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The Pliocene hominin fossil 'Lucy' (A.L. 288-1

Bowman et al. [K.O. Bowman, M.A. Kastenbaum, L.R. Shenton, Fitting multi-parameter distributions to SCE data, Mutat. Res., 358 (1996) 15-24.] showed how discrete Pearson and discrete Johnson translation-system distributions may be fitted to sister chromatid exchange (SCE) data presented by Bender et al. [M.A. Bender, R.J. Pearston, R.C. Leonard, B.E. Pyatt, P.C. Gooch, On the distribution of spontaneous SCE in human peripheral blood lymphocytes, Mutat. Res., 281 (1992) 227-232.]. When their performances were measured by the chi-squared test of goodness of fit, these distributions proved to be only moderately better alternatives to the poorly fitting Poisson, binomial, and negative binomial distributions. In this paper, we extend our search for better characterizations of the SCE data by calling upon the Gram-Charlier type B approximation of the negative binomial distribution. We introduce an innovative extension of methods described in a little-known paper by Aitken and Gonin [A.C. Aitken, H.T. Gonin, On fourfold sampling with and without replacement, Proc. R. Soc. Edinburgh, 55 (1934) 114-125.], and show how this leads to fits of the SCE data that, in general, are within acceptable levels of probability. Moreover, we show how a theorem by Cramér [H. Cramér, Mathematical Methods of Statistics, Princeton Univ. Press, 1946.], relating to the scale factor m2/m'1 and its asymptotic distribution, may be used to discriminate between smokers and nonsmokers of the same gender.

The previously published genetic identification of presumptive samples attributed to two French kings, Henri IV and Louis XVI, by Charlier et al., was recently refuted by a genetic genealogic approach. This (provisional) refutation illustrates the difficulties in confirming the identification of historical DNA samples using limited genetic data. Therefore, we want to stress the necessity of including the genetic genealogic approach--which relies on DNA typing of living relatives of the presumptive donor as a confirmed reference--to validate genetic results in historical cases. Moreover, the popularity and broad media coverage of such studies are useful in bringing awareness to the general public, non-DNA forensic experts and lawyers about the complexity of DNA typing in forensic cases.

18 páginas, 1 figura, 2 tablas., Fasciola hepatica is a trematode parasite with a global distribution, which is responsible for considerable disease and production losses in a range of food producing species. It is also identified by WHO as a re-emerging neglected tropical disease associated with endemic and epidemic outbreaks of disease in human populations. In Europe, F. hepatica is mostly associated with disease in sheep, cattle and goats. This study reviews the most recent advances in our understanding of the transmission, diagnosis, epidemiology and the economic impact of fasciolosis. We also focus on the impact of the spread of resistance to anthelmintics used to control F. hepatica and consider how vaccines might be developed and applied in the context of the immune-modulation driven by the parasite. Several major research gaps are identified which, when addressed, will contribute to providing focussed and where possible, bespoke, advice for farmers on how to integrate stock management and diagnosis with vaccination and/or targeted treatment to more effectively control the parasite in the face of increasing the prevalence of infection and spread of anthelmintic resistance that are likely to be exacerbated by climate change., All authors are members of the Livestock Helminth Research Alliance (LiHRA), whose vision is to improve the health, wealth and productivity of European livestock by providing sustainable helminth control options. This review was commissioned by DISCONTOOLS (www.discontools.eu) as part of the process of identifying research gaps which impinge on effective and sustainable control of fasciolosis in food producing animals in Europe. DJLW, JC, LR, CC, JPA, AMM all received funding from the European Union through the following awards: FPVI‐FOOD‐CT‐200X‐023025‐DELIVER; FPVII‐KBBE‐2011‐5‐288975‐GLOWORM; FPVII‐KBBE‐2010‐4‐265862‐PARAVAC; H2020‐635408‐PARAGONE. DJLW, JEH, NJB received funding from the Biotechnology and Biological Sciences Research Council (BBSRC) through awards: BB/K015591/1 and BBI002480/1, and RJF was supported by BBSRC award BB/M018520/1. MMV was funded by the Spanish “Ramón y Cajal” Programme of the Ministry of Economy and Competitiveness (RYC‐2015‐18368). CC was funded by the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Emerging and Zoonotic Infections at the University of Liverpool in partnership with Public Health England (PHE) and Liverpool School of Tropical Medicine (LSTM). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, the Department of Health or PHE.

Titanium dioxide (in the form of E171) is a ubiquitous excipient in tablets and capsules for oral use. In the coating of a tablet or in the shell of a capsule the material disperses visible and UV light so that the contents are protected from the effects of light, and the patient or caregiver cannot see the contents within. It facilitates elegant methods of identification for oral solid dosage forms, thus aiding in the battle against counterfeit products. Titanium dioxide ensures homogeneity of appearance from batch to batch fostering patient confidence. The ability of commercial titanium dioxide to disperse light is a function of the natural properties of the anatase polymorph of titanium dioxide, and the manufacturing processes used to produce the material utilized in pharmaceuticals. In some jurisdictions E171 is being considered for removal from pharmaceutical products, as a consequence of it being delisted as an approved colorant for foods. At the time of writing, in the view of the authors, no system or material which could address both current and future toxicological concerns of Regulators and the functional needs of the pharmaceutical industry and patients has been identified. This takes into account the assessment of materials such as calcium carbonate, talc, isomalt, starch and calcium phosphates. In this paper an IQ Consortium team outlines the properties of titanium dioxide and criteria to which new replacement materials should be held.

Hippocrates, a Greek physician during the fifth century BC., is often considered the father of medicine. The Corpus Hippocraticum comprising of 58 volumes was writing between 450 and 150 BC. The objective of our study was to detail the management of nasal polyps during this period. We read and analyzed all volumes of the Corpus Hippocraticum in French translation and extracted all passages dealing with nasal polyps (n = 6). Surgical procedures in the Corpus Hippocraticum are described in great detail. The first surgical strategy for the removal of nasal polyps was by mini-invasive nasal approach: the lopping method and the sponge method. We explain the two mini-invasive nasal approaches with drawings. The meticulously detailed observations of the corpus give us a precious insight into the early perception of diseases, their progression and early attempts of treatment.

Background It is important for dermatologists and other physicians in refugee-receiving countries to acquire knowledge of forensic dermatology to identify lesions from torture. Objective Review forensic dermatology in cases of torture. Results In providing medical assessment and care to refugees and migrants, chronic skin lesions will be the most readily identifiable signs of torture. Beatings are very common, with blunt force trauma resulting in post-inflammatory hyperpigmentation. Torture burns can be thermal, chemical or electrothermal, causing distinct lesions determined by the method, duration and intensity of exposure, and area of skin affected. Sharp instruments inflict a wide range of lesions arising from stabbing/perforation or cuts from knives. Wound healing without medical attention and in unsanitary conditions will affect the scarring process. Lesions from suspension and ligatures may occur alongside scars from other forms of torture. Differential diagnoses include self-inflicted wounds, ethnic scarification and scars from traditional healing practices. Conclusion Physicians who may encounter survivors of torture in community or specialist practice would benefit from basic training in forensic dermatology, whilst knowledge of common forms of torture and cultural practices in refugees’ countries of origin is important when considering differential diagnoses of skin lesions.

