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BACKGROUND: Many children with pulmonary tuberculosis remain undiagnosed and untreated with related high morbidity and mortality. Recent advances in childhood tuberculosis algorithm development have incorporated prediction modelling, but studies so far have been small and localised, with limited generalisability. We aimed to evaluate the performance of currently used diagnostic algorithms and to use prediction modelling to develop evidence-based algorithms to assist in tuberculosis treatment decision making for children presenting to primary health-care centres. METHODS: For this meta-analysis, we identified individual participant data from a WHO public call for data on the management of tuberculosis in children and adolescents and referral from childhood tuberculosis experts. We included studies that prospectively recruited consecutive participants younger than 10 years attending health-care centres in countries with a high tuberculosis incidence for clinical evaluation of pulmonary tuberculosis. We collated individual participant data including clinical, bacteriological, and radiological information and a standardised reference classification of pulmonary tuberculosis. Using this dataset, we first retrospectively evaluated the performance of several existing treatment-decision algorithms. We then used the data to develop two multivariable prediction models that included features used in clinical evaluation of pulmonary tuberculosis-one with chest x-ray features and one without-and we investigated each model's generalisability using internal-external cross-validation. The parameter coefficient estimates of the two models were scaled into two scoring systems to classify tuberculosis with a prespecified sensitivity target. The two scoring systems were used to develop two pragmatic, treatment-decision algorithms for use in primary health-care settings. FINDINGS: Of 4718 children from 13 studies from 12 countries, 1811 (38·4%) were classified as having pulmonary tuberculosis: 541 (29·9%) bacteriologically confirmed and 1270 (70·1%) unconfirmed. Existing treatment-decision algorithms had highly variable diagnostic performance. The scoring system derived from the prediction model that included clinical features and features from chest x-ray had a combined sensitivity of 0·86 [95% CI 0·68-0·94] and specificity of 0·37 [0·15-0·66] against a composite reference standard. The scoring system derived from the model that included only clinical features had a combined sensitivity of 0·84 [95% CI 0·66-0·93] and specificity of 0·30 [0·13-0·56] against a composite reference standard. The scoring system from each model was placed after triage steps, including assessment of illness acuity and risk of poor tuberculosis-related outcomes, to develop treatment-decision algorithms. INTERPRETATION: We adopted an evidence-based approach to develop pragmatic algorithms to guide tuberculosis treatment decisions in children, irrespective of the resources locally available. This approach will empower health workers in primary health-care settings with high tuberculosis incidence and limited resources to initiate tuberculosis treatment in children to improve access to care and reduce tuberculosis-related mortality. These algorithms have been included in the operational handbook accompanying the latest WHO guidelines on the management of tuberculosis in children and adolescents. Future prospective evaluation of algorithms, including those developed in this work, is necessary to investigate clinical performance. FUNDING: WHO, US National Institutes of Health.

Background Persistence of Ebola virus (EBOV) in semen remains of deep concern, as sexual transmission of EBOV seems plausible up to 6 months after acute phase of Ebola virus disease (EVD). Favipiravir, a broad spectrum antiviral product, has been evaluated in reducing EVD mortality in Guinea in 2014–2015 in the JIKI trial, the pharmacokinetic results of which suggest that an increase of dose might be necessary to achieve a therapeutically relevant exposure. In FORCE trial, we aimed at evaluating the tolerance and activity of high doses of favipiravir in male EVD survivors with EBOV RNA detection in semen in Guinea. Case In 2016, we launched a phase IIa open-labeled multicenter dose escalation study. Male survivors of EVD with EBOV RT-PCR positive on semen received a loading dose of 2400 mg BID of favipiravir on day 1 then a maintenance dose of 1800 mg BID from day 2–14. The primary outcome was the tolerance, assessed daily during period treatment and up to day 90. Unfortunately only two participants were included and the trial was stopped for lack of recruitment. No clinical adverse event of grade 3/4 was reported for both patients. One patient experienced a grade 3 hypocalcemia at day 10 and 14. Conclusions High doses of favipiravir were well tolerated in these two participants. Better characterized tolerance and pharmacokinetics of high doses of favipiravir are of utmost importance considering that favipiravir is a candidate treatment for a variety of emerging severe viral diseases with poor prognosis., Highlights • Ebola virus (EBOV) RNA in semen of survivors of EBOV disease up to 17 months after disease onset. • High doses of Favipiravir were well tolerated in EBOV disease survivors. • No QTc interval prolongation of grade 2, 3 or 4 with high doses of Favipiravir.

