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Background: The MOVIE phase I/II trial (NCT03518606) evaluated the safety and antitumor activity of durvalumab and tremelimumab combined with metronomic oral vinorelbine in patients with advanced tumors. We present the results of the recurrent advanced cervical cancer cohort., Methods: Patients received tremelimumab (intravenously, 75 mg, every four weeks (Q4W); four cycles max) plus durvalumab (intravenously, 1,500 mg, Q4W; 26 cycles max) and metronomic oral vinorelbine (40 mg, every three weeks (3QW)) until disease progression. The primary efficacy endpoint was the clinical benefit rate (CBR) based on the Response Evaluation Criteria in Solid Tumors V.1.1, which was analyzed using a Bayesian approach RESULTS: A total of 31 patients were enrolled and treated in the cervical cancer cohort. The median number of previous lines of chemotherapy for advanced disease was 2 (0-6), with all (100%) and 12 (38.7%) patients pretreated with cisplatin and bevacizumab, respectively. At the data cut-off, the median follow-up duration was 12.8 (Q1-Q3, 6.1-34.6) months. The CBR was 53.1% (95% CI, 36.0% to 69.8%), using a non-informative prior distribution (beta(1, 1)). The overall response rate was 41.9%, five patients achieved a complete response (16.1%), and eight patients (25.8%) had a partial response irrespective of histological subtype or programmed death-ligand 1 (PD-L1) expression. Of the 31 patients, 28 (90.3%) experienced treatment-related adverse events (TRAEs), 13 (41.9%) reported grade ≥3 immune-related adverse events (AEs), and 13 (41.9%) reported grade ≥3 chemotherapy-related AEs. The definitive discontinuation rate due to TRAEs was 16.1%., Conclusions: Dual checkpoint blockade of PD-L1 and cytotoxic T-lymphocyte-associated antigen-4 combined with metronomic oral vinorelbine demonstrated meaningful and durable clinical activity in patients with previously treated advanced cervical cancer. Toxicity was significant but manageable., Competing Interests: Competing interests: J-SF reported consulting fees from AstraZeneca, GSK, Esai, MSD, Lilly, Pfizer, Novartis, Daichi Sankyon and Seagen; honoraria from AstraZeneca, GSK, Esai, MSD, Lilly, Pfizer, Novartis, Daichi Sankyon and Seagen; support for attending meetings from AstraZeneca, GSK, Esai, MSD, Lilly, Pfizer, Novartis, Daichi Sankyon and Seagen; and participant on advisory board from AstraZeneca, GSK, Esai, MSD, Lilly, Pfizer, Novartis, Daichi Sankyon and Seagen outside the submitted work. EB reported consulting fees from Egle Tx; honoraria from Eisai, MSD, Sandoz and Amgen; and support for attending meetings from Daiichi Sankyo, Eisai, Amgen, Sandoz, MSD, Bristol-Myers Squibb, Novartis, Pfizer and Roche outside the submitted work. EC reported honoraria from AstraZeneca, Pfizer, Ipsen, BMS, MSD and Janssen; and support for attending meeting from Novartis, AstraZeneca and Janssen outside the submitted work. TDLMR reported grants from MSD, Novartis, Pfizer and Seagen; consulting fees from AstraZeneca, GSK, Clovis oncology, Pfizer, Gilead, Seagen and Sanofi; honoraria from GSK and MSD; support for attending meetings from Pfizer, Gilead and Eisai; and participant on advisory board from MSD outside the submitted work. ES-B reported grants from Merck Serono and AstraZeneca; honoraria from Merck Serono and MSD; support for attending meetings from Merck Serono, MSD and Novartis outside the submitted work. RS reported grants from AstraZeneca; consulting fees from DSK, Eisai and MSD; honoraria from GSK, Pharmaand, MSD, Eisai, Seattle Genetics and Novartis; and support for attending meetings from Eisai, Novartis, GSK and MSD outside the submitted work. PL reported grants from Servier; honoraria from BMS, AstraZeneca, Sanofi and Astellas; supports for attending meetings from Daicho, Ipsen, Astellas, Sanofi, Janssen and Pfizer; and participant on advisory board from Daichi outside the submitted work. OLS reported grants from AstraZeneca and BMS; honoraria from GSK, Pharmaand and MSD; and support for attending meetings from AstraZeneca, Pfizer and Accord outside the submitted work. AG reported received payments to his institution for grants from Roche/Genentech, AstraZeneca, Daiichi Sankyo, MSD, Gilead and Novartis; received payments to his institution for consulting fees from Novartis, AstraZeneca, MSD and Gilead; received payments to his institution for honoraria from Novartis; support for attending meetings from Mylan and Menarini outside the submitted work. No other disclosures were reported., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

This study aims at modelling the aerodynamic interaction between a world-class runner and several pacers running in line, the objective being to determine the best drafting position in terms of potential speed gain and running time. Computational Fluid Dynamics calculations were performed to determine the aerodynamic drag forces exerted on the runners. Secondly, we estimated the metabolic savings for each of the runner's positions in the pack of pacers. Finally, we estimated a potential equivalent running speed and a corresponding running time gain for each of the runner's positions. Running second in a group of 5 runners would be the most effective drafting strategy, with a reduction of aerodynamic drag reaching 63.3%, corresponding to an improvement of 4.4% of the running economy. Furthermore, decreasing the drag forces acting on the runner would results in greater running speed. For example, a 63.3% reduction in the aerodynamic forces yields a 2.9% faster running speed (20.7 to 21.31 km/h) for an equal metabolic cost. Running in the wake of a leading runner (in a pack of five runners) over a marathon is estimated to provide a significant time saving of 3 min 28 s.