In Maltot (Normandy, France), one grave containing the remains of a German soldier, who died in 1944, was excavated amongst other graves and isolated elements. A dozen whole vials were unearthed, resulting in questions about their content. Various screenings were carried out on the contents of one single vial: HPLC-DAD and HR-LC-MS screening after 1/10 dilution in mobile phase, GC-MS and HS-GC-MS after 1/10 dilution in methanol, multi-element research by HR-ICP-MS after total mineralization, and cyanide analysis. Analyzed vial contained approximately 300 µL of a colorless, water-immiscible liquid with a characteristic solvent odor. HPLC-DAD, GC-MS, HR-LC-MS/MS, ICP-MS, and cyanide screenings were negative excluding the presence of cyanide, arsenic, barbiturates, amphetamines, or narcotics. HS-GC-MS analysis highlighted the presence of ethanol, chloroform, and diethyl ether at significant concentrations. Chloroform and diethyl ether were anesthetic products mainly reserved for urgent situations. We hypothesized that the soldier may have been a combat medic working on battlefields. as he was wounded, another possibility could be that he may have used the vials to relieve his pain; however, the immediate severity of the wounds drove us to assess the second hypothesis of delayed death as being less plausible. The high number of vials containing ethanol, chloroform, and diethyl ether, and the massive blood loss leading to quick death led us to support the combat medic or paramedic hypothesis.

The Quality Assurance project for stage III non-small cell lung cancer radiotherapy ProCaLung performed a multicentric two-step exercise evaluating mediastinal nodal Target Volume Definition and Delineation (TVD) variability and the opportunity for standardization. The TVD variability before and after providing detailed guidelines and the value of qualitative contour reviewing before applying quantitative measures were investigated. The case of a patient with stage III NSCLC and involved mediastinal lymph nodes was used as a basis for this study. Twenty-two radiation oncologists from nineteen centers in Belgium and Luxembourg participated in at least one of two phases of the project (before and after introduction of ProCaLung contouring guidelines). The resulting thirty-three mediastinal nodal GTV and CTV contours were then evaluated using a qualitative-before-quantitative (QBQ) approach. First, a qualitative analysis was performed, evaluating adherence to most recent guidelines. From this, a list of observed deviations was created and these were used to evaluate contour conformity. The second analysis was quantitative, using overlap and surface distance measures to compare contours within qualitative groups and between phases. A 'most robust' reference volume for these analyses was created using the STAPLE-algorithm and an averaging method. Five GTV and seven CTV qualitative groups were identified. Second step contours were more often in higher-conformity groups (p = 0.012 for GTV and p = 0.024 for CTV). Median Residual Mean Square Distances improved from 2.34 mm to 1.36 mm for GTV (p = 0.01) and from 4.53 mm to 1.58 mm for CTV (p

Exercise training (ET) is a natural activator of silent mating type information regulation 2 homolog 1 (SIRT1), a stress-sensor able to increase the endogenous antioxidant system. SIRT1 activators include polyphenols and vitamins, the antioxidant properties of which are well-known. Antioxidant supplements are used to improve athletic performance. However, they might blunt ET-related benefits. Middle-distance runners (MDR) taking (MDR-S) or not taking antioxidant supplements (MDR-NoS) were compared with each other and with sedentary subjects (CTR) to evaluate the ET effects on SIRT1 levels and oxidative stress, and to investigate whether an exogenous source of antioxidants could interfere with such effects. Thirty-two MDR and 14 CTR were enrolled. MDR-S took 240 mg vitamin C and 15 mg vitamin E together with mineral salts. SIRT1 mRNA and activity were measured in PBMCs. Total oxidative status (TOS) and total antioxidant capacity (TEAC) were determined in plasma. MDR showed higher levels of SIRT1 mRNA (p = 0.0387) and activity (p = 0.0055) than did CTR. MDR-NoS also showed higher levels than did MDR-S without reaching statistical significance. SIRT1 activity was higher (p = 0.0012) in MDR-NoS (1909 ± 626) than in MDR-S (1276 ± 474). TOS did not differ among the groups, while MDR showed higher TEAC levels than did CTR (2866 ± 581 vs. 2082 ± 560, p = 0.0001) as did MDR-S (2784 ± 643) and MDR-NoS (2919 ± 551) (MDR-S vs. CTR, p = 0.0007 and MDR-NoS vs. CTR, p = 0.003). TEAC (β = 0.4488356, 95% CI 0.2074645 0.6902067; p < 0.0001) and the MDR-NoS group (β = 744.6433, 95% CI 169.9954 1319.291; p= 0.012) predicted SIRT1 activity levels. Antioxidant supplementation seems to hinder the role of ET as a natural activator of SIRT1.

Agricultural and food production systems are constantly evolving in response to societal and environmental factors. These sectors are also laden with occupational hazards, creating an opportunity for emerging and re-emerging issues such as emerging markets and changing worker demographics. The Upper Midwest is a region of intensive agricultural production, with many states leading the United States in livestock and crop production. As a National Institute of Occupational Safety and Health Center for Agricultural Safety and Health, the Upper Midwest Agricultural Safety and Health Center (UMASH) is tasked with protecting the health and safety of the region's agricultural workers. UMASH implements an Emerging Issues program to effectively respond to emerging and re-emerging issues impacting agricultural health and safety in the Upper Midwest. To direct such work, UMASH developed a novel Selection, Planning and Action Process Model. This model guides all stages of the UMASH Emerging Issues response and emphasizes the ongoing need for monitoring, evaluation, and feedback from agricultural communities. In conjunction with the UMASH Process Model, the International Association for Public Participation (IAP2) Spectrum of Public Participation frames the work of the Emerging Issues Program in meaningfully engaging the community of stakeholders across all stages.

International audience; Objectives: Our aim was to assess if switching from a protease inhibitors (PI)-based regimen to a PI-free one is associated with an increased risk of Kaposi Sarcoma (KS) relapse among patients living with HIV (PLHIV) with history of KS and controlled HIV replication.Methods: In a retrospective analysis of the prospectively collected Dat'AIDS database we selected patients who both had a past KS history and a HIV-1 viral load below 200 copies/mL while being PI-treated. We searched for KS relapses while persistent virological success was maintained for at least 6 months, whether patients kept taking the PI, or switched to PI-free regimen.Results: Among the 216 patients with past KS event and a history of HIV-1 infection efficiently treated by a PI-based regimen, 148 patients (68.5%) later switched to a PI-sparing regimen. Their baseline characteristics were not different from non-switching patients. We described 7 cases of relapse (3.2% of the 216 patients). Five cases of relapse occurred in switching patients (3.4%). The remaining two relapses occurred in PI-treated patients (2.9%). At KS relapse, CD4 cell count was 459 cells/μL (range 225-560) for switching patients, compared with 362 and 136 cells/μL for the other two patients.Conclusions: In this large cohort of PLHIV with a history of KS and ART-controlled HIV replication, KS relapses were described in 3.2% of the patients, and were not more frequent when a PI-containing ART regimen has been switched to a PI-free regimen. Our results do not support a specific effect of PI on KS.