International audience; The 2014-2016 Ebola outbreak in West Africa has triggered accelerated development of several preventive vaccines against Ebola virus. Under the EBOVAC1 consortium, three phase I studies were carried out to assess safety and immunogenicity of a two-dose heterologous vaccination regimen developed by Janssen Vaccines and Prevention in collaboration with Bavarian Nordic. To describe the immune responses induced by the two-dose heterologous vaccine regimen, we propose a mechanistic ODE based model, which takes into account the role of immunological memory. We perform identifiability and sensitivity analysis of the proposed model to establish which kind of biological data are ideally needed in order to accurately estimate parameters, and additionally, which of those are non-identifiable based on the available data. Antibody concentrations data from phase I studies have been used to calibrate the model and show its ability in reproducing the observed antibody dynamics. Together with other factors, the establishment of an effective and reactive immunological memory is of pivotal importance for several prophylactic vaccines. We show that introducing a memory compartment in our calibrated model allows to evaluate the magnitude of the immune response induced by a booster dose and its long-term persistence afterwards.

International audience; OBJECTIVES: The overall death toll from COVID-19 in Africa is reported to be low but there is little individual-level evidence on the severity of the disease. This study examined the clinical spectrum and outcome of patients monitored in COVID-19 care centres (CCCs) in two West-African countries. METHODS: Burkina Faso and Guinea set up referral CCCs to hospitalise all symptomatic SARS-CoV-2 carriers, regardless of the severity of their symptoms. Data collected from hospitalised patients by November 2020 are presented. RESULT: A total of 1,805 patients (64% men, median age 41 years) were admitted with COVID-19. Symptoms lasted for a median of 7 days (IQR 4-11). During hospitalisation, 443 (25%) had a SpO2 < 94% at least once, 237 (13%) received oxygen and 266 (15%) took corticosteroids. Mortality was 5% overall, and 1%, 5% and 14% in patients aged

Background Insufficient sleep duration among university students was commonly associated with many detrimental effects. University students experience substantial environmental and psychological changes. Female and male university students may differ in many spheres. However, most research on sleep duration of university students is based on an aggregate sample rather than digging the sex-specific profiles. The objective of this study is to examine potential sex differences in the correlates of sleep duration and explore the underlying mechanism of correlations. Methods This is a large-scale university-based mental health survey, which was conducted in university students in Qinghai Province in Northwest China in December 2019. A multi-stage logistic regression was separately fitted by sex to examine the factors associated with short sleep duration in university students. Results A total of 5,552 university students with an average sleep duration of 6.88 h (SD = 1.04) were included, among which 35.0% of the participants may currently be sleeping less than the optimal duration. Female students (6.84 h, SD = 1.00) slept shorter than males (6.94 h, SD = 1.09). The only parallel between sexes was that both female and male students with 3–5 times weekly breakfast were less likely to have short sleep duration. Adjusting for depressive symptoms in the following step eliminated the association between anxiety symptoms and short sleep duration in the model for female students. Female-specific associated factors with short sleep duration were age, grade, academic pressure, weekly physical exercise, depressive symptoms. Male-specific characteristics were current smoking tobacco cigarette, self-perceived health, duration of daily Internet use. Conclusion Characteristic profiles of sleep duration differed between female and male university students; only a few male-specific factors were identified. Psychological guidance and education courses as well as other interventions to improve university students’ sleep and related health should be designed and implemented based on sex differences.

