried out on blood samples, contributing minimally to the diagnosis. For the treatment of EBV encephalitis, Aciclovir was used alone in 29% of cases, and in association with other drugs in 40% of cases. Ganciclovir (30%), corticoids (52%), and immunoglobulins (15%) were mainly used in association with other drugs. Cerebral imaging was abnormal in 69% of cases, mostly in the cerebellum and basal ganglia. This work highlights that the EBV PCR test on CSF samples is currently the main laboratory diagnostic test to diagnose EBV encephalitis. This diagnostic test is useful; however, it is imperfect. New complementary diagnostic tools, approved treatments, and standardized practices could improve patient management.

BackgroundEarly action by bystanders is particularly important for the survival of individuals in need of emergency care, especially those experiencing a cardiac arrest or an airway obstruction. However, only a few bystanders are willing to perform cardiopulmonary resuscitation. The use of a live video during emergency calls appears to have a positive effect on the number of cardiopulmonary resuscitations performed by bystanders. ObjectiveThe objective of this study is to propose and evaluate the relevance of a living lab methodology involving video calls in simulated life-threatening emergency situations. MethodsThe first study aimed at analyzing the process of dealing with out-of-hospital cardiac arrest at a dispatch center and identifying the needs of the dispatchers. The second study is a pretest of a living lab. The third study focuses on a living lab in which 16 situations of cardiac arrest and airway obstruction are simulated. The simulation includes both a live video and transmission of a video demonstration of emergency procedures. The measures focus on 3 areas: the impact of video tools, development of collaboration within the community, and evaluation of the method. ResultsThe results of the first study show that dispatchers have an interest in visualizing the scene with live video and in broadcasting a live demonstration video when possible. The initial results also show that collaboration within the community is enhanced by the shared simulation and debriefing experiences, clarifying regulation procedures, and improving communication. Finally, an iterative development based on the lessons learned, expectations, and constraints of each previous study promotes the existence of a living lab that aims to determine the place of live video tools in the sequence of care performed by dispatchers. ConclusionsLiving labs offer the opportunity to grasp previously undetected insights and refine the use of the applications while potentially developing a sense of community among the stakeholders. International Registered Report Identifier (IRRID)DERR1-10.2196/40699

Objective Cognitive dysfunction in SLE is common, but clinical risk factors are poorly understood. This study aims to explore the associations of cognitive dysfunction in SLE with disease activity, organ damage, biomarkers and medications.Methods We performed cross-sectional cognitive assessment using a conventional neuropsychological test battery, with normative values derived from demographically matched healthy subjects. Endpoints included two binary definitions of cognitive dysfunction and seven individual cognitive domain scores. Clinical parameters included disease activity (SLEDAI-2K) and organ damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index). We performed regression analyses to determine associations between clinical parameters and cognitive endpoints.Results 89 patients with SLE were studied, with median age of 45 and disease duration of 15 years. Organ damage was significantly associated with severe cognitive dysfunction (OR 1.49, CI 1.01–2.22) and worse cognitive test performance in three of the seven individual cognitive domains. In contrast, no significant associations were found between SLEDAI-2K at the time of cognitive assessment and any cognitive endpoints on multivariate analysis. Higher time-adjusted mean SLEDAI-2K was associated with better verbal memory scores but had no significant associations with other cognitive endpoints. The presence of anti-dsDNA antibodies and high IFN gene signature were negatively associated with severe cognitive dysfunction; there were no significant associations with the other autoantibodies studied or any medications. Substance use was significantly associated with lower psychomotor speed. Only 8% of patients who had cognitive dysfunction on testing had been recognised by clinicians on their SDI score.Conclusions In SLE, cognitive dysfunction was positively associated with organ damage, but not associated with disease activity, and serological activity and high IFN signature were negatively associated. Cognitive dysfunction was poorly captured by clinicians. These findings have implications for preventative strategies addressing cognitive dysfunction in SLE.

Drug development in lupus has improved over the past 10 years but still lags behind that of other rheumatic disease areas. Assessment of prospective lupus therapies in clinical trials has proved challenging for reasons that are multifactorial including the heterogeneity of the disease, study design limitations and a lack of validated biomarkers which greatly impacts regulatory decision-making. Moreover, most composite outcome measures currently used in trials do not include patient-reported outcomes. Given these factors, the Addressing Lupus Pillars for Health Advancement Global Advisory Committee members who serve on the drug development team identified an opportunity to convene a meeting to facilitate information sharing on completed and existing outcome measure development efforts. This meeting report highlights information presented during the meeting as well as a discussion on how the lupus community may work together with regulatory agencies to simplify and standardise outcome measures to accelerate development of lupus therapeutics.

Although vasculo-protective effects of flavan-3-ols are widely accepted today, their impact on endothelial cell functions and molecular mechanisms of action involved is not completely understood. The aim of this study was to characterize the potential endothelium-protective effects of circulating epicatechin metabolites and to define underlying mechanisms of action by an integrated systems biology approach. Reduced leukocyte rolling over vascular endothelium was observed following epicatechin supplementation in a mouse model of inflammation. Integrative pathway analysis of transcriptome, miRNome and epigenome profiles of endothelial cells exposed to epicatechin metabolites revealed that by acting at these different levels of regulation, metabolites affect cellular pathways involved in endothelial permeability and interaction with immune cells. In-vitro experiments on endothelial cells confirmed that epicatechin metabolites reduce monocyte adhesion and their transendothelial migration. Altogether, our in-vivo and in-vitro results support the outcome of a systems biology based network analysis which suggests that epicatechin metabolites mediate their vasculoprotective effects through dynamic regulation of endothelial cell monocyte adhesion and permeability. This study illustrates complex and multimodal mechanisms of action by which epicatechin modulate endothelial cell integrity.