Background Intra-partum cefazolin is used to prevent group B Streptococcus (GBS) vertical transmission in mothers allergic to penicillin without a history of anaphylaxis. Objectives To investigate the maternal cefazolin dose–exposure relationship and subsequent maternal and neonatal target attainment at delivery. Methods Data were obtained from 24 healthy, GBS-colonized pregnant women (20–41 years), undergoing vaginal delivery (gestational age ≥37 weeks). During labour, all women received a 2 g cefazolin IV infusion. Eight hours later, eight women received another 1 g in the event of delayed (>8 h) delivery. Next to maternal plasma concentrations (up to 10 per dosing interval, until delivery), venous and arterial umbilical cord concentrations were determined at delivery. Target attainment in maternal/neonatal plasma was set at 1 mg/L for 60% of the dosing interval (unbound cefazolin, worst-case clinical breakpoint). A population pharmacokinetic (popPK) model was built (NONMEM 7.4). ClinicalTrials.gov Identifier: NCT01295606. Results At delivery, maternal blood and arterial umbilical cord unbound cefazolin concentrations were >1 mg/L in 23/24 (95.8%) and 11/12 (91.7%), respectively. The popPK of cefazolin in pregnant women was described by a two-compartment model with first-order elimination. Two additional compartments described the venous and arterial umbilical cord concentration data. Cefazolin target attainment was adequate in the studied cohort, where delivery occurred no later than 6.5 h after either the first or the second dose. PopPK simulations showed adequate maternal and umbilical cord exposure for 12 h following the first dose. Conclusions PopPK simulations showed that standard pre-delivery maternal cefazolin dosing provided adequate target attainment up to the time of delivery.

International audience; Purpose: Invasive pneumococcal disease (IPD) is responsible for substantial mortality and morbidity worldwide. We aimed to identify host and bacterial factors associated with 30-day mortality in 18-year-old patients hospitalized with IPD in France from 2013 to 2015.Methods: This study analyzed data collected from consecutives IPD cases included in two parallel multi-center cohort studies: COMBAT study (280 patients with pneumococcal community-acquired bacterial meningitis) and SIIP study (491 patients with non-meningitis IPD). Factors associated with 30-day mortality were identified using logistic regression.Results: Among the 771 enrolled patients (median age 66 years, IQR [52.0-79.7]), 592/767 (77.2%) had at least one chronic disease. Patients with meningitis were younger (60.2 vs 70.9 years; p < 0.001) and had fewer chronic diseases than those with non-meningitis IPD (73.3% vs 79.4%; p = 0.05). Non-vaccine serotypes were more frequent in meningitis patients than in those with other IPD (36.1% vs 23.1%; p < 0.001). The overall 30-day mortality was 16.7% and patients with concurrent meningitis and extra-cerebral IPD had the highest 30-day mortality rate (26.5%). On multivariate analyses, older age, history of malignant solid tumor, meningeal IPD and serotypes previously identified with high mortality potential were independently associated with 30-day mortality. Of the serotypes with high mortality potential, 80% were included in licensed (PCV13 or PPV23) vaccines.Conclusion: We observed an effect of both host factors and pneumococcal serotypes on 30-day mortality in IPD. This highlights the need for a focused strategy to vaccinate at-risk patients.Clinical trial: ClinicalTrial. Gov identification number: NCT01730690.

Teamwork training and evaluation are essential to enhance safety and quality of care. The lack of the psychometric testing of the TeamSTEPPS® Teamwork Attitudes Questionnaire (T-TAQ) and Teamwork Perceptions Questionnaire (T-TPQ) across different language and cultural settings has questioned their widespread use because such attitudes and perceptions are highly subjective and context-bound. The present study aims to translate the T-TAQ and T-TPQ into the French language and validate the psychometric properties of the two questionnaires in a public health context. A forward-backward translation process, panel reviewing, and pilot testing in two rounds were followed to develop the French versions. Confirmatory factor analysis (CFA) and Cronbach's alpha were used to examine the factor structure and internal consistency, whereas two-way mixed Intraclass Correlation Coefficient (ICC) was performed to assess test-retest reliability. A total of 235 healthcare professionals in the French-speaking community of Belgium completed the T-TAQ and T-TPQ. After two to four weeks, 102 participants took part in the second round. Despite good fit indices as revealed by the CFA and Cronbach's alpha from 0.53 to 0.75 for the five dimensions of the T-TAQ and 0.76 to 0.79 for the T-TPQ, the squared correlations among the constructs were higher than the average variance extracted. Two-way mixed ICCs indicated fair to good test-retest reliability for all the five constructs of the two questionnaires, except the leadership scale of the T-TAQ. The French-language versions of the T-TAQ and T-TPQ were semantically equivalent and culturally relevant with adequate test-retest reliability as compared to the English versions. These two instruments might be used to capture the overall attitude toward teamwork and perceptions of team skills and behaviors. Yet, further research is advisable to refine the scales to establish the discriminant validity of the different dimensions and discriminative power of the instruments.

International audience; Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the infectious agent that has caused the current coronavirus disease (COVID) pandemic. Viral infection relies on the viral S (spike) protein/cellular receptor ACE2 interaction. Disrupting this interaction would lead to early blockage of viral replication. To identify chemical tools to further study these functional interfaces, 139,146 compounds from different chemical libraries were screened through an S/ACE2 in silico virtual molecular model. The best compounds were selected for further characterization using both cellular and biochemical approaches, reiterating SARS-CoV-2 entry and the S/ACE2 interaction. We report here two selected hits, bis-indolyl pyridine AB-00011778 and triphenylamine AB-00047476. Both of these compounds can block the infectivity of lentiviral vectors pseudotyped with the SARS-CoV-2 S protein as well as wild-type and circulating variant SARS-CoV-2 strains in various human cell lines, including pulmonary cells naturally susceptible to infection. AlphaLISA and biolayer interferometry confirmed a direct inhibitory effect of these drugs on the S/ACE2 association. A specific study of the AB-00011778 inhibitory properties showed that this drug inhibits viral replication with a 50% effective concentration (EC 50) between 0.1 and 0.5 mM depending on the cell lines. Molecular docking calculations of the interaction parameters of the molecules within the S/ACE2 complex from both wild-type and circulating variants of the virus showed that the molecules may target multiple sites within the S/ACE2 interface. Our work indicates that AB-00011778 constitutes a good tool for modulating this interface and a strong lead compound for further therapeutic purposes.

Background The need to detect new psychoactive substances in biological samples is of crucial interest. In this paper, the specificity of a benchtop immunoanalyzer commercialized by Randox was evaluated on real patient samples. Method The Evidence Investigator was assessed to screen for NPS on 80 serum and urine samples coming from patients admitted to the emergency department. Targeted NPS were included in various categories such as synthetic cannabinoids, opioids and benzodiazepines. Results were compared with a chromatographic technique coupled with mass spectrometry. Results No NPS was detected by the reference technique. Concerning immunoanalysis, some piperazines were positive, caused by the presence of medicine containing this chemical structure. Clonazepam and fentanyl derivatives were confirmed in some cases, but sometimes the positivity was explained by other opiates or benzodiazepines, which also explained two samples falsely positive for etizolam. Conclusions The Randox Evidence Investigator was rapid and easy to use. It can be used as a first intention but always followed by a more specific technique in order to detect false positive result.

A close-up photograph of a Teke community Chief (Congo, circa 1880–1890) seemed to be of diagnostic interest, as areas of achromic maculae were visible on the hands: the most relevant diagnoses were a Koebner phenomenon on a background of vitiligo, or a diagnosis of lupus. However, examination of the entire photograph showed that the ‘maculae’ were in fact tribal makeup, showing the methodological limits of icono-diagnosis.

