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Multicenter field evaluation of Xpert MTB/XDR in Sub-Saharan Africa
No full textInternational audienceThe WHO-endorsed Xpert MTB/XDR assay provides a rapid method to detect resistance to isoniazid, fluoroquinolones, injectables aminoglycosides and ethionamide yet evaluation of its performance, particularly in endemic settings, remains limited. We conducted a prospective multicenter study (June 2017-March 2021), in nine sub-Saharan African countries enrolling adults with confirmed pulmonary tuberculosis by Xpert MTB/RIF or Ultra. Xpert MTB/XDR results were compared to a WHO-endorsed targeted next-generation sequencing reference used on the same sputum, with discordance resolved using whole genome sequencing and phenotypic drug-susceptibility testing when available. Diagnostic accuracy for each drug was calculated, also accounting for genotypic heteroresistance detection. Among 1238 included patients, Xpert MTB/XDR demonstrated high specificity (≥98%) across all drugs yet showed variable sensitivity by detecting 606/637 isoniazid-resistant (95%; CI 94–97), 22/33 fluoroquinolones-resistant (67%; CI 48–81) and 159/279 ethionamide-resistant (57%; CI 51–63) samples. The assay reliably detected most common resistance-conferring mutations such as katG _S315T, fabG1 _C-15T and gyrA_A90V and D94G, yet failed to detect low-frequency heteroresistance (≤ 10–35%) and off-target mutations mostly for ethionamide. Amikacin resistance was rare (0.2%). Sensitivity for fluoroquinolones was higher (78%) among rifampicin-resistant samples, highlighting its utility as a reflex test in rifampicin-resistant patients. Xpert MTB/XDR offers rapid diagnosis of resistance with high specificity. While limitations in detecting low-frequency and off-target variants affect its sensitivity, most frequent, fixed in-target mutations are readily detected. Future studies should evaluate strategies to integrate Xpert MTB/XDR with other diagnostic approaches in national tuberculosis programs
Superior GVHD-Free, Relapse-Free Survival for Haploidentical Transplant With PTCy Than Matched Unrelated Donor for AML Patients Transplanted in Second Complete Remission: A Study From the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.
No full textInternational audienceDonor preference for acute myeloid leukemia (AML) patients transplanted in second complete remission (CR2) remains unclear, and hematopoietic cell transplantation (HCT) with post-transplant cyclophosphamide (PTCy) from a haploidentical donor (HAPLO) merits attention. Data of 3878 adult AML patients receiving a first allo-HCT in CR2 from the European Society of Blood and Marrow Transplantation registry between 2010 and 2022 were analyzed. Univariate analyses and Cox regression models were used. Results of HCTs from 803 HAPLO PTCy, 1271 matched sibling donor (MSD), and 1804 matched unrelated donor (MUD) were analyzed. A higher proportion (80.7%) of patients with European LeukemiaNet (ELN2022) intermediate-/adverse-risk cytogenetics received an allo-HCT from HAPLO PTCy than from either MUD (79.6%) or MSD (70.2%). On multivariate analysis, HAPLO PTCy grafts (hazard ratio [HR] = 0.65, 95% confidence interval [CI] 0.51-0.82; p < 0.001) were associated with a lower relapse incidence (RI) compared with MSD HCTs, although non-relapse mortality was higher (HR = 1.77, 95% CI 1.34-2.34; p < 0.001). No difference was observed with respect to leukemia-free survival and graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) for HAPLO PTCy compared to MSD grafts. Notably, HAPLO PTCy HCT was associated with significantly lower RI (HR = 0.64, 95% CI 0.48-0.82; p < 0.001), chronic GVHD (cGVHD) (HR = 0.64, 95% CI 0.51-0.81; p < 0.001) and extensive cGVHD (HR = 0.47, 95% CI 0.34-0.66; p < 0.001) incidences compared to MUD HCTs. Collectively, HAPLO PTCy HCT was associated with superior GRFS (HR = 0.81, 95% CI 0.68-0.95; p = 0.013) than MUD HCT. For AML patients in CR2, HAPLO PTCy HCT is associated with lower RI and cGVHD, leading to superior GRFS compared with MUD HCTs
Whole exome sequencing identifies a new DPY19L2 variant c.1232_1233insA in Tunisian infertile patient with globozoospermia