The Graduate Student Internships for Career Exploration (GSICE) program at the University of California, San Francisco (UCSF), offers structured training and hands-on experience through internships for a broad range of PhD-level careers. The GSICE program model was successfully replicated at the University of California, Davis (UC Davis). Here, we present outcome data for a total of 217 PhD students participating in the UCSF and UC Davis programs from 2010 to 2015 and 2014 to 2015, respectively. The internship programs at the two sites demonstrated comparable participation, internship completion rates, and overall outcomes. Using survey, focus group, and individual interview data, we find that the programs provide students with career development skills, while increasing students' confidence in career exploration and decision making. Internships, in particular, were perceived by students to increase their ability to discern a career area of choice and to increase confidence in pursuing that career. We present data showing that program participation does not change median time to degree and may help some trainees avoid "default postdocs." Our findings suggest important strategies for institutions developing internship programs for PhD students, namely: including a structured training component, allowing postgraduation internships, and providing a central organization point for internship programs.

ObjectiveAfrican Americans, East Asians, and Hispanics with systemic lupus erythematous (SLE) are more likely to develop lupus nephritis (LN) than are SLE patients of European descent. The etiology of this difference is not clear, and this study was undertaken to investigate how genetic variants might explain this effect.MethodsIn this cross-sectional study, 1244 SLE patients from multiethnic case collections were genotyped for 817,810 single-nucleotide polymorphisms (SNPs) across the genome. Continental genetic ancestry was estimated utilizing the program ADMIXTURE. Gene-based testing and pathway analysis was performed within each ethnic group and meta-analyzed across ethnicities. We also performed candidate SNP association tests with SNPs previously established as risk alleles for SLE, LN, and chronic kidney disease (CKD). Association testing and logistic regression models were performed with LN as the outcome, adjusted for continental ancestries, sex, disease duration, and age.ResultsWe studied 255 North European, 263 South European, 238 Hispanic, 224 African American and 264 East Asian SLE patients, of whom 606 had LN (48.7%). In genome-wide gene-based and candidate SNP analyses, we found distinct genes, pathways and established risk SNPs associated with LN for each ethnic group. Gene-based analyses showed significant associations between variation in ZNF546 (p = 1.0E-06), TRIM15 (p = 1.0E-06), and TRIMI0 (p = 1.0E-06) and LN among South Europeans, and TTC34 (p = 8.0E-06) was significantly associated with LN among Hispanics. The SNP rs8091180 in NFATC1 was associated with LN (OR 1.43, p = 3.3E-04) in the candidate SNP meta-analysis with the highest OR among African-Americans (OR 2.17, p = 0.0035).ConclusionDistinct genetic factors are associated with the risk of LN in SLE patients of different ethnicities. CKD risk alleles may play a role in the development of LN in addition to SLE-associated risk variants. These findings may further explain the clinical heterogeneity of LN risk and response to therapy observed between different ethnic groups.

Zoonotic emergence requires spillover from animals to humans, hence animal-human interactions. A lot has been emphasized on human intrusion into wild habitats (e.g., deforestation, hunting) and the development of agricultural and farming activities. However, the highly human-modified urban and peri-urban socio-ecosystems are also of great concern due to huge amounts of pet, domesticated and wild animals (e.g., birds, rodents and bats) that live in very close contact to very dense human populations. This adds to the existence of wet wildlife markets, urban parks and wastelands, zoos and even labs, where spillover from wildlife to humans may also occur. Furthermore, cities are transport hubs that form hotspots of import/export of living resources including animals, thus potentially promoting rapid and wide-scale spread of reservoir and vectors, hence pathogens, as well as pathogen admixture through viral recombination or bacterial plasmid exchanges. Finally, cities are deeply modified environments where living organisms, including reservoirs, vectors and pathogens, undergo strong selective pressures, thus opening the gate to evolutionary novelties, hence potential new infectious threats. As such, we believe urban socio-ecosystems should be paid more attention in terms of drivers of zoonotic emergence in humans needing adapted surveillance and mitigation. Accordingly, we propose and discuss several avenues of research and examples of actions that could be tested or generalized (e.g., focus on hotspots of emergence risks like informal settlements, wet markets or transport hubs; development of participative surveillance programs; shift towards inter-sectoral academic courses; massive investment into education and community information) in order to operationalize effective zoonotic surveillance. We advocate that this would allow ones to add emergence-preventive and early warning to usual outbreaks response strategies, thus significantly improving our collective ability to prevent zoonotic emergence and subsequent pandemics.