Trial registration: ClinicalTrial.Gov identification number NCT01730690. the COMBAT study group; International audience; Introduction: COMBAT is a prospective, multicentre cohort study that enrolled consecutive adults with community-acquired bacterial meningitis (CABM) in 69 participating centres in France between February 2013 and July 2015 and followed them for 1 year.Methods: Patients aged at least 18 years old, hospitalised with CABM were followed during their hospitalisation and then contacted by phone 12 months after enrolment. Here we present the prevalence of sequelae at 12 months in a subgroup of patients with meningococcal meningitis.Results: Five of the 111 patients with meningococcal meningitis died during initial hospitalisation and two died between discharge and 12 months, leaving 104 patients alive 1 year after enrolment, 71 of whom provided 12-month follow-up data. The median age was 30.0 years and 54.1% of the patients had no identified risk factor for meningitis. More than 30% reported persistent headache, more than 40% were not satisfied with their sleep and 10% had concentration difficulties. Hearing loss was present in about 15% of the patients and more than 30% had depressive symptoms. About 13% of the patients with a previous professional activity had not resumed work. On the SF-12 Health Survey, almost 50% and 30% had physical component or mental component scores lower than the 25th percentile of the score distribution in the French general population. There was a non-significant improvement in the patients' disability scores from hospital discharge to 12 months (p = 0.16), but about 10% of the patients had residual disability.Conclusions: Although most patients in our cohort survive meningococcal meningitis, the long-term burden is substantial and therefore it is important to ensure a prolonged follow-up of survivors and to promote preventive strategies, including vaccination.

Immunocompromised patients have an increased risk of a severe form of COVID-19. The clinical efficacy of the tixagevimab/cilgavimab monoclonal antibody combination as pre-exposure prophylaxis against BA.1 and BA.2 SARS-CoV-2 Omicron sublineages is unknown. We aimed to describe the incidence and outcomes of COVID-19 among immunocompromised patients receiving tixagevimab/cilgavimab as preexposure prophylaxis during the Omicron wave in France.This was an observational multicentre cohort study of immunocompromised patients receiving tixagevimab/cilgavimab as preexposure prophylaxis between December 28, 2021 and March 31, 2022. Patients received tixagevimab/cilgavimab 150/150 mg intramuscularly if they had impaired vaccine response and a high risk of severe form of COVID-19.Tixagevimab/cilgavimab was administered to 1112 immunocompromised patients. After a median (range) follow-up of 63 (49-73) days, COVID-19 was confirmed in 49/1112 (4.4%) ≥5 days after treatment. During the study period, mean weekly incidence rate was 1669 in 100 000 inhabitants in Ile-de-France and 530 in 100 000 among patients who received tixagevimab/cilgavimab prophylaxis. Among infected patients, 43/49 (88%) had a mild-to-moderate form and 6/49 (12%) had a moderate-to-severe form of COVID-19. Patients with moderate-to-severe illnesses were less likely to have received early therapies than patients with mild forms (53.5% vs. 16.7% respectively) and 2/49 (4%) patients died from COVID-19.Our study reported a low rate of infections and severe illnesses among immunocompromised patients treated with tixagevimab/cilgavimab. A global preventive strategy including vaccines, preexposure prophylaxis with monoclonal antibodies, and early therapies might be effective to prevent severe forms of COVID-19 among severely immunocompromised patients.

A human biomonitoring study was carried out in 2015 within an adult population living in Liege (Belgium). Some phthalate metabolites and parabens were measured in the urine of 252 participants, and information were collected about their food habits, life styles and home environment to identify some predictors of exposure. Concomitantly, an awareness campaign was initiated by the Provincial Authorities of Liege and spread over 2 years. Three years later (2018), 92 of the initial participants provided again urine samples, and the levels of phthalate metabolites, phthalate substitute (DINCH), parabens, bisphenol-A and bisphenol alternatives (bisphenol-S, -F, -Z, -P) were determined and compared to those obtained in 2015 to assess time trends. In 2015, methyl- and ethylparaben were the most abundant parabens (P50 = 9.12 μg/L and 1.1 μg/L respectively), while propyl- and butylparaben were sparsely detected. Except for mono-2-ethylhexyl phthalate and 6-OH-mono-propyl-heptyl phthalate, all other targeted phthalate metabolites were positively quantified in most of the urine samples (between 89 and 98%) with median concentrations ranging between 2.7 μg/L and 21.3 μg/L depending on the metabolite. The multivariate regression models highlighted some significant associations between urinary phthalate metabolite or paraben levels and age, rural or urban character of the residence place, and the use of some personal care products. However, all determination coefficients were weak meaning that the usual covariates included in the models only explained a small part of the variance. Between 2015 and 2018, levels of parabens and phthalate metabolites significantly decreased (from 1.3 to 2.5 fold) except for monoethyl phthalate which seemed to remain quite constant. Contrariwise, all bisphenol alternatives and DINCH metabolites were measured in higher concentrations in 2018 vs 2015 while BPA levels did not differ significantly. However, it was not feasible to unequivocally highlight an impact of the awareness campaign on the exposure levels of the population.

Background The Centers for Disease Control and Prevention contracted with laboratories to sequence the SARS-CoV-2 genome from positive samples across the United States to enable public health officials to investigate the impact of variants on disease severity as well as the effectiveness of vaccines and treatment. Herein we present the initial results correlating RT-PCR quality control metrics with sample collection and sequencing methods from full SARS-CoV-2 viral genomic sequencing of 24,441 positive patient samples between April and June 2021. Methods RT-PCR confirmed (N Gene Ct value Results An association was observed between higher sequencing coverage, quality, and samples with a lower Ct value, with 99% of positives sequenced was Omicron. Conclusion These initial analyses highlight the importance of sequencing platform, sample collection methods, and RT-PCR Ct values in guiding surveillance efforts. These surveillance studies evaluating genetic changes of SARS-CoV-2 have been identified as critical by the CDC that can affect many aspects of public health including transmission, disease severity, diagnostics, therapeutics, and vaccines.

Fifty percent of children are anemic after a critical illness. Iatrogenic blood testing may be a contributor to this problem. The objectives of this study were to describe blood sampling practice in a PICU, determine patient factors associated with increased sampling, and examine the association among blood sampling volume, anemia at PICU discharge, and change in hemoglobin from PICU entry to PICU discharge.Prospective observational cohort study.PICU of Sainte-Justine University Hospital.All children consecutively admitted during a 4-month period.Four hundred twenty-three children were enrolled. Mean blood volume sampled was 3.9 (±19) mL/kg/stay, of which 26% was discarded volume. Children with central venous or arterial access were sampled more than those without access (p0.05). Children with sepsis, shock, or cardiac surgery were most sampled, those with a primary respiratory diagnosis; the least (p0.001). We detected a strong association between blood sample volume and mechanical ventilation (H, 81.35; p0.0001), but no association with severity of illness (Worst Pediatric Logistic Organ Dysfunction score) (R, -0.044; p = 0.43). Multivariate analysis (n = 314) showed a significant association between the volume of blood sampled (as continuous variable) and anemia at discharge (adjusted OR, 1.63; 95% CI, 1.18-2.45; p = 0.003). We lacked power to detect an association between blood sampling and change in hemoglobin from PICU admission to PICU discharge.Diagnostic blood sampling in PICU is associated with anemia at discharge. Twenty-five percent of blood losses from sampling is wasted. Volumes are highest for patients with sepsis, shock, or cardiac surgery, and in patients with vascular access or ventilatory support.