No full textInternational audienceBackground Globozoospermia is a rare male infertility disorder characterized by the presence in the ejaculate of round-headed sperm cells lacking an acrosome, a crucial structure for fertilization. While genetic factors play a significant role in the etiology of this condition, the precise mechanisms remain elusive. Recent studies have identified mutations in the DPY19L2 gene as a major cause of globozoospermia. This gene encodes a protein involved in the development and maturation of sperm cells, particularly the acrosome biogenesis. Mutations in DPY19L2 disrupt this process, leading to the production of abnormal sperm cells. However, DPY19L2 mutations account for only a subset of globozoospermia cases, suggesting the involvement of other genetic factors. Patients and methods Eighteen infertile men with total and partial globozoospermia were investigated. For all patients, screening of DPY19L2 total deletions was carried out by a qualitative PCR. When a positive diagnosis was not obtained (absence of a homozygous deletion), WES was conducted. Results Total deletion of DPY19L2 was found in 33% of all patients and in 60% of total globozoospermic ones. WES conducted in only two patients identified a novel DPY19L2 frameshift mutation (c.1232_1233insA) p.Arg412GlufsTer3 in one patient with total globozoospermia. The pathogenesis of this new variant is supported by In Silico prediction tools and by its absence in control patients and different published databases. Conclusions We confirm here the large implication of DPY19L2 in Globozoospermia, and we enrich the gene spectral mutation. Identification of the genetic basis of globozoospermia is crucial for accurate diagnosis, genetic counseling, and the development of potential therapeutic interventions
Medical management of pancreatic cancer: from personalization to broadening treatment strategies
No full textInternational audiencePancreatic ductal adenocarcinoma (PDAC) is one of the most heterogeneous and deadly cancers. This review examines recently implemented strategies to integrate predictive tools and targeted therapies to improve treatments personalization and patient outcomes. Predictive transcriptomic signatures based on machine learning should optimize first-line chemotherapy selection, while organoid-based chemo-profiling could help late-line or non-standard treatments, particularly when transcriptomic signatures are unavailable to guide therapeutic decisions. Liquid biopsies enable real-time, non-invasive monitoring of tumour progression and resistance. Targeted therapies, even limited to a small subset of PDAC patients, exploit specific molecular vulnerabilities and several of those are under clinical evaluation to join PDAC armamentarium. Given PDAC's biological complexity, a multimodal approach combining predictive tools, functional testing, and molecularly-guided therapies is required to progress. Implementing those strategies in routine practice, combined with technological and clinical advances should enhance the precision, accessibility, and effectiveness of personalized PDAC treatment, as well as expand therapeutic options with new targets
Epidémiologie de la Peste Porcine Africaine à Bangui et Bobassa en République Centrafricaine
No full textInternational audienceThe aim of this study was to evaluate the prevalence of African swine fever and risk factors in Bangui and Bobassa. For this, a survey was carried out among 50 pig breeders and 250 samples were collected and analyzed by PCR test at Institut Pasteur in Bangui. It emerged from the study that breedings were mostly managed by man and used mainly traditional breed. The average number of pigs per breeding was 23 pigs. Sick pigs are isolated in 48% of breedings. Cases of unexplained deaths in breeding are frequent. To get rid to corpses of sick animals, 16% of breeders claim to use them in feeding pigs. Breeders are more familiar with the clinical signs of ASF. Slightly more than half (56%) of the breeders report having ASF cases, and observed characteristic symptoms. Our study revealed an apparent prevalence of 16% (IC = [11.7% -21.1%]) and an actual prevalence of 13.47% (IC = [9.4% -18.3%]). The main risk factors for ASF are presence of older pigs on breedings and especially lack of hygiene.Cette étude avait pour but d’estimer la prévalence de la Peste Porcine