Rechenzentren (auch Datenzentren, data centres) werden in Zukunft knapp vier Prozent des gesamten schweizerischen Stromverbrauchs ausmachen. Ihr hoher Strombedarf und ihre enorme Wärmeerzeugung lassen es sinnvoll erscheinen, Rechenzentren in Regionen mit umweltfreundlicher Stromerzeugung oder kühlen Aussentemperaturen zu platzieren. Die Realität zeigt, dass insbesondere die USA als attraktiver Standort für den Bau von Rechenzentren gilt. Wird mit Cloud-Lösungen ausländischer Anbieter gearbeitet, macht es aus datenschutzrechtlicher Sicht durchaus Sinn, trotzdem Rechenzentren in der Schweiz zu nutzen. Um den negativen Umwelteinfluss dabei zu reduzieren, sind insbesondere die Kantone gefragt, gesetzgeberisch tätig zu werden und ihre Energiegesetze um verpflichtende Bestimmungen zur Abwärmenutzung und Energieeffizienz zu ergänzen. -- Les centres de données (ou data centers) représenteront à l'avenir près de quatre pour cent de la consommation totale d'électricité en Suisse. Au regard de leur besoin élevé en électricité et leur immense capacité de production de chaleur, il semble judicieux de les placer dans des régions où la production d'électricité est respectueuse de l'environnement ou dans des zones climatiquement froides. La pratique montre que les États-Unis sont particulièrement attrayants et appréciés pour la construction de tels centres. Si l'on travaille avec des solutions cloud de fournisseurs étrangers, il est préférable, du point de vue de la protection des données, de recourir malgré tout à des centres de données en Suisse. Afin de réduire l'impact négatif sur l'environnement, les cantons sont invités à légiférer et à compléter leurs lois sur l'énergie par des dispositions contraignantes sur l'utilisation des rejets thermiques et l'efficacité énergétique.

Objectives To evaluate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine acceptance among patients with rheumatic diseases (RMD). Methods All rheumatology patients attending a large suburban health network were invited to participate in an anonymized online survey. The primary outcome of interest was SARS-COV-2 vaccine acceptance. Results The mean (SD) age of respondents (n = 641) was 52.7 (15.1) years and 74.4% (n = 474) were female. Sixty-five percent were willing to have a SARS-COV-2 vaccine, while 34.4% were vaccine-hesitant (unwilling or undecided). On multivariate analysis, vaccine acceptance was associated with smoking (OR: 2.25 [95% CI: 1.22–4.15; p = .009]), history of malignancy (OR: 2.51 [95% CI: 1.19–5.26; p = .015]), influenza or pneumococcal vaccination in the preceding year (OR: 2.69 [95% CI: 1.78–4.05; p

Abstract Background Scrub typhus is an important neglected vector-borne zoonotic disease across the Asia–Pacific region, with an expanding known distribution. The disease ecology is poorly understood, despite the large global burden of disease. The key determinants of high-risk areas of transmission to humans are unknown. Methods Small mammals and chiggers were collected over an 18-month period at three sites of differing ecological profiles with high scrub typhus transmission in Chiang Rai Province, northern Thailand. Field samples were identified and tested for Orientia tsutsugamushi by real-time PCR. The rates and dynamics of infection were recorded, and positive and negative individuals were mapped over time at the scale of single villages. Ecological analyses were performed to describe the species richness, community structure and interactions between infected and uninfected species and habitats. Generalised linear modelling (GLM) was applied to examine these interactions. Results The site with the highest rates of human infection was associated with the highest number of infected chigger pools (41%), individual chiggers (16%), proportion of the known vector species Leptotrombidium deliense (71%) and chigger index (151). Chigger species diversity was lowest (Shannon diversity index H′: 1.77) and rodent density appeared to be high. There were no consistent discrete foci of infection identified at any of the study sites. The small mammals Rattus tanezumi and Bandicota indica and the chiggers L. deliense and Walchia kritochaeta emerged as central nodes in the network analysis. In the GLM, the end of the dry season, and to a lesser extent the end of the wet season, was associated with O. tsutsugamushi-infected small mammals and chiggers. A clear positive association was seen between O. tsutsugamushi-positive chigger pools and the combination of O. tsutsugamushi-positive chigger pools and O. tsutsugamushi-positive small mammals with lowland habitats. Conclusions These findings begin to reveal some of the factors that may determine high-risk foci of scrub typhus at a fine local scale. Understanding these factors may allow practical public health interventions to reduce disease risk. Further studies are needed in areas with diverse ecology. Graphical abstract

Abstract Background Head and neck cutaneous squamous cell carcinoma (HNCSCC) is a non-melanoma skin cancer that is mostly caused by solar ultraviolet radiation exposure. While it usually has an excellent prognosis, a subset of patients (5%) develops nodal metastasis and has poor outcomes. The aim of this study was to systematically review the literature and evaluate the prognostic factors of HNCSCC in order to better understand which patients are the most likely to develop metastatic disease. Methods A comprehensive literature search was performed on PubMed and EMBASE to identify the studies that evaluated the prognostic factors of HNCSCC. Prognostic factors were deemed significant if they had a reported p-value of