We integrate research on global work demands (Shaffer et al., 2012) with transactional stress theory to examine both the harmful and beneficial effects of three global work demands-international travel, cognitive flexibility, and nonwork disruption-for employees engaged in global work. We propose that global work demands have indirect, and conditional, effects on burnout and work-to-family conflict (WFC), as well as thriving and work-family enrichment, through employees' appraisals that their global work is both hindering and challenging, respectively. We tested the hypotheses with a matched sample of 229 global employees and their spouses. We found that cognitive flexibility demands are related to harmful and beneficial outcomes: It increases WFC through hindrance appraisals of the global work, but also increases thriving through challenge appraisals. In comparison, international travel demands have only beneficial outcomes, such that it positively related to employee thriving through challenge appraisals, but only among employees working in jobs that have fewer nonwork disruption demands. Finally, nonwork disruption demands had only harmful effects in that it positively related to burnout and WFC through hindrance appraisals. Exploratory analyses also revealed that nonwork disruption demands negatively related to employee thriving, through challenge appraisals, when employees experienced

Background The 2011 4th European Conference on Infections in Leukemia (ECIL4) guidelines recommend antibiotics de-escalation/discontinuation in selected febrile neutropenia (FN) patients. We aimed to assess the impact of an antimicrobial stewardship (AMS) program based on these guidelines on antibiotics use and clinical outcomes in high-risk FN patients. Methods We conducted an observational study in the hematology department of Cochin University Hospital in Paris, France. An ECIL4-based antibiotics de-escalation and discontinuation strategy was implemented jointly by the hematologists and the AMS team. The pre-intervention (January–October 2018) and post-intervention (January-October 2019) periods were compared. We retrospectively collected clinical and microbiological data. We compiled antibiotics consumptions via hospital pharmacy data and standardized them by calculating defined daily doses per 1000 patient-days. We analyzed the two-monthly antibiotic consumption using an interrupted time series method and built a composite endpoint for clinical outcomes based on transfer to the intensive care unit (ICU) and/or hospital death. Results Overall, 273 hospital stays (164 patients) in the pre-intervention and 217 (148 patients) in the post-intervention periods were analyzed. Patients were mainly hospitalized for intensive chemotherapy for acute leukemia or autologous stem-cell transplant for myeloma. Patients were slightly younger in the pre-intervention compared to the post-intervention period (median age 60.4 vs 65.2 years, p = 0.049), but otherwise comparable. After implementation of the AMS program, glycopeptide and carbapenem use decreased by 85% (p = 0.03) and 72% (p = 0.04), respectively. After adjustment on confounders, the risk of transfer to the ICU/death decreased significantly after implementation of the AMS program (post-intervention period: odds-ratio = 0.29, 95% Confidence Interval: 0.15–0.53, p Conclusion Implementation of a multidisciplinary AMS program for high-risk neutropenic patients was associated with lower carbapenem and glycopeptide use and improved clinical outcomes.

Objectives Fast and reliable ethanol assays analysis are used in a clinical context for patients suspected of ethanol intoxication. Mostly, automated systems using an enzymatic reaction based on ethanol dehydrogenase are used. The manuscript focusses on the evaluation of the performance of these assays. Methods Data included 30 serum samples used in the Belgian EQA scheme from 2019 to 2021 and concentrations ranged from 0.13 to 3.70 g/L. A regression line between target concentrations and reported values was calculated to evaluate outliers, bias, variability and measurement uncertainty. Results A total of 1,611 results were taken into account. Bias was the highest for Alinity c over the whole concentration range and the lowest for Vitros for low concentrations and Cobas 8000 using the c702 module for high concentrations. The Architect and Cobas c501/c502 systems showed the lowest variability over the whole concentration range. Highest variability was observed for Cobas 8000 using the 702 module, Thermo Scientific and Alinity c. Cobas 8000 using the c702 module showed the highest measurement uncertainty for lower concentrations. For higher concentrations, Alinity c, Thermo Scientific and Vitros were the methods with the highest measurement uncertainty. Conclusions The bias of the enzymatic techniques is nearly negligible for all methods except Alinity c. Variability differs strongly between measurement procedures. This study shows that the Alinity c has a worse measurement uncertainty than other systems for concentrations above 0.5 g/L. Overall, we found the differences in measurement uncertainty to be mainly influenced by the differences in variability.

Increasing cultural and linguistic diversity among children and families brings new challenges for early intervention professionals. The purpose of this study was to identify the specific roles and needs of speech-language pathologists (SLPs) who practice in early intervention settings with culturally and linguistically diverse families of d/Deaf multilingual learners (DMLs). Thirteen SLPs completed an online survey about their practices and needs. Interviews were conducted with five parents of DMLs. Results showed that SLPs have lower self-satisfaction with families of DMLs compared to mainstream families. Parents were highly satisfied with the support they received. Both groups of participants reported a need for specific tools or adaptations, especially if there was no shared language. Thematic analysis identified three themes: communication and partnership, professional resources for responding to diversity, and diversity of parental profiles. This article provides an insight into the perspectives of both professionals and culturally and linguistically diverse parents, and identifies specific aspects of early intervention services with parents of DMLs: developing partnership in the context of cultural and/or linguistic differences, discussing topics related to multilingualism, and providing highly adaptable family-centered services.

Alkylating agents damage DNA and proteins and are widely used in cancer chemotherapy. While cellular responses to alkylation-induced DNA damage have been explored, knowledge of how alkylation affects global cellular stress responses is sparse. Here, we examined the effects of the alkylating agent methylmethane sulfonate (MMS) on gene expression in mouse liver, using mice deficient in alkyladenine DNA glycosylase (Aag), the enzyme that initiates the repair of alkylated DNA bases. MMS induced a robust transcriptional response in wild-type liver that included markers of the endoplasmic reticulum (ER) stress/unfolded protein response (UPR) known to be controlled by XBP1, a key UPR effector. Importantly, this response is significantly reduced in the Aag knockout. To investigate how AAG affects alkylation-induced UPR, the expression of UPR markers after MMS treatment was interrogated in human glioblastoma cells expressing different AAG levels. Alkylation induced the UPR in cells expressing AAG; conversely, AAG knockdown compromised UPR induction and led to a defect in XBP1 activation. To verify the requirements for the DNA repair activity of AAG in this response, AAG knockdown cells were complemented with wild-type Aag or with an Aag variant producing a glycosylase-deficient AAG protein. As expected, the glycosylase-defective Aag does not fully protect AAG knockdown cells against MMS-induced cytotoxicity. Remarkably, however, alkylation-induced XBP1 activation is fully complemented by the catalytically inactive AAG enzyme. This work establishes that, besides its enzymatic activity, AAG has noncanonical functions in alkylation-induced UPR that contribute to cellular responses to alkylation.

