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Like other Immunoreceptor Tyrosine-based Activation Motif (ITAM)-containing receptors, high-affinity IgE receptors (FcγRI), which initiate allergic reactions, generate activation signals when engaged on mast cells and basophils. By contrast, low-affinity receptors for IgG, FcγRIIB contain an Immunoreceptor Tyrosine-based Inhibition Motif (ITIM) generating inhibitory signals when co-aggregated with ITAM-bearing receptors. They can also inhibit mast cell proliferation induced by Tyrosine Kinase Receptors such as Kit. Inhibitory capabilities of FcγRIIB depend on the recruitment of the SH2 domain-containing Inositol 5-Phosphatase SHIP1, which in turn decreases the amount of the secondary messenger Phosphatidyl Inositol trisphosphate PI(3,4,5)P3. The aim of my thesis was to investigate whether the coligation of an activating receptor with FcγRIIB could inhibit cell activation induced by other receptors that were not co-engaged with FcγRIIB. I could show that, indeed, FcγRIIB when co-aggregated with FcγRI, inhibited not only activation signals induced by co-aggregated FcγRI (cis-inhibition), but also by independently engaged FcγRI or by Kit (trans-inhibition). Vice versa, the co-aggregation of Kit with FcγRIIB inhibited mast cell activation induced by FcγRI. Trans-inhibition was not limited to mast cells but was also effective in mouse and human basophils. Finally, the co-aggregation of Kit and FcγRIIB inhibited the oncogen Abl-dependent proliferation of a mouse mastocytoma. In conclusion, trans-inhibition is a novel SHIP1-dependent regulatory mechanism that can generate an anergic state, preventing cells from responding to various activation and proliferation signals, L'engagement des récepteurs de forte affinité pour les IgE (RFcγI), qui contiennent des motifs d'activation nommés ITAM, induit l'activation des mastocytes et des basophiles. Les récepteurs de faible affinité pour les IgG (RFcγIIB) contiennent des motifs d'inhibition nommés ITIM et inhibent l'activation cellulaire lorsqu'ils sont coagrégés aux récepteurs à ITAM. Les RFcγIIB inhibent également la prolifération cellulaire induite par les récepteurs à activité tyrosine kinase comme Kit. Les propriétés inhibitrices des RFcγIIB reposent sur le recrutement de l'inositol phosphatase SHIP1, qui dégrade le Phosphatidyl Inositol tri-phosphate PI(3,4,5)P3, une molécule impliquée dans de nombreuses voies de signalisation. Au cours de ma thèse, j'ai montré que lorsqu'ils sont coagrégés avec les RFcγI, les RFcγIIB, inhibent non seulement l'activation induite par ces RFcγI (cis-inhibition), mais aussi l'activation induite par d'autres RFcγI et la prolifération induite par Kit. Nous avons appelé cette nouvelle propriété, la trans-inhibition. De même, la coagrégation de Kit avec les RFcγIIB inhibe l'activation des mastocytes induite par les RFcγI. La trans-inhibition peut être également induite dans les basophiles murins et humains. Finalement, la coagrégation de Kit et des RFcyIIB inhibe la prolifération, dépendante de l'oncogène Abl, d'un mastocytome murin. En conclusion, la trans-inhibition est un nouveau mécanisme de régulation, dépendant de SHIP1, qui induit un état d'anergie de la cellule, l'empêchant de répondre à des signaux d'activation et de prolifération