Trypanosoma lewisi belongs to the so-called atypical trypanosomes that occasionally affect humans. It shares the same hosts and flea vector of other medically relevant pathogenic agents as Yersinia pestis, the agent of plague. Increasing knowledge on the population structure (reproductive mode, population size, dispersal) of this parasite thus represents a challenging but important issue. The use of polymorphic genetic markers, together with suitable population genetics tools, is a convenient way to achieve such objectives. To date, the population biology of T. lewisi is poorly known and, to our knowledge, no population genetics studies have ever been conducted. Here, we present the development of nine microsatellite markers of this species. We investigated their polymorphism in different countries from Africa and South-East Asia from DNAs extracted from the spleen of their rodent reservoirs (essentially rat species). Several amplification problems arose, especially with South-East Asian individuals. This led to retain only those individuals with complete genotypes (most of them originating from West Africa, notably Cotonou, Benin) to ensure an optimal estimate of heterozygosity. Our results pointed towards a mainly (at least 95-99%) clonal mode of propagation, a strong subdivision at the smallest scale available (i.e., urban neighborhoods, i.e. 0.250 km²), and a generation time most probably shorter than 4 months. In future studies, more extensive sampling at smaller geographic scales (i.e., households), within a one- or two-months window and with improved amplification conditions, should lead to a more precise picture of the fine population structure of this parasite.

SLE is a systemic multi-organ autoimmune condition associated with reduced life expectancy and quality of life. Glucocorticoids (GC) are heavily relied on for SLE treatment but are associated with detrimental metabolic effects. Type 1 interferons (IFN) are central to SLE pathogenesis and may confer GC insensitivity. Glucocorticoid-induced leucine zipper (GILZ) mediates many effects of GC relevant to SLE pathogenesis, but the effect of IFN on GC regulation of GILZ is unknown. We performed in vitro experiments using human PBMC to examine the effect of IFN on GILZ expression. JAK inhibitors tofacitinib and tosylate salt were used in vivo and in vitro respectively to investigate JAK-STAT pathway dependence of our observations. ChiP was performed to examine glucocorticoid receptor (GR) binding at the GILZ locus. Several public data sets were mined for correlating clinical data. High IFN was associated with suppressed GILZ and reduced GILZ relevant to GC exposure in a large SLE population. IFN directly reduced GILZ expression and suppressed the induction of GILZ by GC in vitro in human leukocytes. IFN actions on GILZ expression were dependent on the JAK1/Tyk2 pathway, as evidenced by loss of the inhibitory effect of IFN on GILZ in the presence of JAK inhibitors. Activation of this pathway led to reduced GR binding in key regulatory regions of the GILZ locus. IFN directly suppresses GILZ expression and GILZ upregulation by GC, indicating a potential mechanism for IFN-induced GC resistance. This work has important implications for the ongoing development of targeted GC-sparing therapeutics in SLE.

IntroductionAdding sensory feedback to myoelectric prosthetic hands was shown to enhance the user experience in terms of controllability and device embodiment. Often this is realized non-invasively by adding devices, such as actuators or electrodes, within the prosthetic shaft to deliver the desired feedback. However, adding a feedback system in the socket adds more weight, steals valuable space, and may interfere with myoelectric signals. To circumvent said drawbacks we tested for the first time if force feedback from a prosthetic hand could be redirected to another similarly sensitive part of the body: the foot.MethodsWe developed a vibrotactile insole that vibrates depending on the sensed force on the prosthetic fingers. This self-controlled clinical pilot trial included four experienced users of myoelectric prostheses. The participants solved two types of tasks with the artificial hands: 1) sorting objects depending on their plasticity with the feedback insole but without audio-visual feedback, and 2) manipulating fragile, heavy, and delicate objects with and without the feedback insole. The sorting task was evaluated with Goodman-Kruskal's gamma for ranked correlation. The manipulation tasks were assessed by the success rate.ResultsThe results from the sorting task with vibrotactile feedback showed a substantial positive effect. The success rates for manipulation tasks with fragile and heavy objects were high under both conditions (feedback on or off, respectively). The manipulation task with delicate objects revealed inferior success with feedback in three of four participants.ConclusionWe introduced a novel approach to touch sensation in myoelectric prostheses. The results for the sorting task and the manipulation tasks diverged. This is likely linked to the availability of various feedback sources. Our results for redirected feedback to the feet fall in line with previous similar studies that applied feedback to the residual arm.Clinical trial registrationName: Sensor Glove and Non-Invasive Vibrotactile Feedback Insole to Improve Hand Prostheses Functions and Embodiment (FeetBack). Date of registration: 23 April 2019. Date the first participant was enrolled: 3 September 2021. ClinicalTrials.gov Identifier: NCT03924310.

Respiratory syncytial virus is among the most common causes of respiratory infections. Typically, this viral infection has a seasonality during the cold months but with the SARS-CoV-2 pandemic this has been considerably modified. Here, we studied the epidemiology of this virus in university hospitals of Marseille, South of France, over the period 2020 to 2023. We tested in our laboratory from July 2020 to October 2021 16,516 nasopharyngeal swabs from 16,468 patients for RSV infection using different qPCR assays. We then analyzed data from previous and subsequent winters (from 2018 to 2023) and previous summers (from 2015 to 2021). A total of 676 patients were RSV-positive; their mean age was 3 years and 91 were under 5 years of age. We observed a delay of 4 months of the RSV epidemic’s onset compared to other years with an epidemic that peaked in March 2021. We had significantly more RSV-positive cases during summer 2021 compared to previous summers, whereas the incidence of RSV infections was not significantly higher during winter 2022 versus previous winters. Moreover, 494 patients were diagnosed as RSV-positive in the emergency unit and 181 were subsequently hospitalized, and 34 patients were diagnosed RSV-positive while already in the intensive care unit. Over all the study periods, 38 patients diagnosed as RSV-positive died, the majority of whom (23/28) were over 65 years of age. These data show an atypical evolution of the incidence of RSV infections in our city and is another example of the unpredictability of infectious disease epidemiology.