Allogeneic stem cell transplantation (Allo-SCT) is the only rapidly available curative treatment modality in patients with severe sickle cell disease (SCD). The development of reduced-toxicity myeloablative conditioning (RT-MAC) regimen and the use of partially matched family donors with post-transplantation cyclophosphamide (PT-Cy) have widened the access to Allo-SCT. Antibodies against donor-specific HLA (DSA) increase the risk of engraftment failure in HLA mismatched Allo-SCT. We report the results of five patients with SCD, whereas three with DSA, who underwent an unmanipulated haploidentical stem cell transplantation (Haplo-SCT) after a busulfan-based RT-MAC regimen with PT-Cy. To reduce the risk of engraftment failure, a sequential two courses pharmacological pre-transplant immune suppression (PTIS) phase was added prior to the conditioning regimen. All patients engrafted successfully. The procedure was well tolerated. None of the patients developed acute GVHD, whereas one developed moderate chronic GVHD. After a median follow-up of 5 years (range, 2.2-9), all patients are free of pain with excellent quality of life. Our report shows that Haplo-SCT after a RT-MAC regimen is feasible and safe with stable long-term engraftment and excellent disease control. The risk of graft failure can be abrogated by adding a PTIS phase prior to initiating the conditioning regimen., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

To date, there has been little research on burnout in firefighters despite the acknowledged impact of occupational stress on both individuals and society. According to a survey conducted by the French National Research and Security Institute, the annual cost to society of occupational stress in France is 2-3 billion euros. The aim of the present study was to assess the prevalence of occupational burnout in a large and representative sample of French firefighters. A nationwide survey was conducted in 2021, targeting all categories of firefighters (except for military firefighters in Paris and Marseille) both in metropolitan France and in its overseas departments and territories. This survey came in two parts: questions eliciting basic sociodemographic and job-related data, followed by the Burnout Assessment Tool which assesses the intensity of job-related burnout. We collated results for 3038 firefighters: 2418 men (79.59%), 619 women (20.38%), and 1 gender neutral (0.03%). Findings revealed that while 2455 respondents (80.8%) did not meet the criteria for burnout, 345 (11.4%) reported mild/moderate symptoms of burnout, and 238 (7.8%) could be deemed to have severe burnout symptoms. Further research is warranted into the causes of burnout and its prevention in this specific population., (Copyright © 2023 L'Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)