International audience; BACKGROUND: Associations between socioeconomic status (SES) and breast cancer survival are most pronounced in young patients. We further investigated the relation between SES, subsequent recurrent events and mortality in breast cancer patients < 40 years. Using detailed data on all recurrences that occur between date of diagnosis of the primary tumor and last observation, we provide a unique insight in the prognosis of young breast cancer patients according to SES. METHODS: All women < 40 years diagnosed with primary operated stage I-III breast cancer in 2005 were selected from the nationwide population-based Netherlands Cancer Registry. Data on all recurrences within 10 years from primary tumor diagnosis were collected directly from patient files. Recurrence patterns and absolute risks of recurrence, contralateral breast cancer (CBC) and mortality - accounting for competing risks - were analysed according to SES. Relationships between SES, recurrence patterns and excess mortality were estimated using a multivariable joint model, wherein the association between recurrent events and excess mortality (expected mortality derived from the general population) was included. RESULTS: We included 525 patients. The 10-year recurrence risk was lowest in high SES (18.1%), highest in low SES (29.8%). Death and CBC as first events were rare. In high, medium and low SES 13.2%, 15.3% and 19.1% died following a recurrence. Low SES patients had shorter median time intervals between diagnosis, first recurrence and 10-year mortality (2.6 and 2.7 years, respectively) compared to high SES (3.5 and 3.3 years, respectively). In multivariable joint modeling, high SES was significantly related to lower recurrence rates over 10-year follow-up, compared to low SES. A strong association between the recurrent event process and excess mortality was found. CONCLUSIONS: High SES is associated with lower recurrence risks, less subsequent events and better prognosis after recurrence over 10 years than low SES. Breast cancer risk factors, adjuvant treatment adherence and treatment of recurrence may possibly play a role in this association.

Resumen: Introducción: La representación del menor en los anuncios de publicidad es un tema poco investigado y reflejado en la bibliografía, tanto de la pediatría social como de la comunicación audiovisual. El objetivo del presente estudio es describir cómo se representa al menor en la publicidad que se vehiculiza a través de Internet, y si esa representación es adecuada o no. Material y métodos: Se analizaron todos los anuncios en los que aparecían menores a lo largo de 2 meses, visualizando, 3 días por semana, las páginas web más visitadas en España. La valoración de cómo se representaba al menor se realizó con una herramienta de evaluación, elaborada por los autores, basada en la legislación europea y española, que mostró una alta concordancia interevaluador. Se realizó un análisis descriptivo de las variables categóricas y se estableció la relación de interdependencia entre las mismas a través de la prueba Chi-cuadrado. Resultados: Se identificaron 173 anuncios donde apareció al menos un menor, que es generalmente representado solo (63,5%), en un entorno natural (36,9%) y con edad escolar (44,5%). Las páginas web de «prensa general» son las que más frecuentemente muestran anuncios donde se representan menores, a través del uso de banners (82%). En la mayor parte de los casos el uso inadecuado de la figura del menor tiene lugar mediante la representación táctica del mismo, y no meramente estratégica. Conclusiones: El uso de la imagen del menor en la publicidad que se vehiculiza a través de las páginas web más visitadas en España es inadecuada en 2 de cada 3 anuncios. Dicho mal uso del menor suele objetivarse en la representación del mismo de forma estratégicamente no justificable, y favoreciendo valores no positivos o que favorecen situaciones de desigualdad. Abstract: Introduction: The representation of the minor in advertisements is a topic that is scarcely studied and reflected in the bibliography, in social paediatrics as well as audio-visual communication. The aim of the present study is to describe how the minor is represented in the publicity that is conveyed through the internet, and whether or not that representation is adequate. Material and methods: An analysis was made of all the advertisements in which minors appeared during a period of two months, on three days a week, on the most visited web pages in Spain. The evaluation on how the minor was represented was carried out with an evaluation tool, constructed by the authors, based on European and Spanish legislation, which showed a high concordance between evaluators. A descriptive analysis was performed on the categorical variables, and the inter-dependent relationship was established between them using the chi-squared test. Results: A total of 173 advertisements were identified in which at least one minor appeared, which was generally represented solo (63.5%), in a natural environment (36.9%) and of school age (44.5%). The web pages of the “general press” are those that most frequently show advertisement in which minors are represented, through the use of banners (82%). In the majority of cases the inadequate use of the figure of the minor takes place using tactical representation, and not just strategic. Conclusions: The image of the minor in the publicity that is conveyed via the most visited web pages in Spain is inadequate in 3 of every 3 advertisements. This misuse of the minor is usually seen in as unjustifiably strategic, and favouring non-positive values or that they favour situations of inequality

International audience; The West and Central African region (WCAR) still registers some of the highest rates of new HIV infections worldwide (16%) despite a low prevalence of HIV (1.9%). In this region, only 48% of people living with HIV are aware of their HIV status. To fill this gap, HIV Self testing (HIVST) could potentially be an additional approach to overcome the barriers to diagnose HIV infected patients, therefore being one of the keys to unlock the first 90 as recommended by the World Health Organization (WHO) since 2016. However, many challenges remain for the adoption of HIVST in routine clinical practice in low prevalence settings and need to be contextualized to WCAR settings. We report in this paper some of the challenges and discuss opportunities for a successful implementation of HIVST in the WCAR.