Among emerging zoonotic pathogens, mosquito-borne viruses (MBVs) circulate between vertebrate animals and mosquitoes and represent a serious threat to humans via spillover from enzootic cycles to the human community. Active surveillance of MBVs in their vectors is therefore essential to better understand and prevent spillover and emergence, especially at the human–animal interface. In this study, we assessed the presence of MBVs using molecular and phylogenetic methods in mosquitoes collected along an ecological gradient ranging from rural urbanized areas to highland forest areas in northern Thailand. We have detected the presence of insect specific flaviviruses in our samples, and the presence of the emerging zoonotic Tembusu virus (TMUV). Reported for the first time in 1955 in Malaysia, TMUV remained for a long time in the shadow of other flaviviruses such as dengue virus or the Japanese encephalitis virus. In this study, we identified two new TMUV strains belonging to cluster 3, which seems to be endemic in rural areas of Thailand and highlighted the genetic specificities of this Thai cluster. Our results show the active circulation of this emerging flavivirus in Thailand and the need for continuous investigation on this poorly known but threatening virus in Asia.

Channel waveguides with diffraction gratings at their input and output for light injection and extraction, respectively, constitute the key components for applications in integrated optics and photonics. Here, we report for the first time on such fluorescent micro-structured architecture entirely elaborated on glass by sol-gel processing. This architecture particularly takes advantage of a high-refractive index and transparent titanium oxide-based, sol-gel photoresist that can be imprinted through a single photolithography step. This resist enabled us to photo-imprint the input and output gratings on a photo-imprinted channel waveguide doped with a ruthenium complex fluorophore (Rudpp). In this paper, the elaboration conditions and optical characterizations of derived architectures are presented and discussed with respect to optical simulations. We firstly show how the optimization of a two-step deposition/insolation sol-gel procedure leads to reproducible and uniform grating/waveguide architectures elaborated on rather large dimensions. Then, we show how this reproducibility and uniformity govern the reliability of fluorescence measurements in waveguiding configuration. These measurements demonstrate that: (i) our sol-gel architecture is well adapted to the efficient channel–waveguide/diffraction grating coupling at the Rudpp excitation and emission wavelengths; (ii) it enables an efficient propagation of the emission signal in the core of the waveguide allowing its photo-detection after extraction through the output grating; and (iii) it is affected by very reduced parasitic mechanisms, such as propagation losses and photobleaching features. This work constitutes a promising preliminary step toward the integration of our architecture in a microfluidic platform for further fluorescence measurements in liquid medium and waveguiding configuration.

Abstract Background In healthcare facilities, nosocomial transmissions of respiratory viruses are a major issue. SARS-CoV-2 is not exempt from nosocomial transmission. Our goals were to describe COVID-19 nosocomial cases during the first pandemic wave among patients in a French university hospital and compliance with hygiene measures. Methods We conducted a prospective observational study in Grenoble Alpes University Hospital from 01/03/2020 to 11/05/2020. We included all hospitalised patients with a documented SARS-CoV-2 diagnosis. Nosocomial case was defined by a delay of 5 days between hospitalisation and first symptoms. Hygiene measures were evaluated between 11/05/2020 and 22/05/2020. Lockdown measures were effective in France on 17/03/2020 and ended on 11/05/2020. Systematic wearing of mask was mandatory for all healthcare workers (HCW) and visits were prohibited in our institution from 13/03/2021 and for the duration of the lockdown period. Results Among 259 patients included, 14 (5.4%) were considered as nosocomial COVID-19. Median time before symptom onset was 25 days (interquartile range: 12–42). Eleven patients (79%) had risk factors for severe COVID-19. Five died (36%) including 4 deaths attributable to COVID-19. Two clusters were identified. The first cluster had 5 cases including 3 nosocomial acquisitions and no tested HCWs were positive. The second cluster had 3 cases including 2 nosocomial cases and 4 HCWs were positive. Surgical mask wearing and hand hygiene compliance were adequate for 95% and 61% of HCWs, respectively. Conclusions The number of nosocomial COVID-19 cases in our hospital was low. Compliance regarding mask wearing, hand hygiene and lockdown measures drastically reduced transmission of the virus. Monitoring of nosocomial COVID-19 cases during the first wave enabled us to determine to what extent the hygiene measures taken were effective and patients protected. Trial registration Study ethics approval was obtained retrospectively on 30 September 2020 (CECIC Rhône-Alpes-Auvergne, Clermont-Ferrand, IRB 5891).