Objectives: Optimal blood pressure (BP) control is key to prevent cardiovascular complications in patients with chronic kidney disease (CKD). We described the prevalence and factors associated with masked hypertension in CKD., Methods: We analyzed 1113 ambulatory 24-h BP monitoring (ABPM) records of 632 patients referred for kidney function evaluation. Masked hypertension was defined as office BP less than 140/90 mmHg but daytime BP at least 135/85 mmHg or nighttime BP at least 120/70 mmHg. Factors associated with masked hypertension were assessed with mixed logistic regression models., Results: At inclusion, 424 patients (67%) had controlled office BP, of whom 56% had masked hypertension. In multivariable analysis conducted in all visits with controlled office BP ( n  = 782), masked hypertension was positively associated with male sex [adjusted OR (95% confidence interval) 1.91 (1.16-3.27)], sub-Saharan African origin [2.51 (1.32-4.63)], BMI [1.11 (1.01-1.17) per 1 kg/m 2 ], and albuminuria [1.29 [1.12 - 1.47] per 1 log unit), and was negatively associated with plasma potassium (0.42 [0.29 - 0.71] per 1 mmol/L) and 24-h urinary potassium excretion (0.91 [0.82 - 0.99] per 10 mmol/24 h) as well as the use of renin-angiotensin-aldosterone (RAAS) blockers (0.56 [0.31 - 0.97]) and diuretics (0.41 [0.27 - 0.72])., Conclusion: Our findings support the routine use of ABPM in CKD, as more than half of the patients with controlled office BP had masked hypertension. Weight control, higher potassium intake (with caution in advanced CKD), correction of hypokalemia, and larger use of diuretics and RAAS blockers could be potential levers for better out-of-office BP control., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: To identify patients most likely to respond to everolimus, a mammalian target of rapamycin (mTOR) inhibitor, a prospective biomarker study was conducted in hormone receptor-positive endocrine-resistant metastatic breast cancer patients treated with exemestane-everolimus therapy., Methods: Metastatic tumor biopsies were processed for immunohistochemical staining (p4EBP1, PTEN, pAKT, LKB1, and pS6K). ESR1, PIK3CA and AKT1 gene mutations were detected by NGS. The primary endpoint was the association between the p4EBP1 expression and clinical benefit rate (CBR) at 6 months of everolimus plus exemestane treatment., Results: Of 150 patients included, 107 were evaluable for the primary endpoint. p4EBP1 staining above the median (Allred score ≥6) was associated with a higher CBR at 6 months (62% versus 40% in high-p4EBP1 versus low-p4EBP1, χ2 test, p = 0.026) and a longer progression-free survival (PFS) (median PFS of 9.2 versus 5.8 months in high-p4EBP1 versus low-p4EBP1; p = 0.02). When tested with other biomarkers, only p4EBP1 remained a significant predictive marker of PFS in multivariate analysis (hazard ratio, 0.591; p = 0.01)., Conclusions: This study identified a subset of patients with hormone receptor-positive endocrine-resistant metastatic breast cancer and poor outcome who would derive less benefit from everolimus and exemestane. p4EBP1 may be a useful predictive biomarker in routine clinical practice., Clinical Trial Registration: NCT02444390., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Haploidentical stem cell transplantation (Haplo-SCT) using non-myeloablative conditioning regimen (NMAC) has extended the feasibility of allogeneic transplantation, notably in older patients. However, there is few data specifically focusing on patients aged 70 years and over with AML and MDS. Thus the benefit of transplantation in this population is still debated. Here we report our single center experience of peripheral blood Haplo-SCT with NMAC and post-transplantation cyclophosphamide in AML and MDS patients aged 70 years and over. We analyzed 50 patients (27 AML, 23 MDS) with a median age of 72 years (70-77), 12/50 (24%) with active disease at Haplo-SCT. Cumulative incidence of grade 3-4 acute and moderate or severe chronic GVHD were 6% and 25%, respectively. Non-relapse mortality (NRM) at day +100 was 0%. NRM, relapse, PFS and OS at 3 years were 16%, 18%, 66%, and 69%, respectively. Among patients who were disease free at 2 years post Haplo-SCT, 88% are living without immunosuppressive treatment. Peripheral blood Haplo-SCT is feasible in selected AML/MDS patients over 70 years, without any early NRM. It produces long-term disease control and survival. Thus, age by itself should not be considered as a formal barrier to Haplo-SCT., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Sarcoma is a heterogeneous group of diseases with few treatment options. Immunotherapy has shown little activity in studies including unselected sarcomas, but immune checkpoint blockers have shown activity in specific histotypes. We evaluated the activity of pembrolizumab in rare and ultra-rare sarcomas., Methods: AcSé Pembrolizumab is an ongoing phase 2, basket, multitumour study investigating the activity of pembrolizumab monotherapy in rare cancers. Here, we report the results obtained in patients with selected histotypes of rare sarcomas (incidence of less than one case per 1 000 000 people per year) recruited at 24 French hospitals. Key inclusion criteria were age 15 years or older, Eastern Cooperative Oncology Group performance status of 0-1, and advanced disease that was untreated and resistant to treatment. Patients were given pembrolizumab 200 mg intravenously on day 1 of every 21-day cycle for a maximum of 24 months. The primary endpoint was objective response rate at week 12 using Response Evaluation Criteria in Solid Tumours version 1.1, assessed by local investigators. The primary endpoint and safety were analysed in the intention-to-treat population. The AcSé Pembrolizumab study is registered with ClinicalTrials.gov, NCT03012620., Findings: Between Sept 4, 2017, and Dec 29, 2020, 98 patients were enrolled, of whom 97 received treatment and were included in analyses (median age 51 years [IQR 35-65]; 53 [55%] were male; 44 [45%] were female; no data were collected on race or ethnicity). 34 (35%) patients had chordomas, 14 (14%) had alveolar soft part sarcomas, 12 (12%) had SMARCA4-deficient sarcomas or malignant rhabdoid tumours, eight (8%) had desmoplastic small round cell tumours, six (6%) had epithelioid sarcomas, four (4%) had dendritic cell sarcomas, three (3%) each had clear cell sarcomas, solitary fibrous tumours, and myxoid liposarcomas, and ten (10%) had other ultra-rare histotypes. As of data cutoff (April 11, 2022), median follow-up was 13·1 months (range 0·1-52·8; IQR 4·3-19·7). At week 12, objective response rate was 6·2% (95% CI 2·3-13·0), with no complete responses and six partial responses in the 97 patients. The most common grade 3-4 adverse events were anaemia (eight [8%] of 97), alanine aminotransferase and aspartate aminotransferase increase (six [6%]), and dyspnoea (five [5%]). 86 serious adverse events were reported in 37 patients. Five deaths due to adverse events were reported, none of which were determined to be related to treatment (two due to disease progression, two due to cancer, and one due to unknown cause)., Interpretation: Our data show the activity and manageable toxicity of pembrolizumab in some rare and ultra-rare sarcoma histotypes, and support the PD-1/PD-L1 pathway as a potential therapeutic target in selected histotypes. The completion of the basket study will provide further evidence regarding the activity and toxicity of pembrolizumab in identified rare types of cancer., Funding: The Ligue contre le cancer, INCa, MSD., Translation: For the French translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests J-YB received support for the present research from INCa (Institut National du Cancer; French National Cancer Institute), Unicancer, Fondation ARC, and MSD (drug supply) as well as research support from MSD Avenir Foundation for unrelated research. ALC reports personal fees from Pharmamar and Deciphera. CE received consulting fees from BMS, MSD, Novartis, F Star therapeutics, and Merck Serono, as well as grant support from MSD and Merck Serono. CM was principal investigator or investigator of clinical trials for Abbvie, Aduro, Agios, Amgen, Argen-x, Astex, AstraZeneca, Aveo pharmaceuticals, Bayer, Beigene, Blueprint, BMS, Boeringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 biomedecine, Incyte, Innate Pharma, Janssen, Kura,Oncology, Kyowa, Lilly, Loxo, Lysarc, Lytix,Biopharma, Medimmune, Menarini, Merus, MSD, Nanobiotix, Nektar Therapeutics, Novartis, Octimet, Oncoethix, Oncopeptides AB, Orion, Pfizer, Pharmamar, Pierre Fabre, Roche, Sanofi, Servier, Sierra Oncology, Taiho, Takeda, Tesaro, and Xencor; received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Amgen, Astellas, AstraZeneca, Bayer, BeiGene, BMS, Celgene, Debiopharm, Genentech, Ipsen, Janssen, Lilly, MedImmune, MSD, Novartis, Pfizer, Roche, Sanofi, and Orion; and travel grants from Janssen and AstraZeneca. PBR received consulting fees from Ipsen and travel grants from Pharmamar and Pfizer. MC reported support for attending meetings or travel from Ipsen, Janssen, Pfizer, Amgen, MSD, Biogaran, and Novartis. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Failure of gastrointestinal acute graft- versus -host disease (GI-aGvHD) to respond to steroid therapy is associated with limited further therapeutic options. We aimed to assess the safety and efficacy of the first-in-human use of the pooled allogeneic faecal microbiota, MaaT013, for the treatment of steroid-refractory GI-aGvHD., Methods: This prospective, international, single-arm, phase 2a study reports clinical outcomes from a 24-patient cohort with grade III-IV, steroid refractory GI-aGvHD treated with the pooled allogeneic faecal microbiota MaaT013. MaaT013 involved pooling faecal matter from 3 to 8 screened donors then transplanting the pooled batches into patients to treat GI-aGVHD. The 24 patients were treated in the HERACLES study (Aug 2018 to Nov 2020) at 26 sites in Europe and an additional 52 patients were treated in a compassionate use/expanded access program (EAP) in France (July 2018 to April 2021). The primary endpoint was GI response at day 28, defined as the proportion of patients with GI-aGvHD who had a complete response (CR) or very good partial response (VGPR). GvHD grading and staging were assessed according to the revised Glucksberg criteria. Adverse events and severe adverse events were monitored for 6 months and 12 months, respectively. The HERACLES study was registered with ClinicalTrials.gov (NCT03359980)., Findings: Compared with single donors, MaaT013 is characterised by higher microbial richness and reduced variability across batches. At day 28 (D28), the GI-overall response rate (ORR) was 38% in the prospective population, including 5 complete responses (CR), 2 very good partial responses (VGPR) and 2 partial responses (PR). In the EAP, the GI-ORR was 58% (17 CR, 9 VGPR and 4 PR). The 12-month overall survival (OS) was 25% in the prospective study and 38% in the EAP. Regarding safety, five infectious complications, including 3 sepsis, could not be excluded from being related to the study procedure in HERACLES. Shotgun sequencing analyses of the identified strains suggest that none were found in MaaT013. In the EAP, 18 pharmacovigilance cases were reported among 52 treated patients, including 11 bacteraemia/sepsis. In HERACLES, we observed in stools from responding patients at D28 a higher microbiota richness and increased levels of beneficial bacteria, in particular butyrate producers, along with increased levels of short-chain fatty acid and bile acids. In contrast, stools from non-responding (NR) patients displayed increased levels of pathogenic pro-inflammatory bacteria along with increased systemic inflammatory parameters., Interpretation: Overall, MaaT013 was safe in this population of highly immunocompromised patients and was associated with responses in some patients with GI-aGvHD and deserves further investigation., Funding: MaaT Pharma., Competing Interests: FM reports honoraria from Therakos/Mallinckrodt, Sanofi and Novartis. TC reports consulting fee from Celgene, Abbvie, Jazz Pharma, Roche, Novartis, Agios and Servier and honoraria from Novartis, Amgen, Astellas, Celgene/BMS and Gilead/Kite. ED report payment for expert testimony from Astellas and support for attending meetings and/or travel from Neovii and Novartis. MJGTV report grants or contracts from MSD, Heel, Biontech and Roche, consulting fees from MaaT Pharma, Tillots, MSD/Merck, Roche and EUMEDICA and payment or honoraria from Merck/MSD, 3M, Ferring, Astellas, Uniklinik Karlsruhe, Uniklinik Köln, Akademie für Infektionsmedizin, Klinikum Essen, Pfizer, Universitätsklinikum Heidelberg, Uniklinik Frankfurt, Landesärztekammer Hessen, Janssen, Intitur Merieux, Forum für medizinische Fortbildung Gmbh, Universitätsklinikum Freiburg, Berliner Dialy Seminar, ADKA, Falk Foundation, St. Johannes Hospital, DiaLog Service, CED Service, Ärztekammer Niedersachsen, St. Josef Hospital, Limbach Gruppe SE, SUMIT OXFORD Ltd. EUMEDICA Kit Kongress, Tillots Pharma, Helios Kliniken, Lahn-Dill-Kliniken, GILEAD and Klinikum Leverkusen. CEB report honoraria from Astellas. EH report grants from Medac, payment for expert testimony from Novartis, participation on Advisory Board of Maat Pharma and Pharmabiome. JD is cofounder and member of the advisory board of MaaT Pharma, report consulting fees from MaaT Pharma, support for attending meetings and/or travel from MaaT Pharma and shares from MaaT Pharma. EPr, CG and EPl are MaaT Pharma employees and have patents as part of company inventor compensation policy MM reports grants and consulting fees from Sanofi, Novartis, and Janssen, honoraria from Sanofi, Novartis, Janssen, and MaaT Pharma, participation on Advisory Board of Janssen and leadership role in The European Group for Blood & Marrow Transplantation. All other authors declare no competing interests., (© 2023 The Author(s).)