Africaine et les facteurs de risque chez les porcs à Bangui et Bobassa. Pour cela, une enquête a été faite auprès de 50 éleveurs de porcs et 250 prélèvements ont été récoltés et analysés par le test de PCR conventionnelle à l’Institut Pasteur de Bangui. Il ressort de l’étude que les élevages sont gérés surtout par des hommes et utilisent principalement les porcs de race locale et des bâtiments traditionnel. L’effectif moyen par élevage est de 23 porcs. Les porcs malades seraient isolés que dans 48% des élevages. Les cas de morts inexpliqués dans les élevages sont fréquents. Pour se débarrasser des cadavres d’animaux malades, 16% des éleveurs affirment les utiliser dans l’alimentation des porcs. Les éleveurs connaissent plutôt bien les signes cliniques de la PPA. Un peu plus de la moitié (56%) des éleveurs déclarent avoir eu des cas de PPA, et observé des symptômes caractéristiques de cette pathologie. Notre étude a révélé une prévalence apparente de 16% (IC = [11,7% - 21,1%]) et une prévalence réelle de 13,47% (IC = [9,4% -18,3%]). Les principaux facteurs de risques de la PPA sont la présence des porcs âgés dans les exploitations et surtout le manque d’hygiène
Acute myeloid leukemia after CAR T-cell therapy: role of pre-existing clonal hematopoiesis and inflammation in leukemogenesis
No full textInternational audienceAmong the late complications associated with CAR T-cell therapies, secondary malignancies, and particularly acute myeloid leukemia, are a growing concern. Here, we report four cases of acute myeloid leukemia (AML) that emerged following anti-CD19 CAR T-cell therapy. We assess clonal evolution and factors contributing to leukemogenesis
Association Between Thrombus Composition and Etiology in Patients With Acute Ischemic Stroke Treated by Thrombectomy.
No full textInternational audienceBACKGROUND:In ischemic stroke due to large vessel occlusion, cerebral blood flow is impaired by thromboemboli, which can originate from various sources in the body. A better understanding of thromboembolus composition can improve our understanding of the underlying pathophysiology and potentially guide improvement of prevention strategies. The aim of this study therefore was to perform a large-sample multi-parameter quantitative histological analysis of retrieved thromboemboli from stroke patients.METHODS:Thromboemboli (n=501) were collected from thrombectomy-treated ischemic stroke patients at AZ Groeninge Hospital (Kortrijk, Belgium) and CHU Lille (Lille, France). Stroke etiology was determined by the treating stroke specialist using the TOAST classification system (Trial of ORG 10172 in Acute Stroke Treatment). Extensive histological analysis, blinded to stroke etiology, was performed for key thrombus constituents including red blood cells (RBCs), platelets, fibrin, von Willebrand Factor, leukocytes, citrullinated histone H3 (as a marker for neutrophil extracellular traps), and extracellular (ex)DNA. Quantitative histology results were linked to etiology.RESULTS:Compared with large-artery atherosclerotic thromboemboli, cardioembolic thromboemboli contained significantly fewer RBCs and significantly more platelets, fibrin, leukocytes, and exDNA. Interestingly, cryptogenic thromboemboli contained relatively low amounts of RBCs and high amounts of platelets, similar to cardioembolic thromboemboli. A multivariable logistic regression model indicated that it is difficult to predict stroke etiology based on the individual thrombus composition.CONCLUSIONS:Based on a large sample cohort of stroke thromboemboli, we found that cardiac thromboemboli contained fewer RBCs and more platelets than atherosclerotic thromboemboli and that cryptogenic thromboemboli have a similar composition to cardiac thromboemboli in terms of RBCs and platelets
Engineering a microfluidic platform for cell extravasation monitoring and downstream characterization of disseminated cells