International audience; Background: Outpatient physicians in private practice, as inpatient physicians, are on the frontline of the COVID-19 pandemic. Mental-health consequences of the pandemic on hospital staff have been published, but the psychological distress among outpatient physicians in private practice due to COVID-19 has never been specifically assessed.Methods: A French national online cross-sectional survey assessed declared psychological distress among outpatient physicians in private practice linked to COVID-19, sociodemographic and work conditions, mental health (Copenhagen Burn-out Inventory, Hospital Anxiety and Depression Scale, and the Insomnia severity Index), consequences on alcohol, tobacco, and illegal substance misuse, and sick leave during the 2nd COVID-19 wave.Findings: Among the 1,992 physicians who answered the survey, 1,529 (76.8%) declared psychological distress linked to COVID-19. Outpatient physicians who declared psychological distress linked to COVID-19 had higher rates of insomnia (OR = 1.4; CI95 [1.1-1.7], p = 0.003), burnout (OR = 2.7; CI95 [2.1; 3.2], p < 0.001), anxiety and depressive symptoms (OR = 2.4; CI95 [1.9-3.0], p < 0.001 and OR = 1.7; CI95 [1.3-2.3], p < 0.001) as compared to physicians who did not. They also had higher psychotropic drug use in the last twelve months, or increased alcohol or tobacco consumption due to work-related stress and were more frequently general practitioners.Interpretation: The feeling of being in psychological distress due to COVID-19 is highly frequent among outpatient physicians in private practice and is associated with mental health impairment. There is a need to assess specific interventions dedicated to outpatient physicians working in private practice.

Background Although maternal death is rare in the United Kingdom, 90% of these women had multiple health/social problems. This study aims to estimate the prevalence of pre-existing multimorbidity (two or more long-term physical or mental health conditions) in pregnant women in the United Kingdom (England, Northern Ireland, Wales and Scotland). Study design Pregnant women aged 15–49 years with a conception date 1/1/2018 to 31/12/2018 were included in this population-based cross-sectional study, using routine healthcare datasets from primary care: Clinical Practice Research Datalink (CPRD, United Kingdom, n = 37,641) and Secure Anonymized Information Linkage databank (SAIL, Wales, n = 27,782), and secondary care: Scottish Morbidity Records with linked community prescribing data (SMR, Tayside and Fife, n = 6099). Pre-existing multimorbidity preconception was defined from 79 long-term health conditions prioritised through a workshop with patient representatives and clinicians. Results The prevalence of multimorbidity was 44.2% (95% CI 43.7–44.7%), 46.2% (45.6–46.8%) and 19.8% (18.8–20.8%) in CPRD, SAIL and SMR respectively. When limited to health conditions that were active in the year before pregnancy, the prevalence of multimorbidity was still high (24.2% [23.8–24.6%], 23.5% [23.0–24.0%] and 17.0% [16.0 to 17.9%] in the respective datasets). Mental health conditions were highly prevalent and involved 70% of multimorbidity CPRD: multimorbidity with ≥one mental health condition/s 31.3% [30.8–31.8%]). After adjusting for age, ethnicity, gravidity, index of multiple deprivation, body mass index and smoking, logistic regression showed that pregnant women with multimorbidity were more likely to be older (CPRD England, adjusted OR 1.81 [95% CI 1.04–3.17] 45–49 years vs 15–19 years), multigravid (1.68 [1.50–1.89] gravidity ≥ five vs one), have raised body mass index (1.59 [1.44–1.76], body mass index 30+ vs body mass index 18.5–24.9) and smoked preconception (1.61 [1.46–1.77) vs non-smoker). Conclusion Multimorbidity is prevalent in pregnant women in the United Kingdom, they are more likely to be older, multigravid, have raised body mass index and smoked preconception. Secondary care and community prescribing dataset may only capture the severe spectrum of health conditions. Research is needed urgently to quantify the consequences of maternal multimorbidity for both mothers and children.

Background HIV-1 DNA persists in infected cells, forming viral reservoirs. Pre-antiretroviral treatment (ART) HIV-1 DNA load was reported to predict ART success in European severely immunocompromised patients. The aim of this study was to determine whether HIV-1 DNA levels are associated with virological success in less severely immunocompromised patients who receive early ART in sub-Saharan Africa. Methods The association between pre-ART HIV-1 DNA and the virological response after 30 months on ART was studied in multivariate logistic regression in patients randomised to immediate ART groups in the Temprano trial, which assessed the benefits of early ART in HIV-infected adults in Côte d’Ivoire. HIV-1 DNA was quantified in peripheral blood mononuclear cell (PBMC) using real-time PCR. Results HIV-1 DNA levels were measured in 1013 patients. Their medians [IQR] of pre-ART CD4 count, HIV-1 RNA and HIV-1 DNA levels were 465 [379–578]/mm3, 4.7 [4.0–5.3] log10 copies/ml and 2.9 [2.5–3.2] log10 copies/million PBMC, respectively. Pre-ART HIV-1 DNA was significantly correlated with pre-ART HIV-1 RNA (R = 0.59, p 10 copies/million PBMC was significantly associated with virological success at M30 after adjustment for other key variables (ART regimen, IPT, sex, age, WHO clinical stage, CD4 and HIV-1 RNA; aOR 1.57; 95% CI 1.08–2.30; p = 0.02). Conclusion Low HIV-1 DNA was statistically associated with virological success in this population of sub-Saharan African adults who started treatment with a median pre-ART CD4 count at 465/mm3. HIV-1 DNA could become a useful tool for guiding some therapeutic decisions in the test-and-treat era. Trial registration TEMPRANO ANRS 12136 ClinicalTrials.gov, number NCT00495651, date of registration 03/07/2007.