Objectives: Dengue fever is an arbovirosis expanding worldwide, for which hydration has been reported to reduce the risk of hospitalization. Our objective was to estimate the volume of hydration in Reunionese patients with dengue., Methods: A prospective observational study included patients presenting with a 'dengue-like' syndrome in ambulatory care. General practitioners recruited patients during consultation, and beverage consumption over the previous 24 hours was reported at two different times. Warning signs were defined according to the 2009 WHO guidelines., Results: GPs included 174 patients from April to July 2019. Average oral hydration volume was 1863 mL and 1944 mL, at the 1st and 2nd medical consultations, respectively. Water was the most wide consumed liquid. Drinking at least 5 glasses of liquid was significantly associated with fewer clinical warning signs at the 1st medical consultation (p = 0.044)., Conclusions: Sufficient hydration volume could prevent dengue warning signs. Further studies with standardized measurement of hydration would be needed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

This 16-month-long multicentre retrospective study of 225 allogeneic haematopoietic stem cell transplantation (alloHSCT) recipients with COVID-19 examines risk factors for severity and mortality, describing the successive waves of infections (from March to June 2020 and from August 2020 to June 2021). We confirm the negative role of low respiratory tract disease and immunosuppressive treatment. We highlight significantly lower percentages of severe forms and COVID-19-related mortality during the second wave. Monthly comparative evolution of cases in alloHSCT recipients and in the French population shows a higher number of cases in alloHSCT recipients during the first wave and a decrease from February 2021., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

Deep learning-based methods for cardiac MR segmentation have achieved state-of-the-art results. However, these methods can generate incorrect segmentation results which can lead to wrong clinical decisions in the downstream tasks. Automatic and accurate analysis of downstream tasks, such as myocardial tissue characterization, is highly dependent on the quality of the segmentation results. Therefore, it is of paramount importance to use quality control methods to detect the failed segmentations before further analysis. In this work, we propose a fully automatic uncertainty-based quality control framework for T1 mapping and extracellular volume (ECV) analysis. The framework consists of three parts. The first one focuses on segmentation of cardiac structures from a native and post-contrast T1 mapping dataset (n=295) using a Bayesian Swin transformer-based U-Net. In the second part, we propose a novel uncertainty-based quality control (QC) to detect inaccurate segmentation results. The QC method utilizes image-level uncertainty features as input to a random forest-based classifier/regressor to determine the quality of the segmentation outputs. The experimental results from four different types of segmentation results show that the proposed QC method achieves a mean area under the ROC curve (AUC) of 0.927 on binary classification and a mean absolute error (MAE) of 0.021 on Dice score regression, significantly outperforming other state-of-the-art uncertainty based QC methods. The performance gap is notably higher in predicting the segmentation quality from poor-performing models which shows the robustness of our method in detecting failed segmentations. After the inaccurate segmentation results are detected and rejected by the QC method, in the third part, T1 mapping and ECV values are computed automatically to characterize the myocardial tissues of healthy and cardiac pathological cases. The native myocardial T1 and ECV values computed from automatic and manual segmentations show an excellent agreement yielding Pearson coefficients of 0.990 and 0.975 (on the combined validation and test sets), respectively. From the results, we observe that the automatically computed myocardial T1 and ECV values have the ability to characterize myocardial tissues of healthy and cardiac diseases like myocardial infarction, amyloidosis, Tako-Tsubo syndrome, dilated cardiomyopathy, and hypertrophic cardiomyopathy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of haematopoietic cell transplantation (HCT) conditioning. The DEFIFrance post-marketing registry study evaluated effectiveness and safety in patients who received defibrotide. It collected retrospective/prospective patient data from 53 French HCT centres from July 2014 to March 2020. Primary endpoints were survival and complete response (CR; total serum bilirubin <2 mg/dL, multiorgan failure resolution) at Day 100 post-HCT among patients with severe/very severe VOD/SOS. A secondary endpoint was evaluation of treatment-emergent serious adverse events (TESAEs) of interest. Of 798 patients analysed, 251 and 81 received defibrotide treatment for severe/very severe VOD/SOS and mild/moderate VOD/SOS post-HCT, respectively; 381 received defibrotide for VOD/SOS prophylaxis. In patients with severe/very severe VOD/SOS post-HCT, Kaplan-Meier-estimated CR at Day 100 was 74% (95% confidence interval [CI]: 66%, 81%). At Day 100, 137/251 (55%) were alive and in CR. Kaplan-Meier-estimated Day 100 post-HCT survival was 61% (95% CI: 55%, 67%) in patients with severe/very severe VOD/SOS. TESAEs of interest occurred in 29% of these patients; VOD/SOS-related mortality at 12 months was 15%. DEFIFrance represents the largest collection of real-world data on post-registration defibrotide use, supporting the real-world utility of defibrotide for patients with severe/very severe VOD/SOS post-HCT., (© 2022. The Author(s).)