International audience; BACKGROUND: Healthcare-associated infections pose a serious problem in terms of health and mortality. Their prevention is a necessity, and healthcare professionals are one of their main vectors. Thus, they must be at the centre of preventative strategies. As hydro-alcoholic solutions (alcohol-based hand rub) represent the most effective means of preventing these infections, it is necessary to identify the representations, barriers, and facilitators of their use. METHOD: Forty-six healthcare professionals from two areas in France, New Aquitaine and Guadeloupe, were questioned about their practices through semi-structured registered interviews and four focus groups. Each interview and focus group were transcribed then analysed through lexicometric and thematic content analyses. RESULTS: The interviewed identified several barriers and facilitators related to the composition and characteristics of hydro-alcoholic solutions (unpleasantness, harmfulness, personal preferences for other hand hygiene products), personal factors (work habits, cognitive bias, lack of knowledge and communication) and organizational (professional constraints, product accessibility, financial resources). CONCLUSION: Strategies to prevent healthcare-associated infections should be constructed with consideration of psychosocial facilitators and barriers for healthcare professionals in using hydro-alcoholic solutions. These strategies should also ensure that they are well informed about the effectiveness of alcohol-based solutions, through prevention campaigns and scientific articles. This awareness should equally be conveyed with educational tools that involve healthcare professionals and use the social dynamics of their work environment.

Deep learning-based convolutional neural networks have recently proved their efficiency in providing fast segmentation of major brain fascicles structures, based on diffusion-weighted imaging. The quantitative analysis of brain fascicles then relies on metrics either coming from the tractography process itself or from each voxel along the bundle.Statistical detection of abnormal voxels in the context of disease usually relies on univariate and multivariate statistics models, such as the General Linear Model (GLM). Yet in the case of high-dimensional low sample size data, the GLM often implies high standard deviation range in controls due to anatomical variability, despite the commonly used smoothing process. This can lead to difficulties to detect subtle quantitative alterations from a brain bundle at the voxel scale.Here we introduce TractLearn, a unified framework for brain fascicles quantitative analyses by using geodesic learning as a data-driven learning task. TractLearn allows a mapping between the image high-dimensional domain and the reduced latent space of brain fascicles using a Riemannian approach.We illustrate the robustness of this method on a healthy population with test-retest acquisition of multi-shell diffusion MRI data, demonstrating that it is possible to separately study the global effect due to different MRI sessions from the effect of local bundle alterations. We have then tested the efficiency of our algorithm on a sample of 5 age-matched subjects referred with mild traumatic brain injury.Our contributions are to propose an algorithm based on:1/ A manifold approach to capture controls variability as standard reference instead of an atlas approach based on a Euclidean mean2/ The ability to detect global variation of voxels quantitative values, which means that all the voxels interaction in a structure are considered rather than analyzing each voxel independently.With this regard, TractLearn is a ready-to-use algorithm for precision medicine.KEY POINTWe provide a statistical test taking into account the interaction between voxelsWe propose to use a Riemaniann manifold as reference instead of a Euclidean meanWe demonstrate the usefulness and reliability of the track-weighted contrast