Abstract This study evaluated the safety and immunogenicity of BNT162b2 vaccine in patients with hematological malignancies. Antibodies blocking spike binding to immobilized ACE-2 (NAb) correlated with anti-Spike (S) IgG d42 titers (Spearman r = 0.865, p

Abstract Background Colorectal cancer is a major public concern, being the second deadliest cancer in the world. Whereas survival is high for localized forms, metastatic colorectal cancer has showed poor prognosis, with a 5-year survival barely surpassing 11%. Conventional chemotherapies against this disease proved their efficiency and remain essential in first-line treatment. However, the large number of authorized protocols complexifies treatment decision. In common practice, such decision is made on an empirical basis, by assessing benefits and risks for the patient. In other words, there is currently no efficient means of predicting the efficacy of any chemotherapy protocol for metastatic colorectal cancer. Methods/design The use of a chemosensitivity assay, the Oncogramme®, should help clinicians administer the best chemotherapy regimen to their patients. We hypothesize it would ultimately improve their survival. In this multicentred, prospective trial (ONCOGRAM), eligible patients with metastatic colorectal cancer are randomized to determine whether they will receive an Oncogramme®. For clinicians whose patients benefited from the assay (arm A), results are used as a decision support tool. Patients not undergoing the Oncogramme® procedure are treated according to current practice, without the assistance of the assay (arm B). Primary outcome is 1-year progression-free survival. Secondary outcomes include response rates, as well as 6-month and 1-year survival rates. Discussion This study aims at investigating the clinical utility of the Oncogramme® as a decision support tool for the treatment of patients with metastatic colorectal cancer. If the Oncogramme® positively influenced patient overall survival and/or progression-free survival, it would be of great value for clinicians to implement this assay within the current landscape of personalized medicine tools, which include genomics and biomarker assays. Trial registration ClinicalTrials.gov identifier NCT03133273 . Registered on April 28, 2017.

Neisseria meningitidis (meningococcus) is a Gram-negative bacterium responsible for two devastating forms of invasive diseases: purpura fulminans and meningitis. Since the first description of the epidemic nature of the illness at the dawn of the nineteenth century, the scientific knowledge of meningococcal infection has increased greatly. Major advances have been made in the management of the disease with the advent of antimicrobial therapy and the implementation of meningococcal vaccines. More recently, an extensive knowledge has been accumulated on meningococcal interaction with its human host, revealing key processes involved in disease progression and new promising therapeutic approaches.

Abstract Background We sought to examine the disease course of High Disease Activity Status (HDAS) patients and their different disease patterns in a real-world longitudinal cohort. Disease resolution till Lupus Low Disease Activity State (LLDAS) has been a general treatment goal, but there is limited information on this subset of patients who achieve this. Methods All consenting patients of the Monash Lupus Cohort who had at least 12 months of observation were included. HDAS was defined as SLEDAI-2K ≥ 10 ever, and HDAS episode as the period from the first HDAS clinic visit until attainment of LLDAS. We examined the associations of different HDAS patterns with the likelihood of damage accrual. Results Of 342 SLE patients, 151 experienced HDAS at least once, accounting for 298 HDAS episodes. The majority of HDAS patients (76.2%) experienced Recurrent HDAS (> 1 HDAS visit), and a smaller subset (47.7%) had Persistent HDAS (consecutive HDAS visits for longer than 2 months). Recurrent or Persistent HDAS patients were younger at diagnosis and more likely to experience renal or serositis manifestations; persistent HDAS patients were also more likely to experience neurological manifestations. Baseline SLEDAI greater than 10 was associated with longer HDAS episodes. Recurrent and Persistent HDAS were both associated with an increased likelihood of damage accrual. The total duration of HDAS episode greater than 2 years and experiencing multiple HDAS episodes (≥4) was also associated with an increased likelihood of damage accrual (OR 1.80, 95% CI 1.08–2.97, p = 0.02, and OR 3.31, 95% CI 1.66–13.26, p = 0.01, respectively). Conclusion HDAS episodes have a highly variable course. Recurrent and Persistent HDAS, and longer duration of HDAS episodes, increased the risk of damage accrual. In addition to a major signifier of severity in SLE, its resolution to LLDAS can determine the subsequent outcome in SLE patients.

Objectives: Isoniazid-monoresistant tuberculosis (HR-TB) is the most prevalent form of drug-resistant TB worldwide and in France and is associated with poorer treatment outcomes compared with drug-susceptible TB (DS-TB). The objective of this study was to determine the characteristics of HR-TB patients in France and to compare outcomes and safety of treatment for HR-TB and DS-TB. Methods: We performed a case-control multicenter study to identify risk factors associated with HR-TB and compare treatment outcomes and safety between HR-TB patients and DS-TB patients. Results: Characteristics of 99 HR-TB patients diagnosed and treated in the university hospitals of Paris, Lille, Caen and Strasbourg were compared with 99 DS-TB patients. Female sex (OR = 2.2; 1.0–4.7), birth in the West-Pacific World Health Organization region (OR = 4.6; 1.1–18.7) and resistance to streptomycin (OR = 77.5; 10.1–594.4) were found to be independently associated with HR-TB. Rates of treatment success did not differ significantly between HR-TB and DS-TB. Conclusions: Factors associated with HR-TB are not significant enough to efficiently screen TB patients at risk of HR-TB. The systematic implementation of rapid molecular testing on clinical samples remains the only effective way to make the early diagnosis of HR-TB and adapt treatment.