Background Genome-wide association studies (GWAS) have identified genetic variants associated with multiple complex diseases. We can leverage this phenomenon, known as pleiotropy, to integrate multiple data sources in a joint analysis. Often integrating additional information such as gene pathway knowledge can improve statistical efficiency and biological interpretation. In this article, we propose statistical methods which incorporate both gene pathway and pleiotropy knowledge to increase statistical power and identify important risk variants affecting multiple traits. Methods We propose novel feature selection methods for the group variable selection in multi-task regression problem. We develop penalised likelihood methods exploiting different penalties to induce structured sparsity at a gene (or pathway) and SNP level across all studies. We implement an alternating direction method of multipliers (ADMM) algorithm for our penalised regression methods. The performance of our approaches are compared to a subset based meta analysis approach on simulated data sets. A bootstrap sampling strategy is provided to explore the stability of the penalised methods. Results Our methods are applied to identify potential pleiotropy in an application considering the joint analysis of thyroid and breast cancers. The methods were able to detect eleven potential pleiotropic SNPs and six pathways. A simulation study found that our method was able to detect more true signals than a popular competing method while retaining a similar false discovery rate. Conclusion We developed feature selection methods for jointly analysing multiple logistic regression tasks where prior grouping knowledge is available. Our method performed well on both simulation studies and when applied to a real data analysis of multiple cancers.

Resume Introduction L’information transmise au diagnostic de Tumeur de vessie non infiltrant le muscle (TVNIM) est variable. Or, les patients bien informes sont plus impliques dans les decisions partagees. L’objectif de cette etude etait d’evaluer l’information percue par le patient au moment du diagnostic de TVNIM. Materiel La cohorte francaise VICAN consiste en un echantillon representatif de 4174 patients pris en charge pour un cancer et survivants a 5 ans. Les donnees reportees par les patients ont ete collectees prospectivement par entretiens telephoniques et auto-questionnaires. Parmi les 118 patients pris en charge pour une TVNIM, le terme utilise au diagnostic pour definir la pathologie et l’impact sur la qualite de vie (questionnaires SF12, EORTC-QLQ-C30 et echelle HAD) et sur l’observance (suivi cystoscopique a 1 an selon les donnees du SNIIR-AM) ont ete evalues. Resultats Seuls 26,8 % des patients ont declare avoir entendu le terme “Cancer” a l’annonce du diagnostic de TVNIM. A l’inverse, 73,2 % d’entre eux ont reporte l’utilisation d’autres termes, incluant “Tumeur” (22,0 %), “Polype” (24,8 %) et “Carcinome” (17,1 %). Il n’y avait pas de difference en termes de qualite de vie, physique et mentale, ni d’anxiete ressentie, en fonction du terme utilise. L’observance etait significativement meilleure chez les patients pour qui le mot « Cancer » a ete utilise. Conclusion Trois quarts des patients ayant une TVNIM n’avaient pas integre la notion de “Cancer” au diagnostic. La terminologie utilisee au diagnostic n’influence pas la qualite de vie mais semble impacter l’observance et l’adhesion aux protocoles de soins. Niveau de preuve 3.