Background: The learning needs of newly diagnosed diabetic patients followed up in medical offices in Reunion Island are unknown, although necessary for the improvement of education programmes and disease control., Aim: To assess the knowledge of type 2 diabetic patients in primary care followed for less than 5 years., Method: A cross-sectional study was carried out, using a self-questionnaire to assess patients' knowledge of diabetes, complications, follow-up, diet and physical activity. Patients were recruited from medical offices in the western region of Reunion Island., Results: From 23 rd April to 31 st July 2021, 89 patients were included. The knowledge level of the total sample was moderate (mean correct answers 65 % ± 17). The best knowledge levels were in the areas "generalities on diabetes" and "complications", while the lowest levels were in the categories "follow-up" and "diet and physical activity". Glycated haemoglobin, libido disorders, frequency of urinalysis and dental consultation, and the recommended diet for patients with diabetes which is the same as for the general population, were the least known concepts., Conclusion: This study revealed gaps in patients' knowledge that could be used to improve education programmes which in turn could reduce or prevent diabetes complications., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Pudendal Neuralgia (PN) is a rare, debilitating disease caused by damage to the pudendal nerve, which innervates the anus, rectum, perineum, lower urinary tract, and genitalia. Although its etiology remains scientifically unknown, a number of sports practices, including horse-riding, are reported as triggering and/or aggravating factors. The present work summarizes the experimental measurements of the contact pressure at the interface between the rider and saddle, for a population of 12 experienced female riders. These tests reveal that dynamic horseback-riding leads to high levels of peak pressures in the perineal region, which confirms that the practice of equine sports may cause neuropathologies such as PN. All collected data will be used as boundary conditions in a future numerical 3D model aimed at locating the possible areas of pudendal nerve crushing.

Background: Anti-programmed cell death protein 1 (PD1)/programmed death-ligand 1 (PD-L1) agents have only moderate antitumor activity in some advanced solid tumors (AST), including breast cancer (BC), prostate cancer (PC), cervical cancer (CC), and head and neck cancer (HNC). Combining anti-PD-L1 with anti-cytotoxic T-lymphocyte-associated protein (CTLA) and chemotherapy may significantly improve efficacy., Patients and Methods: MOVIE is a multicohort phase I/II study examining the combination of anti-PD-L1 durvalumab (Durv; 1500 mg IV Q4W) plus anti-CTLA tremelimumab (Trem; 75 mg IV Q4W) with metronomic vinorelbine (MVino; 20-40 mg orally daily) in various AST resistant to conventional therapies. The primary objective of the phase I part was to determine the maximum tolerated dose (MTD) and recommended dose for phase II (RP2D)., Results: Among the 14 patients enrolled during phase I, including 13 women and 1 man, 9 had BC, 1 PC, 2 CC, and 2 miscellaneous cancers with high mutational loads. Median age was 53 years. A total of 12 patients were assessable for the dose-escalation part in which only one dose-limiting toxicity (DLT) was observed [one neutropenia without fever, grade (G) 4]. Two (14.3%), four (28.6%), and four (28.6%) patients had G ≥3 adverse events (AEs) related to MVino, Durv, and Trem, respectively. Treatment-related events included mostly clinical AEs with asthenia (eight G2; three G3), colitis (one G2, one G3), diarrhea (one G3), nausea (two G2), dry skin (two G2), maculopapular rash (one G3), and hyperthyroidism (three G2). No toxic death was reported. Preliminary data showed one patient (CC) who presented a complete response and four patients with stable disease (SD)., Conclusions: MTD was not reached and dose level 2 (MVino 40 mg, Durv 1500 mg, Trem 75 mg) was selected as RP2D. The safety profile of the combination was manageable and consistent with previous reports of Trem + Durv or MVino. Phase II is currently ongoing in BC, PC, CC, HNC, and miscellaneous cohorts., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

To determine the survival benefit of allogeneic hematopoietic cell transplantation (allo-HCT) in chronic myelomonocytic leukemias (CMML), we assembled a retrospective cohort of CMML patients 18-70 years old diagnosed between 2000 and 2014 from an international CMML dataset (n = 730) and the EBMT registry (n = 384). The prognostic impact of allo-HCT was analyzed through univariable and multivariable time-dependent models and with a multistate model, accounting for age, sex, CMML prognostic scoring system (low or intermediate-1 grouped as lower-risk, intermediate-2 or high as higher-risk) at diagnosis, and AML transformation. In univariable analysis, lower-risk CMMLs had a 5-year overall survival (OS) of 20% with allo-HCT vs 42% without allo-HCT (P < .001). In higher-risk patients, 5-year OS was 27% with allo-HCT vs 15% without allo-HCT (P = .13). With multistate models, performing allo-HCT before AML transformation reduced OS in patients with lower-risk CMML, and a survival benefit was predicted for men with higher-risk CMML. In a multivariable analysis of lower-risk patients, performing allo-HCT before transformation to AML significantly increased the risk of death within 2 years of transplantation (hazard ratio [HR], 3.19; P < .001), with no significant change in long-term survival beyond this time point (HR, 0.98; P = .92). In higher-risk patients, allo-HCT significantly increased the risk of death in the first 2 years after transplant (HR 1.46; P = .01) but not beyond (HR, 0.60; P = .09). Performing allo-HCT before AML transformation decreases life expectancy in lower-risk patients but may be considered in higher-risk patients., (© 2022 by The American Society of Hematology.)