INTRODUCTION: Liver disease is currently one of the leading causes of death in older adults and the only option deemed curative is liver transplantation. However, it is uncertain whether the successful results obtained in older adults that receive a liver transplant in developed countries can be replicated in developing countries. AIM: To determine if there are differences in the survival time between older (>/=60years) and younger adults that underwent liver transplantation at a university-affiliated tertiary care center in Mexico City.MATERIALS AND METHODS: A 2-year longitudinal study was conducted. It included 244 participants that were divided into 2groups according to age at the time of transplantation: older adults (>/=60years) and younger adults (18-59years). Survival time was defined as the number of days that elapsed between transplantation and death. Survival was expressed as Kaplan-Meier curves.RESULTS: Median age in the older adults (n=52) was 63.0 (IQR=60-69) and 23 participants were females (44.2%). In the younger adults (n=196) median age was 47.0 (IQR=16-59) and 104 were females (52%). The leading indication for transplant was hepatitisC virus. After the follow-up, fifteen participants died (12 younger adults and 3 older adults). No significant differences were observed between older and younger participants in postoperative complications, the number of re-admissions, or mean post-transplantation survival time.CONCLUSIONS: There were no statistically significant differences in relation to survival times between older and younger adults that received a liver transplant. Older patients in developing countries should not be excluded from the selection process due only to age., Introducción: Las enfermedades hepáticas son una causa importante de muerte en las personas adultas mayores, y el trasplante de hígado suele ser la única opción curativa. Sin embargo, es incierto si los buenos resultados obtenidos en esta población trasplantada en países desarrollados pueden ser replicados en los países de economías emergentes.Objetivo: Determinar si hay una diferencia en la sobrevida de adultos mayores (≥ 60 años) y adultos jóvenes sometidos a trasplante hepático en un hospital universitario de tercer nivel en la Ciudad de México.Material y métodos: Estudio longitudinal de 244 personas con 2 años de seguimiento y que se dividieron por edad al momento del trasplante: adultos mayores y jóvenes. La sobrevida se definió como el número de días ocurridos entre trasplante y muerte. Esta se analizó mediante curvas de Kaplan-Meier.Resultados: El promedio de edad en los adultos mayores (n = 52) fue de 63.0 (RIC = 60-69) y 23 participantes fueron mujeres (44.2%). En los adultos jóvenes (n = 196) el promedio de edad fue de 47.0 (RIC = 16-59) y 104 fueron mujeres (52%). La principal indicación para trasplante fue infección por el virus de la hepatitis C. Durante el seguimiento, 15 personas murieron (12 adultos jóvenes y 3 adultos mayores). No hubo diferencia estadísticamente significativa entre los grupos con respecto a la frecuencia de complicaciones postoperatorias, número de reingresos hospitalarios o sobrevida postrasplante.Conclusiones: No hay diferencia en la sobrevida entre los adultos mayores y jóvenes que reciben un trasplante hepático. Los adultos mayores en los países de economías emergentes no deberían ser excluidos del proceso de selección para recibir este órgano solo por el criterio de edad.

Background: Dioxins, Group 1 carcinogens, are emitted by industrial chlorinated combustion processes and suspected to increase breast cancer risk through receptor-mediated pathways. Objectives: We estimated breast cancer risk associated with airborne dioxin exposure, using geographic information system (GIS) methods and historical exposure data. Methods: We designed a case-control study (429 breast cancer cases diagnosed between 1990 and 2008, matched to 716 controls) nested within the E3N (Etude Epidémiologique auprès de femmes de la Mutuelle Générale de l'Education Nationale) cohort. Airborne dioxin exposure was assessed using a GIS-based metric including participants' residential history, technical characteristics of 222 dioxin sources, residential proximity to dioxin sources, exposure duration and wind direction. Odds ratios (OR) and 95% confidence intervals (CI) associated with quintiles of cumulative exposure were estimated using multivariate logistic regression models. Results: We observed no increased risk of breast cancer for higher dioxin exposure levels overall and according to hormone-receptor status. We however observed a statistically significant OR for Q2 versus Q1 overall (1.612, 95% CI: 1.042–2.493) and for estrogen-receptor (ER) positive breast cancer (1.843, 95% CI: 1.033–3.292). Conclusions: Overall, as well as according to hormone-receptor status, no increased risk was observed for higher airborne dioxin exposure. The increased risk for low exposure levels might be compatible with non-monotonic dose-response relationship. Confirmation of our findings is required. Our GIS-based metric may provide an alternative in absence of ambient dioxin monitoring and may allow assessing exposure to other pollutants. Keywords: Breast cancer, Endocrine disruptors, Dioxins, Geographic information system, Tumor receptor

International audience; Background: : Physical functioning may be limited in older, frail patients with missing teeth without prosthetic correction. This cross-sectional study examined the relationship between physical performance and the geriatric masticatory coefficient (GMC) in patients who underwent both a comprehensive gerontological assessment (CGA) to improve poly-pathology management and an intra-oral exam. Methods: : All patients were evaluated based on the following: (corrected) GMC, number of posterior occluding pairs (POPs), short physical performance battery (SPPB) or timed up and go (TUG) test, and mini-nutritional assessment (MNA). Results: : Of the 256 patients (mean age 83.76[SD 6.16], 148F), 75 (29.30%) were malnourished. The corrected GMC was lower in malnourished patients. When adjusted for age, gender, and MNA, the corrected GMC correlated with the TUG time (r=-0.198, p=0.005) and SPPB score (r=0.282, p=0.009). Correlations between GMC and POPs were determined for the SPPB (r=0.269, p=0.013; r=0.319, p=0.004, respectively) but not for the TUG (r=-0.108, p=0.128; r=-0.136, p=0.072). Conclusion: : The correlation between physical performance and decreased masticatory capacity was not fully explained by malnutrition in mildly to severely frail and multi-morbid patients; posture may also be impaired by missing teeth. The study of dental care effects on physical performance will provide further insights.