Background To manage severe or potentially severe cases of CoronaVirus Disease 2019 (COVID-19), therapeutic monoclonal antibodies targeting Spike protein of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) have been designed. It has been noted in vitro that upon exposure to these treatments, mutations could be selected. Case presentation We here report the case of an immunosuppressed patient infected with a B.1.1.7 variant, who received a combination of monoclonal antibodies, and subsequently selected mutations K417N, E484K and Q493R on Spike protein of SARS-CoV-2. Conclusions Our case raises the importance of monitoring SARS-CoV-2 mutations in patients receiving monoclonal antibodies and having persistent excretion of the virus, in order to offer optimal management of their infection, and strengthen prevention measures to avoid subsequent transmission of these selected variants.

Background Lipid species are accurately distributed in the eukaryotic cell so that organelle and plasma membranes have an adequate lipid composition to support numerous cellular functions. In the plasma membrane, a precise regulation of the level of lipids such as phosphatidylserine, PI(4)P, and PI(4,5)P2, is critical for maintaining the signaling competence of the cell. Several lipid transfer proteins of the ORP/Osh family contribute to this fine-tuning by delivering PS, synthesized in the endoplasmic reticulum, to the plasma membrane in exchange for PI(4)P. To get insights into the role of these PS/PI(4)P exchangers in regulating plasma membrane features, we question how they selectively recognize and transfer lipid ligands with different acyl chains, whether these proteins exchange PS exclusively for PI(4)P or additionally for PI(4,5)P2, and how sterol abundance in the plasma membrane impacts their activity. Results We measured in vitro how the yeast Osh6p and human ORP8 transported PS and PI(4)P subspecies of diverse length and unsaturation degree between membranes by fluorescence-based assays. We established that the exchange activity of Osh6p and ORP8 strongly depends on whether these ligands are saturated or not, and is high with representative cellular PS and PI(4)P subspecies. Unexpectedly, we found that the speed at which these proteins individually transfer lipid ligands between membranes is inversely related to their affinity for them and that high-affinity ligands must be exchanged to be transferred more rapidly. Next we determined that Osh6p and ORP8 cannot use PI(4,5)P2 for exchange processes, because it is a low-affinity ligand, and do not transfer more PS into sterol-rich membranes. Conclusions Our study provides new insights into PS/PI(4)P exchangers by indicating the degree to which they can regulate the acyl chain composition of the PM, and how they control PM phosphoinositide levels. Moreover, we establish general rules on how the activity of lipid transfer proteins relates to their affinity for ligands.

Background Potentially Inappropriate Medications (PIMs) and polypharmacy are widely used indicators of suboptimal prescribing for older people. The aim of this study was to describe the changes in the prevalence of PIMs and polypharmacy among people aged 75 years and over between 2011 and 2019 in France. Methods PIMs and polypharmacy were assessed among people aged 75 years and over every two years between 2011 and 2019 using the French health insurance data system. Sixteen PIM criteria from the 2015 Beers and STOPP lists were assessed. Polypharmacy (5 to 9 drugs) and hyper-polypharmacy (≥10 drugs) were defined based on the average number of drugs dispensed per quarter. The Annual Percent Change (APC) and 95%CI were assessed using linear regression models after standardization of the prevalence on age and sex. Results The study population included 5,777,645 individuals over 75 years old in 2011 and 6,328,155 in 2019. The prevalence of PIMs decreased from 49.6 to 39.6% over the study period (APC: − 1.19% [− 1.35;-1.04]). Of the sixteen indicators assessed, the prevalence of thirteen decreased between 2011 and 2019. Benzodiazepines were the most frequent PIMs (34.7% in 2011 to 26.9% in 2019), followed by anticholinergic drugs (12.1% in 2011 to 8.3% in 2019), oral non-steroidal anti-inflammatory drugs (11.4 to 7.8%), and PIMs related to antihypertensive drugs (7.4 to 6.0%). Overall, women and individuals aged 85 years and older were more likely to receive PIMs. The prevalence of hyper-polypharmacy decreased from 30.5 to 25.9% over the study period. Conclusion This study, which is the first to assess the change in prevalence of PIMs and polypharmacy over time from comprehensive health data in France, highlights that PIMs and hyper-polypharmacy declined between 2011 and 2019. However, PIMs remains frequent for older people and often involves benzodiazepines.