International audience; Groundwater pollution threatens human and ecosystem health in many regions around the globe. Fast flow to the groundwater through focused recharge is known to transmit short-lived pollutants into carbonate aquifers, endangering the quality of groundwaters where one quarter of the world’s population lives. However, the large-scale impact of such focused recharge on groundwater quality remains poorly understood. Here, we apply a continental-scale model to quantify the risk of groundwater contamination by degradable pollutants through focused recharge in the carbonate rock regions of Europe, North Africa, and the Middle East. We show that focused recharge is the primary reason for widespread rapid transport of contaminants to the groundwater. Where it occurs, the concentration of pollutants in groundwater recharge that have not yet degraded increases from

In spring 2016, a study was carried out to characterize currently used pesticide (CUP) exposure among children living in Wallonia (Belgium). Pesticides were measured in both first morning urine voids of 258 children aged from 9 to 12 years and in ambient air collected close to the children's schools. Out of the 46 pesticides measured in the air, 19 were detected with frequencies varying between 11 % and 100 %, and mean levels ranging from0.04 to 2.37 ng/m³. Only 3 parent pesticides were found in 1-10% of the urine samples, while all the metabolites analyzed were positively detected at least once. The captan metabolite (THPI) was quantified in 23.5 % of the samples, while 3,5,6-trichloro-2-pyridinol (chlopryrifos metabolite) was detected in all urines with levels ranging from 0.36-38.96 μg/l. 3-phenoxybenzoic acid (3-PBA), trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (t-DCCA) and diethylphosphate were the most abundant pyrethroid metabolites and dialkylphosphate measured. The air inhalation was demonstrated to be a minor route of exposure for the selected CUPs. Statistical regressions highlighted predictors of exposure for some pesticides such like consumption of grey bread, presence of carpets at home or indoor use of pesticides, although no clear source was identified for most of them.

We present here a new method for bioethics: systemic modelling. In this method, the complex phenomenon being studied (e.g. personalized medicine, genetic testing, gene therapy, genetically modified organisms) is modelled as a whole, to shed light on its organization and functioning, and major (bio)ethical issues and solutions for their resolution are then identified. This systemic modelling method is ideal for use in the identification of solutions, rather than their validation, with other methods then used to test the solutions found. We provide a description and reproducible instructions for the application of systemic modelling in bioethics, together with a brief example of the application of this method to the study of the impact of personalized medicine on French society.

Blood is apart from the rest of the tissues as this fluid is overseen by basic and applied life and humanistic sciences. Blood is the essence of human functioning. It is the object of one of the most commonly known cancers, leukemia. It is life-saving in transfusion – a property that also gives blood a special credit and questions blood as a valuable merchandise or as no ones’ property but common good. But blood is also scandalous after the tainted blood affair in the 1980s and 1990s. Blood is further inseparable from most religious practices, both forefront and hidden (magic cults). It is frightening as it is versed in legitimate and illegitimate combats; it is poured to compensate offenses or debts in many civilizations. Any time blood comes forefront, rationale science leaves it to irrational digressions. Even the very same life-saving transfusion, is beaten by groups of opponents on religious grounds. Further, at a time blood cells and molecules are scrutinized, no one can claim having a complete understanding of what blood is, off the vasculature, as – to study it – one has to alter it. The study of blood is fascinating for all colleges of an academy and not many topics can share this property: chemists, physicists, geneticists, physiologists, medical doctors, philosophers, ethicists, theologians, artists, historicists, anthropologists, sociologists, etc. have all contributed to depict different, specific, aspects of blood. The present review aims at merging different aspects of blood to give pathophysiologists a platform to better understand fears and hopes related to this special tissue, when dealing with patients of theirs.

International audience; The etiologies of undifferentiated fever in pregnant women have not been studied thoroughly. Because of its non-specific presentation but severe prognosis, listeriosis is often suspected in this setting, but in most cases not confirmed. We studied the causes of undifferentiated fever in pregnant women who received preemptive listeriosis treatment. We conducted from November 1, 2011, to June 30, 2013, a prospective multicentric observational cohort study of pregnant women referred to obstetrical wards with undifferentiated fever and who received listeriosis preemptive treatment. Clinical and biological features, treatment, outcome, and final diagnosis were collected. We enrolled 103 febrile pregnant women. A cause was identified in 77/103 (75%): viral infection in 52/103 (50%, influenza in 21 (20%)), bacterial infection in 22 (21%, including 16 pyelonephritis (16%) and 3 pneumonias (3%)), and TORCH infection in 3 (3%, varicella, toxoplasmosis, and cytomegalovirus primo-infections, n=1, each). Viral infections collected during influenza outbreaks (December–March) accounted for 43/57 (75%) cases. Two fetal losses were reported in the context of febrile pneumonia. Final diagnoses required adapting medical care in 46/77 (60%) of cases, for bacterial, influenza, or TORCH infections. A large array of benign to potentially severe infections manifests as acute undifferentiated fever in pregnant women, requiring careful repeated evaluation.

Rapid preparation of proteins for functional and structural analysis is a major challenge both in academia and industry. The number potential targets continuously increases and many are difficult to express proteins which, when produced in bacteria, result in insoluble and/or misfolded recombinant proteins, protein aggregates, or unusable low protein yield. We focus here on the baculovirus expression vector system which is now commonly used for heterologous production of human targets. This chapter describes simple and cost-effective protocols that enable iterative cycles of construct design, expression screening and optimization of protein production. We detail time- and cost-effective methods for generation of baculoviruses by homologous recombination and titer evaluation. Handling of insect cell cultures and preparation of bacmid for cotransfection are also presented.

Phosphatidylcholine (PC) vesicles loaded with Triiodothyronine (T3) were fabricated using different manufacturing methods: thin layer hydration plus sonication (TF-UF), supercritical liposome formation (SC), and microfluidic technology (MF). Vesicles obtained by MF had the lowest mean diameter (88.61 ± 44.48 nm) with a Zeta Potential of -20.1 ± 5.90 mV and loading of 10 mg/g (encapsulation efficiency: 57%). In contrast, SC vesicles showed extremely low encapsulation efficiency (10%) probably due to T3 solubility in ethanol/carbon dioxide mixture; despite TF-UF vesicles exhibiting good size (167.7 ± 90 nm; Zp -8.50 ± 0.60 mV) and loading (10 mg/g), poor mass recovery was obtained (50% loss). MF vesicles had low cytotoxicity, and they were well enough internalized by both HeLa and human tendon stem/progenitor cells (hTSPCs). Their biological activity was also monitored in both 2D and 3D cultures of hTSPCs supplemented with therapeutical concentrations of PC/T3 nano-liposomes. 2D culture showed almost similar constitutive gene expression compared to control culture supplemented with free-T3. On the contrary, when hTPSCs 3D culture was assembled, it showed a more evident homogeneous distribution of FITC labeled vesicles within the high-density structure and a significant upregulation of cell constitutive genes, such as type I Collagen (4.8-fold; p 0.0001) at day 7, compared to the control, suggesting that T3/PC formulation has increased T3 cytosolic concentration, thus improving cells metabolic activity. The study supported MF technology for nano-carriers fabrication and opens perspectives on the activity of PC/T3 nano-vesicles as innovative formulations for TPSCs stimulation in ECM secretion.