Background: There are currently few data on the outcome of acute myeloid leukemia (AML) in adolescents after allogeneic HSCT. The aim of this study is to describe the outcome and its specific risk factors for children, adolescents and young adults after a first allogeneic HSCT for AML., Methods: In this retrospective study, we compared the outcome of AML patients receiving a first allogeneic HSCT between 2005 and 2017 according to their age at transplantation's time: children (< 15 years, n = 564), adolescent and post-adolescent (APA) patients (15-25 years, n = 647) and young adults (26-40 years; n = 1434)., Results: With a median follow-up of 4.37 years (min-max 0.18-14.73 years), the probability of 2-year overall survival (OS) was 71.4% in children, 61.1% in APA patients and 62.9% in young adults (p = 0.0009 for intergroup difference). Both relapse and non-relapse mortality (NRM) Cumulative Incidence (CI) estimated at 2 years were different between the age groups (30.8% for children, 35.2% for APA patients and 29.4% for young adults-p = 0.0254, and 7.0% for children, 10.6% for APA patients and 14.2% for young adults, p < 0.0001; respectively). Whilst there was no difference between the three groups for grade I to IV acute GVHD CI at 3 months, the chronic GVHD CI at 2 years was higher in APA patients and young adults (31.4% and 36.4%, respectively) in comparison to the children (17.5%) (p < 0.0001). In multivariable analysis, factors associated with death were AML cytogenetics (HR1.73 [1.29-2.32] for intermediate risk 1, HR 1.50 [1.13-2.01] for intermediate risk 2, HR 2.22 [1.70-2.89] for high cytogenetics risk compared to low risk), use of TBI ≥ 8 Grays (HR 1.33 [1.09-1.61]), disease status at transplant (HR 1.40 [1.10-1.78] for second Complete Remission (CR), HR 2.26 [1.02-4.98] for third CR and HR 3.07 [2.44-3.85] for active disease, compared to first CR), graft source (HR 1.26 [1.05-1.50] for Peripheral Blood Stem Cells compared to Bone Marrow) and donor age (HR 1.01 (1-1.02] by increase of 1 year)., Conclusion: Age is an independent risk factor for NRM and extensive chronic GVHD. This study suggests that APA patients with AML could be beneficially treated with a chemotherapy-based MAC regimen and bone marrow as a stem cells source., (© 2021. The Author(s).)

Influx of eosinophils into the lungs is typically associated with type II responses during allergy and fungal and parasitic infections. However, we previously reported that eosinophils accumulate in lung lesions during type I inflammatory responses to Mycobacterium tuberculosis (Mtb) in humans, macaques, and mice, in which they support host resistance. Here we show eosinophils migrate into the lungs of macaques and mice as early as one week after Mtb exposure. In mice this influx is CCR3 independent and instead requires cell-intrinsic expression of the oxysterol receptor GPR183, which is highly expressed on human and macaque eosinophils. Murine eosinophils interact directly with bacilli-laden alveolar macrophages, which upregulate the oxysterol-synthesizing enzyme Ch25h, and eosinophil recruitment is impaired in Ch25h-deficient mice. Our findings show that eosinophils are among the earliest cells from circulation to sense and respond to Mtb infection of alveolar macrophages and reveal a role for GPR183 in the migration of eosinophils into lung tissue., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Missense mutations in the polymerase epsilon (POLE) gene have been reported to generate proofreading defects resulting in an ultramutated genome and to sensitize tumors to checkpoint blockade immunotherapy. However, many POLE-mutated tumors do not respond to such treatment. To better understand the link between POLE mutation variants and response to immunotherapy, we prospectively assessed the efficacy of nivolumab in a multicenter clinical trial in patients bearing advanced mismatch repair-proficient POLE-mutated solid tumors. We found that only tumors harboring selective POLE pathogenic mutations in the DNA binding or catalytic site of the exonuclease domain presented high mutational burden with a specific single-base substitution signature, high T-cell infiltrates, and a high response rate to anti-PD-1 monotherapy. This study illustrates how specific DNA repair defects sensitize to immunotherapy. POLE proofreading deficiency represents a novel agnostic biomarker for response to PD-1 checkpoint blockade therapy., Significance: POLE proofreading deficiency leads to high tumor mutational burden with high tumor-infiltrating lymphocytes and predicts anti-PD-1 efficacy in mismatch repair-proficient tumors. Conversely, tumors harboring POLE mutations not affecting proofreading derived no benefit from PD-1 blockade. POLE proofreading deficiency is a new tissue-agnostic biomarker for cancer immunotherapy. This article is highlighted in the In This Issue feature, p. 1397., (©2022 American Association for Cancer Research.)