Background The prevalence of receptive anal intercourse (RAI) is increasing. A few studies, with heterogeneous designs, have investigated the associated risk of fecal incontinence (FI). Aim The primary objective of this study was to determine FI prevalence in a population of men who have sex with men (MSM) engaging in RAI. The secondary objective was to identify risk factors for severe FI. Methods Outcomes An online survey of 24,308 MSM was performed in 2019. Demographic and socioeconomic data were collected, together with information about RAI sexual practices, and FI defined by: “During the last month, have you experienced any involuntary leakage of stools?” Results Clinical Implications In total, 1,734 (8%) of the 21,762 participants reported FI. Mean age was 35.3 years. The prevalence of FI was correlated with RAI frequency: 12.7% (if RAI ≥ 1 /wk) versus 5.7% (if no RAI). In multivariate analysis, the factors associated with FI were age (OR: 1.01), low socioeconomic status (OR 1.32 to 1.40), HIV-seropositivity (OR: 1.78), high RAI frequency (OR: 1.64), chemsex (OR: 1.67) and fist-fucking (OR: 1.61). Strengths and Limitations Main strengths of our study are population size and assessment of detailed modalities of sexual practices. Main limitations are the use of a convenience non-random sample and the assessment of FI only during the past month. CONCLUSION This study of a large MSM population, highlights risk factors for FI among RAI practices: RAI ≥ 1 /wk, chemsex, fist-fucking, low socioeconomic status.

Background Successful embryogenesis relies on the coordinated interaction between genes and tissues. The transcription factors Pax9 and Msx1 genetically interact during mouse craniofacial morphogenesis, and mice deficient for either gene display abnormal tooth and palate development. Pax9 is expressed specifically in the pharyngeal endoderm at mid-embryogenesis, and mice deficient for Pax9 on a C57Bl/6 genetic background also have cardiovascular defects affecting the outflow tract and aortic arch arteries giving double-outlet right ventricle, absent common carotid arteries and interruption of the aortic arch. Results In this study we have investigated both the effect of a different genetic background and Msx1 haploinsufficiency on the presentation of the Pax9-deficient cardiovascular phenotype. Compared to mice on a C57Bl/6 background, congenic CD1-Pax9–/– mice displayed a significantly reduced incidence of outflow tract defects but aortic arch defects were unchanged. Pax9–/– mice with Msx1 haploinsufficiency, however, have a reduced incidence of interrupted aortic arch, but more cases with cervical origins of the right subclavian artery and aortic arch, than seen in Pax9–/– mice. This alteration in arch artery defects was accompanied by a rescue in third pharyngeal arch neural crest cell migration and smooth muscle cell coverage of the third pharyngeal arch arteries. Although this change in phenotype could theoretically be compatible with post-natal survival, using tissue-specific inactivation of Pax9 to maintain correct palate development whilst inducing the cardiovascular defects was unable to prevent postnatal death in the mutant mice. Hyoid bone and thyroid cartilage formation were abnormal in Pax9–/– mice. Conclusions Msx1 haploinsufficiency mitigates the arch artery defects in Pax9–/– mice, potentially by maintaining the survival of the 3rd arch artery through unimpaired migration of neural crest cells to the third pharyngeal arches. With the neural crest cell derived hyoid bone and thyroid cartilage also being defective in Pax9–/– mice, we speculate that the pharyngeal endoderm is a key signalling centre that impacts on neural crest cell behaviour highlighting the ability of cells in different tissues to act synergistically or antagonistically during embryo development.

Introduction Many recent studies have investigated the hospital volume-outcome relationship in surgery. In some cases, the results have prompted the centralization of surgical activity. However, the methodologies and interpretations differ markedly from one study to another. The objective of the present scoping review was to describe the various features used to assess the volume-outcome relationship: the analyzed datasets, study population, outcome, covariates, confounders, volume modalities, and statistical methods. Methods and analysis The review was conducted according to a study protocol published in BMJ Open in 2020. Two authors (both of whom had helped to design the study protocol) screened publications independently according to the title, the abstract and then the full text. To ensure exhaustivity, all the papers included by each reviewer went through to the next step. Interpretation The 403 included studies covered 90 types of surgery, 61 types of outcome, and 72 covariates or potential confounders. 191 (47.5%) studies focussed on oncological surgery and 37.8% focussed visceral or digestive tract surgery. Overall, 86.6% of the studies found a statistically significant volume-outcome relationship, although the findings differed from one type of surgery to another. Furthermore, the types of outcome and the covariates were highly diverse. The majority of studies were performed in Western countries, and oncological and visceral surgical procedures were over-represented; this might limit the generalizability and comparability of the studies’ results. Supplementary Information The online version contains supplementary material available at 10.1186/s12874-021-01396-6.