International audience

Background Whole exome sequencing and RNA sequencing (WES/RNASeq) should now be implemented in the clinical practice in order to increase access to optimal care for cancer patients. Providing results to Tumour Boards in a relevant time frame—that is, compatible with the clinical pathway—is crucial. Assessing the feasibility of this implementation in the French care system is the primary objective of the Multipli study, as one of the four pilot projects of the national France Genomic Medicine 2025 (FGM 2025) plan. The Multipli study encompasses two innovative trials which will be driven in around 2400 patients suffering from a soft-tissue sarcoma (Multisarc) or a metastatic colorectal carcinoma (Acompli). Methods Prior to launching the FGM 2025 cancer pilot study itself, the performance of the Multipli genomic workflow has been evaluated through each step, from the samples collection to the Molecular Tumour Board (MTB) report. Two Multipli-assigned INCa-labelled molecular genetics centres, the CEA-CNRGH sequencing platform and the Institut Bergonie’s Bioinformatics Platform were involved in a multicentric study. The duration of each step of the genomic workflow was monitored and bottlenecks were identified. Results Thirty barriers which could affect the quality of the samples, sequencing results and the duration of each step of the genomic pathway were identified and mastered. The global turnaround time from the sample reception to the MTB report was of 44 calendar days. Conclusion Our results demonstrate the feasibility of tumour genomic analysis by WES/RNASeq within a time frame compatible with the current cancer patient care. Lessons learnt from the Multipli WES/RNASeq Platforms Workflow Study will constitute guidelines for the forthcoming Multipli study and more broadly for the future clinical routine practice in the first two France Genomic Medicine 2025 platforms.

[EN] Several studies have investigated the differential vulnerability of hippocampal subfields during aging and Alzheimer's disease (AD). Results were often contradictory, mainly because these works were based on concatenations of cross-sectional measures in cohorts with different ages or stages of AD, in the absence of a longitudinal design. Here, we investigated 327 participants from a population-based cohort of nondemented older adults with a 14-year clinical follow-up. MRI at baseline and 4 years later were assessed to measure the annualized rates of hippocampal subfields atrophy in each participant using an automatic segmentation pipeline with subsequent quality control. On the one hand, CA4 dentate gyrus was significantly more affected than the other subfields in the whole population (CA1-3: -0.68%/year; subiculum: -0.99%/year; and CA4-DG: -1.39%/year; p < 0.0001). On the other hand, the annualized rate of CA1-3 atrophy was associated with an increased risk of developing Alzheimer's clinical syndrome over time, independently of age, gender, educational level, and ApoE4 genotype (HR = 2.0; CI 95% 1.4-3.0). These results illustrate the natural history of hippocampal subfields atrophy during aging and AD by showing that the dentate gyrus is the most vulnerable subfield to the effects of aging while the cornu-ammonis is the primary target of AD pathophysiological processes, years before symptom onset., The 3C Study is conducted under a partnership agreement among the Institut National de la Sante et de la Recherche Medicale (INSERM), Bordeaux University, and Sanofi. The Fondation pour la Recherche Medicale funded the preparation and initiation of the study. The 3C Study is also supported by Caisse Nationale Maladie des Travailleurs Salaries, Direction Generale de la Sante, Mutuelle Generale de l'Education Nationale, Institut de la Longevite, Conseils Regionaux d'Aquitaine et Bourgogne, Fondation de France, and the Ministry of Research-INSERM Programme "Cohortes et collections de donnees biologiques". The follow-ups have also been funded by ANR 2007LVIE 003, the "Fondation Plan Alzheimer," and the Caisse Nationale de Solidarite pour l'Autonomie (CNSA). This work benefited from the support of the project DeepvolBrain of the French National Research Agency (ANR-18-CE45-0013) and by the Spanish DPI2017-87743-R grant from the Ministerio de Economia, Industria y Competitividad of Spain. In addition, this study was achieved within the context of the Laboratory of Excellence TRAIL ANR-10-LABX-57 for the BigDataBrain project. Finally, the authors thank the Investments for the future Program IdEx Bordeaux (ANR10-IDEX-03-02, HL-MRI Project), Cluster of excellence CPU, and the CNRS. VP also received grants from Fondation Bettencourt Schueller (CCA-Inserm-Bettencourt). The sponsors did not participate in any aspect of the design or performance of the study, including data collection, management, analysis, and the interpretation or preparation, review, and approval of the manuscript.