Fusarium head blight (FHB) is a devastating fungal disease of small grain cereals including wheat. Causal fungal agents colonize various components of the field during their life cycle including previous crop residues, soil, and grains. Although soil and residues constitute the main inoculum source, these components have received much less attention than grains. This study aimed at disentangling the role of previous crop residues in shaping soil microbiota, including Fusarium spp. communities, in fields under wheat-maize rotation. Such knowledge may contribute to better understand the complex interactions between Fusarium spp. and soil microbiota. Dynamics of bacterial and fungal communities, with a special focus on Fusarium spp., were monitored in soils at 3 time points: during wheat cultivation (April 2015 and 2017) and after maize harvest (November 2016) and in maize residues taken from fields after harvest. Shifts in microbiota were also evaluated under mesocosm experiments using soils amended with maize residues. Fusarium graminearum and F. avenaceum were predominant on maize residues but did not remain in soils during wheat cultivation. Differences in soil bacterial diversity and compositions among years were much lower than variation between fields, suggesting that bacterial communities are field-specific and more conserved over time. In contrast, soil fungal diversity and compositions were more influenced by sampling time. Maize residues, left after harvest, led to a soil enrichment with several fungal genera, including Epicoccum, Fusarium, Vishniacozyma, Papiliotrema, Sarocladium, Xenobotryosphaeria, Ramularia, Cladosporium, Cryptococcus, and Bullera, but not with bacterial genera. Likewise, under mesocosm conditions, the addition of maize residues had a stronger influence on fungal communities than on bacterial communities. In particular, addition of maize significantly increased soil fungal richness, while bacteria were much less prone to changes. Based on co-occurrence networks, OTUs negatively correlated to Fusarium spp. were identified, such as those assigned to Epicoccum and Vishniacozyma. Altogether, our results allowed to gain a deeper insight into the complex microbiota interactions in soils, with bacteria and fungi responding differently to environmental disturbances., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Risk factors for cytomegalovirus (CMV) reactivation and the impact of CMV reactivation on patient outcomes have been extensively investigated after matched related or unrelated donor transplantation, but little is known in the setting of haploidentical stem cell transplantation (Haplo-SCT) with post-transplantation cyclophosphamide (PT-Cy), in which recipients are considered more severely immunocompromised. We retrospectively analyzed a cohort of 554 consecutive patients undergoing Haplo-SCT with PT-Cy at 3 different centers. Early CMV reactivation (occurring within the first 120 days post-transplantation) occurred in 242 patients, for an estimated cumulative incidence of 44%. Among those patients, 74 (30%) had recurrent CMV and 20 (8%) had CMV disease. On multivariable analysis, positive recipient CMV serostatus (hazard ratio [HR] >2.5; P < .001), disease histology (lymphoid versus myeloid: HR, 0.66; P = .003) and increasing recipient age (HR, 1.01; P = .015) were independent predictors of CMV reactivation. At a 4-month landmark analysis, CMV reactivation was associated with higher 1-year and 5-year cumulative incidence of nonrelapse mortality (NRM) relative to patients without reactivation: 13% versus 5% and 22% versus 9%, respectively (P < .001). On multivariable analysis, CMV reactivation was an independent negative predictor of NRM (HR, 2.69; P < .001) and was close to statistically significant for overall survival (HR, 1.38; P = .062). Our results suggest that CMV reactivation plays an important role at determining NRM. Because patient CMV serostatus is the main predictor of CMV reactivation, it should be considered when evaluating strategies for preventing CMV reactivation. 2022 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this cohort study was to develop two scores able to differentiate coronavirus 2019 (COVID-19) from dengue and other febrile illnesses (OFIs)., Methods: All subjects suspected of COVID-19 who attended the SARS-CoV-2 testing center of Saint-Pierre hospital, Reunion, between March 23 and May 10, 2020, were assessed for identifying predictors of both infectious diseases from a multinomial logistic regression model. Two scores were developed after weighting the odd ratios then validated by bootstrapping., Results: Over 49 days, 80 COVID-19, 60 non-severe dengue and 872 OFIs were diagnosed. The translation of the best fit model yielded two scores composed of 11 criteria: contact with a COVID-19 positive case (+3 points for COVID-19; 0 point for dengue), return from travel abroad within 15 days (+3/-1), previous individual episode of dengue (+1/+3), active smoking (-3/0), body ache (0/+5), cough (0/-2), upper respiratory tract infection symptoms (-1/-1), anosmia (+7/-1), headache (0/+5), retro-orbital pain (-1/+5), and delayed presentation (>3 days) to hospital (+1/0). The area under the receiver operating characteristic curve was 0.79 (95%CI 0.76-0.82) for COVID-19 score and 0.88 (95%CI 0.85-0.90) for dengue score. Calibration was satisfactory for COVID-19 score and excellent for dengue score. For predicting COVID-19, sensitivity was 97% at the 0-point cut-off and specificity 99% at the 10-point cut-off. For predicting dengue, sensitivity was 97% at the 3-point cut-off and specificity 98% at the 11-point cut-off., Conclusions: COVIDENGUE scores proved discriminant to differentiate COVID-19 and dengue from OFIs in the context of SARS-CoV-2 testing center during a co-epidemic., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

We report on experimental and numerical implementations of devices based on the negative refraction of elastic guided waves, the so-called Lamb waves. Consisting in plates of varying thickness, these devices rely on the concept of complementary media, where a particular layout of negative index media can cloak an object with its anti-object or trap waves around a negative corner. The diffraction cancellation operated by negative refraction is investigated by means of laser ultrasound experiments. However, unlike original theoretical predictions, these intriguing wave phenomena remain, nevertheless, limited to the propagating component of the wave-field. To go beyond the diffraction limit, negative refraction is combined with the concept of metalens, a device converting the evanescent components of an object into propagating waves. The transport of an evanescent wave-field is then possible from an object plane to a far-field imaging plane. Twenty years after Pendry's initial proposal, this work thus paves the way towards an elastic superlens., (© 2021. The Author(s).)

Background: Diethylcarbamazine citrate (DEC) treatment of loiasis is complicated by adverse reactions that are correlated with the number of circulating microfilariae (mf). The cause of these reactions is unknown, but they are accompanied by a dramatic interleukin-5 (IL-5)-dependent increase in eosinophilia and evidence of eosinophil activation., Methods: To explore the role of IL-5 driven eosinophilia in post-DEC reactions, 8 adults with confirmed loiasis and <5000 mf/mL blood were enrolled in a randomized, double-blind, placebo-controlled trial of the humanized anti-IL-5 antibody, reslizumab, (1.0 mg/kg IV) administered 3 to 7 days prior to initiation of DEC treatment (9 mg/kg/day for 21 days). The primary endpoint was the reduction in absolute eosinophil count (AEC) during the first week of DEC treatment., Results: Baseline characteristics were comparable between the two groups. Single dose reslizumab lowered the AEC by 77% prior to initiation of DEC therapy (vs. 12% in the placebo group, P < .05). More importantly, AEC remained below baseline in the first week of DEC treatment in all subjects who received reslizumab and in none of the placebo subjects. Mf clearance occurred within 2 days of initiation of DEC in all 7 mf-positive subjects. Mild to moderate adverse events were seen in all 8 subjects and were not significantly different between the groups., Conclusions: In summary, although reslizumab was able to blunt peripheral eosinophilia post-DEC treatment in subjects with loiasis and had no effect on microfilarial clearance, the reduction in AEC appeared to have been insufficient to prevent post-treatment AEs., (Published by Oxford University Press for the Infectious Diseases Society of America 2020.)

Shwachman-Diamond syndrome with Shwachman-Bodian-Diamond syndrome (SBDS) biallelic variants is a rare disorder that predisposes the carrier to malignant hemopathies but solid-cancer predisposition is poorly known. Among 155 cases entered in the French Registry for Severe Chronic Neutropenia, three were identified with malignant solid tumors (ovary, breast, and esophagus). All cancers occurred during the fifth decade and, despite being localized at diagnosis, were rapidly fatal thereafter. No cancer was observed post transplantation in the 14 HSCT survivors. Based on the literature and our patient data, we can merely advance that this complication is predominantly diagnosed in adults., (© 2021 Wiley Periodicals LLC.)