Background Portal vein thrombosis (PVT) is a common complication following splenectomy. It affects between 5 and 55% of patients undergoing surgery with no clearly defined pre-operative risk factors. The aim of this study was to determine the pre-operative risk factors of PVT. Patients and method Single centre, retrospective study of data compiled for every consecutive patient who underwent splenectomy at Toulouse University Hospital between January 2009 and January 2019. Patients with pre- and post-surgical CT scans have been included. Results 149 out of 261 patients were enrolled in the study (59% were males, mean age 52 years). The indications for splenectomy were splenic trauma (30.9%), malignant haemopathy (26.8%) and immune thrombocytopenia (8.0%). Twenty-nine cases of PVT (19.5%) were diagnosed based on a post-operative CT scan performed on post-operative day (POD) 5. Univariate analysis identifies three main risk factors associated with post-operative PVT: estimated splenic weight exceeding 500 g with an OR of 8.72 95% CI (3.3–22.9), splenic vein diameter over 10 mm with an OR of 4.92 95% CI (2.1–11.8) and lymphoma with an OR of 7.39 (2.7–20.1). The role of splenic vein diameter with an OR of 3.03 95% CI (1.1–8.6), and splenic weight with an OR of 5.22 (1.8–15.2), as independent risk factors is confirmed by multivariate analysis. A screening test based on a POD 5 CT scan with one or two of these items present could indicate sensitivity of 86.2% and specificity of 86.7%. Conclusion This study suggests that pre-operative CT scan findings could predict post-operative PVT. A CT scan should be performed on POD 5 if a risk factor has been identified prior to surgery.

Background Screen media use in early childhood has largely increased in recent years, even more so during the COVID-19 epidemic, and there is much discussion regarding its influence on neurodevelopment, including Autism Spectrum Disorder (ASD). Methods We examined the relationship between use of TV, computer, tablet and smartphone at age 2 years and risk of ASD assessed in telephone-based questionnaires among 12,950 children participating in the nationally representative ELFE (‘Etude Longitudinale Française sur les Enfants’) birth cohort study in France. Results In inverse-probability weighted (IPW) multinomial regression analyses, children’s weekly or daily screen media use was associated with an increased likelihood of an intermediate risk of ASD (IPW-controlled OR for weekly use:1.07, 95% CI 1.02—1.12; IPW-controlled OR for daily use:1.05, 95% CI 1.02—1.08) but inversely associated with a high risk (IPW-controlled OR for weekly use: 0.60, 95% CI 0.50—0.73; IPW-controlled OR for daily use: 0.75, 95% CI 0.62—0.91), as ascertained by the M-CHAT. This was confirmed when studying TV as well as computer/tablet exposure separately. Conclusions Overall, our nationally-representative study conducted among a large sample of 2-year-old children, indicates a complex relationship between screen exposure and ASD risk.