Highlights • Brain-Computer Interfaces (BCI)-based therapy relies on timely sensory feedback. • Somatosensory loss is usually not reported for these therapies. • Yet, it influences motor imagery, neuroplasticity and motor rehabilitation. • And stroke-induced somatosensory impairments are frequent and diverse. • Thus, BCI-based motor therapy efficiency likely depends on somatosensory abilities., The neuronal loss resulting from stroke forces 80% of the patients to undergo motor rehabilitation, for which Brain-Computer Interfaces (BCIs) and NeuroFeedback (NF) can be used. During the rehabilitation, when patients attempt or imagine performing a movement, BCIs/NF provide them with a synchronized sensory (e.g., tactile) feedback based on their sensorimotor-related brain activity that aims at fostering brain plasticity and motor recovery. The co-activation of ascending (i.e., somatosensory) and descending (i.e., motor) networks indeed enables significant functional motor improvement, together with significant sensorimotor-related neurophysiological changes. Somatosensory abilities are essential for patients to perceive the feedback provided by the BCI system. Thus, somatosensory impairments may significantly alter the efficiency of BCI-based motor rehabilitation. In order to precisely understand and assess the impact of somatosensory impairments, we first review the literature on post-stroke BCI-based motor rehabilitation (14 randomized clinical trials). We show that despite the central role that somatosensory abilities play on BCI-based motor rehabilitation post-stroke, the latter are rarely reported and used as inclusion/exclusion criteria in the literature on the matter. We then argue that somatosensory abilities have repeatedly been shown to influence the motor rehabilitation outcome, in general. This stresses the importance of also considering them and reporting them in the literature in BCI-based rehabilitation after stroke, especially since half of post-stroke patients suffer from somatosensory impairments. We argue that somatosensory abilities should systematically be assessed, controlled and reported if we want to precisely assess the influence they have on BCI efficiency. Not doing so could result in the misinterpretation of reported results, while doing so could improve (1) our understanding of the mechanisms underlying motor recovery (2) our ability to adapt the therapy to the patients’ impairments and (3) our comprehension of the between-subject and between-study variability of therapeutic outcomes mentioned in the literature.

Purpose Restraint is often used when administering procedures to children. However, no metrologically scale to measure the restraint intensity had yet been validated. This study validated the metrological criteria of a scale measuring the restraint intensity, Procedural Restraint Intensity in Children (PRIC), used during procedures in children. Design and methods The PRIC scale performance was measured by a group of 7 health professionals working in a children's hospital, by watching 20 videos of health care procedures. This group included 2 physicians, 1 pediatric resident, and 4 nurses. The intra-class correlation coefficients were calculated to evaluate the inter-rater and test-retest reliability and the construct validity with the correlation between PRIC scale and a numerical rating scale. Results One hundred and forty measurements were made. Inter-rater and test-retest correlation coefficients were 0.98 and 0.98, respectively. The 2 scales were positively correlated with a Spearman coefficient of 0.93. Conclusions This study validated the Procedural Restraint Intensity in Children (PRIC) scale in metrological terms with some limitation. However, there is not gold standard scale to precisely validate the reliability of this tool and this study has been conducted in "experimental" conditions. Nevertheless, this is the first scale measuring the intensity of physical restraint with a metrological validation. The next step will be to validate it in real clinical situations.