No full textInternational audienceMetastatic cancer cells and immune cells spread throughout the body via the bloodstream, reaching target sites for immune clearance or establishing secondary tumors in distant organs. As they move from blood circulation to a targeted organ, cells adhere to activated endothelium and then extravasate through it into a tissue-rich environment. The molecular mechanisms that drive the extravasation of immune and cancer cells are not yet fully understood. Most importantly, the phenotypic state identity of the disseminated cancer cells has yet to be characterized. While various sealed microfluidic devices have been developed to study extravasation, few, if any, allow for the efficient collection of extravasated cells. To address this limitation, we designed a biomimetic microfluidic device comprising a network of 3D blood capillaries and a customizable collecting chamber, separated by a porous membrane. Our device enables i) real-time monitoring of cell extravasation through the endothelium via live imaging and ii) the collection of disseminated cells for subsequent molecular characterization. We validated the functional properties of the 3D endothelial layer under shear stress and inflammation induction. After injecting promyeloblast cells and metastatic cancer cells into the lumen of the capillary network, we observed cell rolling and extravasation under continuous flow conditions. Finally, we collected extravasated cancer cells for gene expression profiling by RT-qPCR. Overall, our novel microfluidic device reconstitutes a functional 3D blood vessel network, allowing real-time observation of extravasation and the collection of disseminated cells for further characterization.</div
Polymers and immersion time shape bacterial pathogen and antibiotic resistance profiles in aquaculture facilities
No full textInternational audienceMost equipment used in aquaculture farms is made of plastic. Plastics-associated biofilms may contain potential human pathogenic bacteria (PHPB) and antibiotic-resistant bacteria (ARB). Understanding the influence of farming practices on the biofouling development and composition is thus essential to control associated microbiological risks. We combined results from metabarcoding analyses, bacterial cultures, and antibiotic susceptibility testing to compare the bacterial pathobiome and resistome associated with plastic aquaculture equipment, including two polyamide nets and a polyester liner, with those associated to a hemp net and a glass control. Over the 3 months of incubation in an aquaculture farm, plastics exhibited neither higher levels of PHPB nor more multiple antibiotic resistance compared to other solid substrates, but they did present specific PHPB and ARB profiles. Bacterial members of the Vibrionaceae and Staphylococcaceae families were more abundant in plastic PHPB communities (respectively 47% and 22% of PHPB reads) than in other substrate ones (4% and 0.22% of PHPB reads). The plastic-associated antibiotic resistance profiles showed higher resistance against quinolones. These results suggest that aquaculture equipment could act as a reservoir for some PHPB and ARB, and that equipment composition and immersion time could be levers to control associated sanitary risks
Enterococcal cell wall remodelling underpins pathogenesis via the release of the Enteroccocal Polysaccharide Antigen (EPA).
No full textInternational audienceEnterococci are opportunistic pathogens displaying a characteristic ovoid shape, typically forming pairs of cells (diplococci) and short chains. Control of cell chain length in Enterococcus faecalis relies on the activity of the major N-acetylglucosaminidase AtlA. The formation of short chains and diplococci is critical during pathogenesis for dissemination in the host and to limit recognition by innate immune effectors such as complement molecules and phagocytes. Here, we identify AtlE, an N-acetylmuramidase that contributes to septum cleavage during stationary phase in the absence of AtlA. AtlE is encoded by the locus required to produce the decoration subunits of the Enterococcal Polysaccharide Antigen (EPA), which mediate evasion of phagocytosis. We show that peptidoglycan hydrolysis by AtlE is essential for pathogenesis and demonstrate that soluble cell wall fragments containing EPA decorations increase the virulence of E. faecalis, suggesting that EPA plays a role as a decoy molecule to evade host defences. This research sheds light on the complex interplay between bacterial cell division, cell wall remodelling, and the host immune system, providing valuable insights into a novel mechanism underlying the virulence of E. faecalis