Gigantism and acromegaly have been observed in past populations; however, analyses usually focus on the morphological features of the post-cranial skeleton. The aim of this study is to characterize the internal anatomical features of the skull (brain endocast anatomy and asymmetry, frontal pneumatization, cranial thickness, sella turcica size) of an adult individual from the 11-14th centuries with these two diseases, in comparison with non-pathological individuals from the same population. The material consisted of 33 adult skulls from a mediaeval population, one of them belonging to an adult female with endocrine disorders (OL-23/77). Based on the CT scans, the internal cranial anatomy was analysed. The sella turcica of OL-23/77 is much larger than in the comparative sample. The endocast of the individual OL-23/77 shows a left frontal/left occipital petalia, while the comparative population mostly had right frontal/left occipital petalias. The asymmetry in petalia location in OL-23/77 comes within the range of variation observed in the comparative population. The individual has high values for cranial thickness. The frontal sinuses of the specimen analysed are similar in size and shape to the comparative sample only for data scaled to the skull length. Enlarged sella turcica is typical for individuals with acromegaly/gigantism. The pattern of the left frontal/left occipital petalia in the specimen OL-23/77 is quite rare. The position of the endocranial petalias has not influenced the degree of asymmetry in the specimen. Despite the large bone thickness values, skull of OL-23/77 does not show any abnormal features. The skull/endocast relationship in this individual shows some peculiarities in relation to its large size, while other internal anatomical features are within the normal range of variation of the comparative sample.

To compare different antibiotic prophylaxis administered after preterm premature rupture of membranes to determine whether any were associated with differences in obstetric and/or neonatal outcomes and/or neurodevelopmental outcomes at 2 years of corrected age.Prospective, nationwide, population-based EPIPAGE-2 cohort study of preterm infants.France, 2011.We included 492 women with a singleton pregnancy and a diagnosis of preterm premature rupture of membranes at 24-31 weeks. Exclusion criteria were contraindication to expectant management or indication for antibiotic therapy other than preterm premature rupture of membranes. Antibiotic prophylaxis was categorised as amoxicillin (n = 345), macrolide (n = 30), third-generation cephalosporin (n = 45) or any combinations covering Streptococcus agalactiae and90% of Escherichia coli (n = 72), initiated within 24 hours after preterm premature rupture of membranes.Population-averaged robust Poisson models.Survival at discharge without severe neonatal morbidity, 2-year neurodevelopment.With amoxicillin, macrolide, third-generation cephalosporin and combinations, 78.5%, 83.9%, 93.6% and 86.0% of neonates were discharged alive without severe morbidity. The administration of third-generation cephalosporin or any E. coli-targeting combinations was associated with improved survival without severe morbidity (adjusted risk ratio 1.25 [95% confidence interval 1.08-1.45] and 1.10 [95 % confidence interval 1.01-1.20], respectively) compared with amoxicillin. We evidenced no increase in neonatal sepsis related to third-generation cephalosporin-resistant pathogen.In preterm premature rupture of membranes at 24-31 weeks, antibiotic prophylaxis based on third-generation cephalosporin may be associated with improved survival without severe neonatal morbidity when compared with amoxicillin, with no evidence of increase in neonatal sepsis related to third-generation cephalosporin-resistant pathogen.Antibiotic prophylaxis after PPROM at 24-31 weeks: 3rd-generation cephalosporins associated with improved neonatal outcomes.

Background Previous studies suggested an elevated risk of venous thromboembolism (VTE) among patients with type 2 diabetes mellitus (T2DM), with a possible sex difference. The impact of glycemic control on the risk of VTE is unclear. Our objective was to analyze the association between glycemic control and the risk of unprovoked (idiopathic) VTE in men and women with T2DM. Methods We conducted a nested case–control analysis (1:4 matching) within a cohort of patients with incident T2DM between 1995 and 2019 using data from the CPRD GOLD. We excluded patients with known risk factors for VTE prior to onset of DM. Cases were T2DM patients with an unprovoked treated VTE. The exposure of interest was glycemic control measured as HbA1c levels. We conducted conditional logistic regression analyses adjusted for several confounders. Results We identified 2′653 VTE cases and 10′612 controls (53.1% females). We found no association between the HbA1c level and the risk of VTE in our analyses. However, when the most recent HbA1c value was recorded within 90 days before the index date, women with HbA1c levels > 7.0% had a 36–55% increased relative risk of VTE when compared to women with HbA1c > 6.5–7.0%. Conclusions Our study raises the possibility that female T2DM patients with HbA1c levels > 7% may have a slightly higher risk for unprovoked VTE compared to women with HbA1c levels > 6.5–7.0%. This increase may not be causal and may reflect differences in life style or other characteristics. We observed no effect of glycemic control on the risk of VTE in men.

The capacity of self-assessment, to learn from experience, to make information-based decisions, and to adapt over time are essential drivers of success for any project aiming at healthcare system change. Yet, many of those projects are managed by healthcare providers' teams with little evaluation capacity. In this article, we describe the support mission delivered by an interdisciplinary scientific team to 12 integrated care pilot projects in Belgium, mobilizing a set of tools and methods: a dashboard gathering population health indicators, a significant event reporting method, an annual report, and the development of a sustainable “learning community.” The article provides a reflexive return on the design and implementation of such interventions aimed at building organizational evaluation capacity. Some lessons were drawn from our experience, in comparison with the broader evaluation literature: The provided support should be adapted to the various needs and contexts of the beneficiary organizations, and it has to foster experience-based learning and requires all stakeholders to adopt a learning posture. A long-time, secure perspective should be provided for organizations, and the availability of data and other resources is an essential precondition for successful work.

BACKGROUND Direct-acting oral anticoagulant use for stroke prevention in atrial fibrillation is limited by bleeding concerns. Asundexian, a novel, oral small molecule activated coagulation factor XIa (FXIa) inhibitor, might reduce thrombosis with minimal effect on haemostasis. We aimed to determine the optimal dose of asundexian and to compare the incidence of bleeding with that of apixaban in patients with atrial fibrillation. METHODS In this randomised, double-blind, phase 2 dose-finding study, we compared asundexian 20 mg or 50 mg once daily with apixaban 5 mg twice daily in patients aged 45 years or older with atrial fibrillation, a CHA2DS2-VASc score of at least 2 if male or at least 3 if female, and increased bleeding risk. The study was conducted at 93 sites in 14 countries, including 12 European countries, Canada, and Japan. Participants were randomly assigned (1:1:1) to a treatment group using an interactive web response system, with randomisation stratified by whether patients were receiving a direct-acting oral anticoagulant before the study start. Masking was achieved using a double-dummy design, with participants receiving both the assigned treatment and a placebo that resembled the non-assigned treatment. The primary endpoint was the composite of major or clinically relevant non-major bleeding according to International Society on Thrombosis and Haemostasis criteria, assessed in all patients who took at least one dose of study medication. This trial is registered with ClinicalTrials.gov, NCT04218266, and EudraCT, 2019-002365-35. FINDINGS Between Jan 30, 2020, and June 21, 2021, 862 patients were enrolled. 755 patients were randomly assigned to treatment. Two patients (assigned to asundexian 20 mg) never took any study medication, resulting in 753 patients being included in the analysis (249 received asundexian 20 mg, 254 received asundexian 50 g, and 250 received apixaban). The mean age of participants was 73·7 years (SD 8·3), 309 (41%) were women, 216 (29%) had chronic kidney disease, and mean CHA2DS2-VASc score was 3·9 (1·3). Asundexian 20 mg resulted in 81% inhibition of FXIa activity at trough concentrations and 90% inhibition at peak concentrations; asundexian 50 mg resulted in 92% inhibition at trough concentrations and 94% inhibition at peak concentrations. Ratios of incidence proportions for the primary endpoint were 0·50 (90% CI 0·14-1·68) for asundexian 20 mg (three events), 0·16 (0·01-0·99) for asundexian 50 mg (one event), and 0·33 (0·09-0·97) for pooled asundexian (four events) versus apixaban (six events). The rate of any adverse event occurring was similar in the three treatment groups: 118 (47%) with asundexian 20 mg, 120 (47%) with asundexian 50 mg, and 122 (49%) with apixaban. INTERPRETATION The FXIa inhibitor asundexian at doses of 20 mg and 50 mg once daily resulted in lower rates of bleeding compared with standard dosing of apixaban, with near-complete in-vivo FXIa inhibition, in patients with atrial fibrillation. FUNDING Bayer.