Cardiometabolic disease, comprising cardiovascular diseases, type 2 diabetes, and their associated risk factors including metabolic syndrome and obesity, is the leading cause of death worldwide. Plant foods are rich sources of different groups of bioactive compounds, which might not be essential throughout life but promote health and well-being by reducing the risk of age-related chronic diseases. However, heterogeneity in the responsiveness to bioactive compounds can obscure associations between their intakes and health outcomes, resulting in the hiding of health benefits for specific population groups and thereby limiting our knowledge of the exact role of the different bioactive compounds for health. The heterogeneity in response suggests that some individuals may benefit more than others from the health effects of these bioactive compounds. However, to date, this interindividual variation after habitual intake of plant bioactive compounds has been little explored. The aim of this review is to provide an overview of the existing research that has revealed interindividual variability in the responsiveness to plant-food bioactive compound consumption regarding cardiometabolic outcomes, focusing on polyphenols, caffeine and plant sterols, and the identified potential determinants involved.

Bioactive compounds in plant-based foods have health properties that contribute to the prevention of age-related chronic diseases, particularly cardiometabolic disorders. Conclusive proof and understanding of these benefits in humans is essential in order to provide effective dietary recommendations but, so far, the evidence obtained from human intervention trials is limited and contradictory. This is partly due to differences between individuals in the absorption, distribution, metabolism and excretion of bioactive compounds, as well as to heterogeneity in their biological response regarding cardiometabolic health outcomes. Identifying the main factors underlying inter-individual differences, as well as developing new and innovative methodologies to account for such variability constitute an overarching goal to ultimately optimize the beneficial health effects of plant food bioactives for each and every one of us. In this respect, this position paper from the COST Action FA1403-POSITIVe examines the main factors likely to affect the individual responses to consumption of plant food bioactives and presents perspectives for assessment and consideration of inter-individual variability.

The processes controlling targeting of glucose transporters to apical and basolateral membranes of polarized cells are complex and not-well understood. We have engineered SGLT1 and GLUT4 constructs linked to fluorescent proteins to highlight the differences in transporter expression and trafficking, in real time, in different cell types. Activity was assessed in parallel using a FRET glucose sensor. In COS cells and HEK cells, SGLT1 was distributed between the plasma membrane and intracellular compartments, but there was little expression in CHO cells. Trafficking was investigated using the lysosome inhibitors NH4Cl (10 mmol/L) and chloroquine (150 μmol/L) and the proteasome inhibitors MG-262 (1 μmol/L) and lactacystin (5 μmol/L). Lysosome inhibitors caused SGLT1 accumulation into intracellular bodies, whereas proteasome inhibitors induced SGLT1 accumulation in the plasma membrane, even in CHO cells. Our data suggest that a fraction of SGLT1 is rapidly degraded by lysosomes and never reached the plasma membrane; another fraction reaches the membrane and is subsequently degraded by lysosomes following internalization. The latter process is regulated by the ubiquitin/proteasome pathway, acting at a late stage of the lysosomal pathway. Using the cholesterol inhibitor MβCD (3 mmol/L), a dominant negative dynamin (K44A) and caveolin, we showed that SGLT1 internalization is lipid raft-mediated, but caveolin-independent. In contrast, GLUT4 internalization is dynamin-dependent, but cholesterol-independent. The physiological relevance of these data is discussed in terms of differential membrane compartmentalization of the transporters and expression under stress conditions.

ObjectivesThe analysis of gene module expression in SLE is emerging as a tool to identify active biological pathways, with the aim of developing targeted therapies for subsets of patients. Detailed information on the effect of immunosuppressants on gene module expression is lacking. We aimed to examine the impact of medication exposure on gene module expression.MethodsA set of commercially available disease-relevant gene modules were measured in 730 whole blood samples from a dedicated lupus clinic on whom prospectively collected, contemporaneous clinical data including medication exposure were available.ResultsCompared to heathy controls, SLE patients showed over-expression of IFN and under-expression of B cell, T cell and pDC modules. Neutrophil module over-expression and under-expression of B and T cell modules were observed in patients with active lupus nephritis or highly active disease (SLEDAI-2K > 8), while Lupus Low Disease Activity State (LLDAS) had inverse associations. Disease activity in other organ domains was not associated with specific gene modules. In contrast, medications were associated with multiple effects. Glucocorticoid use was associated with under-expression of T cell, B cell and plasmablast modules, and over-expression of neutrophil modules. Mycophenolate and azathioprine exposure were associated with plasmablast module and B cell module under-expression respectively. Disease activity associations with neutrophil over-expression and lymphocyte module under-expression were attenuated by multivariable adjustment for medication exposure.ConclusionMedications have significant effect on gene module expression in SLE patients. These findings emphasize the need to control for medications in studies of gene expression in SLE.

ObjectivesThe objectives of this study were to determine the prevalence and patterns of resistance to integrase strand transfer inhibitors (INSTIs) in patients experiencing virological failure on raltegravir-based ART and the impact on susceptibility to INSTIs (raltegravir, elvitegravir and dolutegravir).Patients and methodsData were collected from 502 treatment-experienced patients failing a raltegravir-containing regimen in a multicentre study. Reverse transcriptase, protease and integrase were sequenced at failure for each patient. INSTI resistance-associated mutations investigated were those included in the last ANRS genotypic algorithm (v23).ResultsAmong the 502 patients, at failure, median baseline HIV-1 RNA (viral load) was 2.9 log10 copies/mL. Patients had been previously exposed to a median of five NRTIs, one NNRTI and three PIs. Seventy-one percent harboured HIV-1 subtype B and the most frequent non-B subtype was CRF02_AG (13.3%). The most frequent mutations observed were N155H/S (19.1%), Q148G/H/K/R (15.4%) and Y143C/G/H/R/S (6.7%). At failure, viruses were considered as fully susceptible to all INSTIs in 61.0% of cases, whilst 38.6% were considered as resistant to raltegravir, 34.9% to elvitegravir and 13.9% to dolutegravir. In the case of resistance to raltegravir, viruses were considered as susceptible to elvitegravir in 11% and to dolutegravir in 64% of cases. High HIV-1 viral load at failure (P