International audience; BACKGROUND: Venous thromboembolism (VTE) after total knee or hip replacement (TKR, THR) is usually prevented with low-molecular weight heparin (LMWH), and increasingly by direct oral anticoagulants (DOAC). The aim of the present study was to compare the benefit-risk and medical costs of DOAC vs. LMWH in a real-life setting. METHODS: All patients with THR or TKR in France between Jan-1st 2013 and Sep-30th 2014, discharged to home, were identified and followed-up for 3 months in the French nationwide claims database, SNDS. DOAC users were 1:1 matched with LWMH users on gender, age and propensity score. Relative risks (RR) of hospitalized VTE, hospitalized bleeding and death were estimated using quasi-Poisson models. Medical costs were calculated according to the societal perspective, including total cost for outpatient claims and national DRG costs for hospitalisations. RESULTS: Most DOAC users (>/= 98.8%) were matched to a LMWH patient. For the 63,238 matched THR patients, the 3-month absolute risk of VTE was 0.9 per thousand with DOAC and 2.5 per thousand with LMWH (RR = 0.35 [0.23 to 0.54]), of bleeding 1.8 per thousand and 2.1 per thousand (0.88 [0.62-1.25]), death 0.7 per thousand and 1.1 per thousand (0.68 [0.40-1.15]). For the 31,440 matched TKR patients, risks were 1.6 per thousand and 2.3 per thousand (0.69 [0.42-1.16]) for VTE, 2.4 per thousand and 3.8 per thousand (0.64 [0.43 to 0.97]) for bleeding, and 0.6 per thousand and 0.8 per thousand (0.69 [0.30-1.62]) for all-cause death. Mean medical costs were 28% and 21% lower with DOAC than LMWH for THR and TKR, respectively. This nationwide study found a very low risk of VTE, hospitalized bleeding and death after THR or TKR discharge in patients with VTE prevention in real-life setting, with better benefit-risk profiles of DOAC compared to LMWH, and associated cost savings.

Objective To compare the risk of all-cause death, hospitalizations (any cause), ectopic pregnancy, pelvic inflammatory disease or infection, uterine perforation, device removal, neuro-psychiatric drugs initiation, or new psychiatric visit(s) between levonorgestrel (LNG) 52 mg intrauterine system (IUS) and copper intrauterine device (IUD) users in France. Study design We identified a historical cohort of women aged 20–55 years with a first dispensing of either LNG 52 mg IUS or copper-IUD between January 1, 2010, and December 31, 2014, in the French National Claims database, SNDS. We used propensity score matching to balance the two groups on baseline sociodemographic and clinical characteristics to minimize confounding. We estimated Cox proportional hazards models to compare health outcomes between LNG 52 mg IUS and copper-IUDs users. Results We matched 9318 LNG 52 mg IUS users (mean age 36.2±6.8 years) to 10,185 copper-IUD users (mean age 35.4±7.1 years). After matching and age-adjustment, LNG 52 mg IUS users had a slightly higher risk of anxiolytic drugs initiation (HR 1.08, 95%CI 1.01–1.15) and device removal (HR 1.05, 95%CI 1.01–1.10) compared to copper-IUD users, with no differences for other studied outcomes. Conclusion French IUS users report slightly more anxiolytic treatment initiation and IUD removal compared to copper-IUD users. These results are consistent with a potential pharmacovigilance signal of anxiety-related disorders in LNG 52 mg IUS users. Implications statement In French LNG 52 mg IUS users, there was slightly more anxiolytic treatment initiation and IUD removal compared to copper-IUD users. No risk difference was found for all-cause death, hospitalizations, ectopic pregnancy, pelvic disorders, and uterine perforation. We cannot exclude that the associations are related to differences in characteristics of women who chose each type of type of IUD.

Background Surrogate endpoints (SEs) for overall survival (OS) are specific to therapeutic class. The objective of this review was to document all alternative endpoints studied for their association with OS in Immune-Checkpoint Inhibitors (ICI)-treated patients. Methods We searched PubMed and Embase for publications reporting the association between a clinical endpoint and OS in ICI-treated populations from 01/01/2003 to 03/31/2018. Results Out of 6,335 references identified, 24 were selected. Only 3 studies assessed surrogacy at both the patient and trial levels. The main traditional alternative endpoints included progression-free survival (N = 10) and objective response rate (N = 8). New alternative endpoints, such as durable response rate (N = 1) and intermediate response endpoint (N = 1) statistically better correlate with OS in the cancer types analysed. Conclusion Based on the published evidence, there is insufficient data to support validated SE for OS. Adequate surrogacy assessment of promising composite endpoints which consider a duration component is encouraged.