Background Maintenance ART with dolutegravir-based dual regimens have proved their efficacy among HIV-1-infected subjects in randomized trials. However, real-life data are scarce, with limited populations and follow-up. Objectives We assessed virological failure (VF) and resistance-associated mutations (RAMs) on dolutegravir maintenance regimens in combination with rilpivirine or with lamivudine or emtricitabine (xTC) and analysed the factors associated with VF. Methods Between 2014 and 2018, all HIV-1-infected adults included in the Dat’AIDS cohort and starting dolutegravir/rilpivirine or dolutegravir/xTC as a maintenance dolutegravir-based dual regimen were selected. VF was defined as two consecutive HIV RNA values >50 copies/mL or a single value >400 copies/mL. We compared cumulative genotypes before initiation of a maintenance dolutegravir-based dual regimen with genotype at VF. Results We analysed 1374 subjects (799 on dolutegravir/rilpivirine and 575 on dolutegravir/xTC) with a median follow-up of 20 months (IQR = 11–31) and 19 months (IQR = 11–31), respectively. VF occurred in 3.8% (n = 30) of dolutegravir/rilpivirine subjects and 2.6% (n = 15) of dolutegravir/xTC subjects. Among subjects receiving dolutegravir/rilpivirine, two genotypes harboured emerging RAMs at VF: E138K on NNRTI (n = 1); and E138K+K101E on NNRTI and N155H on INSTI (n = 1). Among subjects receiving dolutegravir/xTC, no new RAM was detected. The only predictive factor of VF on dolutegravir/rilpivirine was the history of failure on an NNRTI-based regimen (adjusted HR = 2.97, 95% CI = 1.28–6.93). No factor was associated with VF on dolutegravir/xTC. Conclusions In this large real-life cohort, dolutegravir/rilpivirine and dolutegravir/xTC sustained virological suppression and were associated with a low rate of VF and RAM emergence. Careful virological screening is essential before switching to dolutegravir/rilpivirine in virologically suppressed patients with a history of NNRTI therapy.

International audience; Several cases of herpes zoster (HZ) following mRNA COVID-19 vaccination (BNT162b2 and mRNA-1273) have been reported, and the first epidemiological evidence suggests an increased risk. We used the worldwide pharmacovigilance database VigiBase to describe HZ cases following mRNA COVID-19 vaccination. We performed disproportionality analyses (case/non-case statistical approach) to assess the relative risk of HZ reporting in mRNA COVID-19 vaccine recipients compared to influenza vaccine recipients and according to patient age. To 30 June 2021, of 716 928 reports with mRNA COVID-19 vaccines, we found 7728 HZ cases. When compared to influenza vaccines, mRNA COVID-19 vaccines were associated with a significantly higher reporting of HZ (reporting odds ratio 1.9, 95% CI 1.8–2.1). Furthermore, we found a reduced risk of reporting HZ among under 40-year-old persons compared to older persons (reporting odds ratio 0.39, 95% CI 0.36–0.41). Mild and infrequent HZ reactions may occur shortly after mRNA COVID-19 vaccination, at higher frequency than reported with influenza vaccination, especially in patients over 40 years old. Further analyses are needed to confirm this risk.

The integration of a viral genome into the host genome has a major impact on the trajectory of the infected cell. Integration location and variation within the associated viral genome can influence both clonal expansion and persistence of infected cells. Methods based on short-read sequencing can identify viral insertion sites, but the sequence of the viral genomes within remains unobserved. We develop PCIP-seq, a method that leverages long reads to identify insertion sites and sequence their associated viral genome. We apply the technique to exogenous retroviruses HTLV-1, BLV, and HIV-1, endogenous retroviruses, and human papillomavirus., SCOPUS: ar.j, info:eu-repo/semantics/published

International audience; On April 7, 1498, Charles VIII, King of France, attended a game of palm in the ditches of the Château d'Amboise. The 27-year-old King suddenly collapsed and became comatose. He laid down, almost on his own, on a straw mat that was hastily arranged, and he died 9 hours later. His contemporaries perceived his death as a perfect reminder of fatality: a king could die alone in a miserable gallery. All who looked into this curious death had dwelled on the frontal blow to head that the king had sustained right before his demise and had not considered alternative scenarios. The present study, still with limited available evidence, aimed to reexamine the historical account of his death in light of modern medical knowledge. It is virtually impossible that a minor bump with low kinetic energy could kill a 27-year-old man. Many historical accounts of Charles VIII’s life and death, including Italian ambassadors' letters, led us to reconsider the commonly held version and to propose an alternative hypothesis. We have concluded that Charles VIII had experienced an acute consciousness disorder with language impairment that could have been related to an epileptic condition secondary to neurosyphilis. We have discussed whether a more accurate diagnosis for the cause of death could be obtained by a pathological analysis of the King’s remains.

VZV infection can involve every level of the neurologic system: from the central nervous system (CNS) to the peripheral nervous system (PNS), including aseptic meningitis. Prognosis seems to differ between these neurological involvements. Prognostic factors remain unknown.This is a retrospective multicenter study including all patients with a positive VZV polymerase chain reaction (PCR) in the cerebrospinal fluid (CSF) from eight centers in Paris (France) between 2011 and 2018. Unfavorable outcome was defined as mortality linked to VZV or incomplete recovery. Modified Rankin Scale (mRS) evaluated disability before and after the infection, with the difference designated as Rankin Delta.Seventy-two patients were included (53% male, median age 51 years, median mRS 0). Immunosuppression was reported in 42%. The clinical spectrum included 26 cases of meningitis, 27 instances of CNS involvement, 16 of PNS involvement, and 3 isolated replications (positive PCR but no criteria for neurological complications from VZV). Antiviral treatment was administered to 69 patients (96%). Sixty-two patients completed follow-up. Death linked to VZV occurred in eight cases. Unfavorable outcome (UO) occurred in 60% and was significantly associated with a higher prior mRS (Odd-ratio (OR) 3.1 [1.4-8.8] p = .012) and the presence of PNS or CNS manifestations (OR 22 [4-181] p = .001, OR 6.2 [1.3-33] p = .03, respectively, compared to meningitis). In the CSF, higher protein level (p .0001) was also significantly associated with a higher Rankin Delta.Neurological complications of VZV with evidence of CSF viral replication are heterogeneous: aseptic meningitis has a good prognosis, whereas presence of CNS and PNS involvement is associated with a higher risk of mortality and of sequelae, respectively.