OBJECTIVES: The neurological disorders in HIV-1-infected patients remain prevalent. The HIV-1 resistance in plasma and CSF was compared in patients with neurological disorders in a multicentre study. METHODS: Blood and CSF samples were collected at time of neurological disorders for 244 patients. The viral loads were >50 copies/mL in both compartments and bulk genotypic tests were realized. RESULTS: On 244 patients, 89 and 155 were antiretroviral (ARV) naive and ARV treated, respectively. In ARV-naive patients, detection of mutations in CSF and not in plasma were reported for the reverse transcriptase (RT) gene in 2/89 patients (2.2%) and for the protease gene in 1/89 patients (1.1%). In ARV-treated patients, 19/152 (12.5%) patients had HIV-1 mutations only in the CSF for the RT gene and 30/151 (19.8%) for the protease gene. Two mutations appeared statistically more prevalent in the CSF than in plasma: M41L (P=0.0455) and T215Y (P=0.0455). CONCLUSIONS: In most cases, resistance mutations were present and similar in both studied compartments. However, in 3.4% of ARV-naive and 8.8% of ARV-treated patients, the virus was more resistant in CSF than in plasma. These results support the need for genotypic resistance testing when lumbar puncture is performed.

Abstract Background Genetic markers are employed widely in molecular studies, and their utility depends on the degree of sequence variation, which dictates the type of application for which they are suited. Consequently, the suitability of a genetic marker for any specific application is complicated by its properties and usage across studies. To provide a yardstick for future users, in this study we assess the suitability of genetic markers for molecular systematics and species identification in helminths and provide an estimate of the cut-off genetic distances per taxonomic level. Methods We assessed four classes of genetic markers, namely nuclear ribosomal internal transcribed spacers, nuclear rRNA, mitochondrial rRNA and mitochondrial protein-coding genes, based on certain properties that are important for species identification and molecular systematics. For molecular identification, these properties are inter-species sequence variation; length of reference sequences; easy alignment of sequences; and easy to design universal primers. For molecular systematics, the properties are: average genetic distance from order/suborder to species level; the number of monophyletic clades at the order/suborder level; length of reference sequences; easy alignment of sequences; easy to design universal primers; and absence of nucleotide substitution saturation. Estimation of the cut-off genetic distances was performed using the ‘K-means’ clustering algorithm. Results The nuclear rRNA genes exhibited the lowest sequence variation, whereas the mitochondrial genes exhibited relatively higher variation across the three groups of helminths. Also, the nuclear and mitochondrial rRNA genes were the best possible genetic markers for helminth molecular systematics, whereas the mitochondrial protein-coding and rRNA genes were suitable for molecular identification. We also revealed that a general gauge of genetic distances might not be adequate, using evidence from the wide range of genetic distances among nematodes. Conclusion This study assessed the suitability of DNA genetic markers for application in molecular systematics and molecular identification of helminths. We provide a novel way of analyzing genetic distances to generate suitable cut-off values for each taxonomic level using the ‘K-means’ clustering algorithm. The estimated cut-off genetic distance values, together with the summary of the utility and limitations of each class of genetic markers, are useful information that can benefit researchers conducting molecular studies on helminths.

Diagnosis of salivary gland neoplasms is often challenging due to their high morphological diversity and overlaps. Several recurrent molecular alterations have been described recently, which can serve as powerful diagnostic tools and potential therapeutic targets (e.g. NTRK or RET fusions). However, current sequential molecular testing can be expensive and time consuming. In order to facilitate the diagnosis of salivary gland neoplasms, we designed an all-in-one RNA-based next generation sequencing panel suitable for the detection of mutations, fusions and gene expression levels (including NR4A3) of 27 genes involved in salivary gland neoplasms. Here we present the validation of the “SalvGlandDx” panel on FFPE histological specimen including fine needle aspiration (FNA) cell block material, against the standard methods currently used at our institution. In a second part we describe selected unique cases in which the SalvGlandDx panel allowed proper diagnosis and new insights into special molecular characteristics of selected salivary gland tumors. We characterize a unique salivary gland adenocarcinoma harboring a ZCCHC7-NTRK2 fusion, a highly uncommon spindle cell and pseudoangiomatoid adenoid-cystic carcinoma with MYBL1-NFIB fusion, and a purely oncocytic mucoepidermoid carcinoma, whereas diagnosis could be made by detection of a CRTC3-MAML2 rearrangement on the cell block specimen of the FNA. Further, a rare case of a SS18-ZBTB7A rearranged low-grade adenocarcinoma previously described as potential spectrum of microsecretory adenocarcinoma, is reported. In addition, features of six cases within the spectrum of polymorphous adenocarcinoma / cribriform adenocarcinoma of salivary gland including PRKD1 p.E710D mutations and novel fusions involving PRKAR2A-PRKD1, SNX9-PRKD1 and ATL2-PRKD3, are described.