Background Providing at-risk communities with uninterrupted access to early diagnosis and treatment is a key component in reducing malaria transmission and achieving elimination. As programmes approach malaria elimination targets it is critical that each case is tested and treated early, which may present a challenge when the burden of malaria is reduced. In this paper we investigate whether malaria testing rates decline over time and assess the impacts of integrating malaria and non-malaria services on testing rates in the malaria elimination task force (METF) programme in the Kayin state of Myanmar. Methods A retrospective analysis was conducted using weekly collected data on testing rates from a network of more than 1200 malaria posts during the period from 2014 to 2020. To determine whether monthly testing rates changed over the years of programme operations, and whether integrating malaria and non-malaria services impacted these testing rates, we fitted negative binomial mixed-effects regression models to aggregate monthly data, accounting for malaria seasonal variation. Results In the first year of malaria post operation, testing rates declined, correlating with a decline in attendance by people from outside the malaria post catchment area, but then remained fairly constant (the Rate Ratio (RR) for 2nd versus 1st year open ranged from 0.68 to 0.84 across the four townships included in the analysis, the RR for 3rd to 6th year versus 1st year open were similar, ranging from 0.59–0.78). The implementation of a training programme, which was intended to expand the role of the malaria post workers, had minimal impact on testing rates up to 24 months after training was delivered (RR for integrated versus malaria-only services ranged from 1.00 to 1.07 across METF townships). Conclusion Despite the decline in malaria incidence from 2014 to 2020, there has been no decline in the malaria testing rate in the METF programme after the establishment of the complete malaria post network in 2016. While the integration of malaria posts with other health services provides benefits to the population, our evaluation questions the necessity of integrated services in maintaining malaria testing rates in areas approaching elimination of malaria.

Background Leishmaniases are regularly seen in non-endemic areas due to the increase of international travels. They include cutaneous leishmaniases (CL) and mucocutaneous (MC) caused by different Leishmania species, and visceral leishmaniases (VL) which present with non-specific symptoms. Methods We reviewed all consecutive leishmaniasis cases seen between September 2012 and May 2020. The diagnostic strategy included microscopy after May-Grünwald-Giemsa staining, a diagnostic quantitative PCR (qPCR) assay, and species identification based on sequencing of the cytochrome b gene. Results Eighty-nine patients had a definitive leishmaniasis diagnosis. Nine patients had VL with Leishmania infantum. Eighty patients had CL. Twelve patients acquired CL after trips in Latin America (7 Leishmania guyanensis, 2 Leishmania braziliensis, 2 Leishmania mexicana, and 1 Leishmania panamensis). Species could be identified in 63 of the 68 CLs mainly after travel in North Africa (59%) with Leishmania major (65%), Leishmania tropica/killicki (24%), and L. infantum (11%), or in West Sub-Saharan Africa (32%), all due to L. major. The median day between appearance of the lesions and diagnosis was 90 [range 60–127]. Conclusions Our diagnostic strategy allows both positive diagnoses and species identifications. Travelers in West Sub-Saharan Africa and North Africa should be better aware of the risk of contracting leishmananiasis., Highlights Imported leishmaniases are regularly seen in non-endemic areas.Cutaneous forms are due to different species that need to be correctly identified for adapting treatment and epidemiologic purposes.The index of suspicion for the visceral form is often low because of the non-specificity of the clinical symptoms and the notion of travel in endemic areas often remote.The strategy, based on diagnostic quantitative PCR followed by sequencing for species identification, allows for rapid and safe diagnoses in a routine laboratory.

International audience; Background: In many clinical applications, evolution of a longitudinal marker is censored by an event occurrence, and, symmetrically, event occurrence can be influenced by the longitudinal marker evolution. In such frameworks joint modeling is of high interest. The Joint Latent Class Model (JLCM) allows to stratify the population into groups (classes) of patients that are homogeneous both with respect to the evolution of a longitudinal marker and to the occurrence of an event; this model is widely employed in real-life applications. However, the finite sample-size properties of this model remain poorly explored. Methods: In the present paper, a simulation study is carried out to assess the impact of the number of individuals, of the censoring rate and of the degree of class separation on the finite sample size properties of the JLCM. A real-life application from the neurology domain is also presented. This study assesses the precision of class membership prediction and the impact of covariates omission on the model parameter estimates. Results: Simulation study reveals some departures from normality of the model for survival sub-model parameters. The censoring rate and the number of individuals impact the relative bias of parameters, especially when the classes are weakly distinguished. In real-data application the observed heterogeneity on individual profiles in terms of a longitudinal marker evolution and of the event occurrence remains after adjusting to clinically relevant and available covariates; Conclusion: The JLCM properties have been evaluated. We have illustrated the discovery in practice and highlights the usefulness of the joint models with latent classes in this kind of data even with pre-specified factors. We made some recommendations for the use of this model and for future research.