The aging of the population is leading to an increase in the number of people with loss of autonomy, placing a strain on the health care system. Its prevention at early stages such as the frailty stage would allow an improvement in the quality of life of seniors while limiting health care expenses. The "Atout Age" prevention program set up by the health public authorities of Reunion Island for retired people and the new frailty assessment tools based on mathematical machine learning algorithms could improve the ambulatory care of senior citizens. At present, referral care remains hospital with comprehensive geriatric assessment and there is a lack of evidence of the effectiveness of a prevention pathway for loss of autonomy in primary care. For these reasons, the 5P program "Personalized and Participative Primary Prevention Pathway" has been started in order to obtain scientific evidence. In this article, we present the objectives, design and first results, used in the 5P program up to the implementation of a clinical trial in general practice. The program is articulated in 3 phases. A first phase to evaluate the acceptability of innovative screening tools for frailty. A second pilot phase evaluates the feasibility of a large-scale ambulatory clinical trial in general practice. The last phase described in this article, is a multisite, pseudo-randomized, controlled clinical trial measuring the impact of the "Atout Age" workshops on the physical performance and the quality of life of seniors compared with their usual ambulatory follow-up., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 Published by Elsevier Inc.)

Squamous cell carcinomas (SCCs) are among the most frequent solid tumors in humans. SCCs, related or not to the human papillomavirus, share common molecular features. Immunotherapies, and specifically immune checkpoint inhibitors, have been shown to improve overall survival in multiple cancer types, including SCCs. However, only a minority of patients experience a durable response with immunotherapy. Epigenetic modulation plays a major role in escaping tumor immunosurveillance and confers resistance to immune checkpoint inhibitors. Preclinical evidence suggests that modulating the epigenome might improve the efficacy of immunotherapy. We herein review the preclinical and the clinical rationale for combining immunotherapy with an epidrug, and detail the design of PEVOsq, a basket clinical trial combining pembrolizumab with vorinostat, a histone deacetylase inhibitor, in patients with SCCs of different locations. Sequential blood and tumor sampling will be collected in order to identify predictive and pharmacodynamics biomarkers of efficacy of the combination. We also present how clinical and biological data will be managed with the aim to enable the development of a prospective integrative platform to allow secure and controlled access to the project data as well as further exploitations., Competing Interests: Disclosure GC: Roche, Seattle Genetics, Novartis, Lilly, Pfizer, Foundation Medicine, Nanostring, Samsung, Celltrion, Ellipsis, Bristol-Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Mylan. CLT: Roche, Seattle Genetics, Rakuten, Nanobiotix, MSD, BMS, Merck Serono, AstraZeneca, GlaxoSmithKline, Novartis, Celgene. XF: Roche, Janssen, BMS, Leo Pharma, Amgen Research. LC: Leo Pharma, Amgen. JG: Roche, Leo Pharma. IP: employee and equity holder in Oncompass Medicine Ltd. RD, PF, and AD are employees of Oncompass Medicine Ltd. All other authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The AcSé-crizotinib program provides extensive screening of crizotinib-targeted genomic alteration in several malignancies. We here report the results in patients with esogastric MET-amplified adenocarcinomas., Objective: The objective of the study was to evaluate the efficacy and tolerability of crizotinib in patients with pretreated esogastric MET-amplified adenocarcinoma who have no alternative treatment options., Patients and Methods: MET expression was evaluated by fluorescence in situ hybridization in tumor samples with immunohistochemistry scores ≥ 2+. Patients with chemo-refractory tumors showing ≥ 6 MET copies were eligible for crizotinib 250 mg twice daily. The primary efficacy outcome was the objective response rate after two cycles of crizotinib., Results: MET was prospectively analyzed in 570 esogastric adenocarcinomas. Amplifications were found in 35/570 adenocarcinomas (29/523 gastric and 6/47 esophageal). Nine patients were treated with crizotinib. The objective response rate after two cycles was 33.3% (95% CI 7.5-70), the best overall response rate was 55.6% (95% CI 21.2-86.3), with median progression-free survival of 3.2 months (95% CI 1.0-5.4), and overall survival of 8.1 months (95% CI 1.7-24.6). Safety was consistent with that previously reported for crizotinib., Conclusions: Large-scale screening for MET-amplified esogastric adenocarcinomas is feasible. MET amplification was observed in 5.5% of gastric and 12.8% of esophageal adenocarcinomas. Crizotinib shows encouraging results in selected patients. Thus, c-MET inhibition for MET-amplified tumors deserves further evaluation., Trial Registration Number: NCT02034981., Date of Registration: 14 January 2014.

We report two cases of foot ischemia combining microvascular thrombosis related to essential thrombocytemia (ET) and a proximal ulcerating atherosclerotic plaque. This suggests that myeloproliferative neoplasms could also trigger distal embolism from an unstable atherosclerotic plaque by creating a prothrombotic status. These distal ischemic events were the first ET manifestation and therefore lead to myeloproliferative neoplasm diagnosis. In ET, thrombosis event can occur with a normal platelet count. Furthermore, hemogram should be regularly controlled among JAK2 muted patients considering the frequent evolution from isolated JAK2 mutation to ET., (Copyright © 2021. Published by Elsevier Masson SAS.)

Background: As coronavirus 2019 (COVID-19) is spreading globally, several countries are handling dengue epidemics. As both infections are deemed to share similarities at presentation, it would be useful to distinguish COVID-19 from dengue in the context of co-epidemics. Hence, we performed a retrospective cohort study to identify predictors of both infections., Methodology/principal Findings: All the subjects suspected of COVID-19 between March 23 and May 10, 2020, were screened for COVID-19 within the testing center of the University hospital of Saint-Pierre, Reunion island. The screening consisted in a questionnaire surveyed in face-to-face, a nasopharyngeal swab specimen for the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) reverse transcription polymerase chain-reaction and a rapid diagnostic orientation test for dengue. Factors independently associated with COVID-19 or with dengue were sought using multinomial logistic regression models, taking other febrile illnesses (OFIs) as controls. Adjusted Odds ratios (OR) and 95% Confidence Intervals (95%CI) were assessed. Over a two-month study period, we diagnosed 80 COVID-19, 61 non-severe dengue and 872 OFIs cases eligible to multivariate analysis. Among these, we identified delayed presentation (>3 days) since symptom onset (Odds ratio 1.91, 95% confidence interval 1.07-3.39), contact with a COVID-19 positive case (OR 3.81, 95%CI 2.21-6.55) and anosmia (OR 7.80, 95%CI 4.20-14.49) as independent predictors of COVID-19, body ache (OR 6.17, 95%CI 2.69-14.14), headache (OR 5.03, 95%CI 1.88-13.44) and retro-orbital pain (OR 5.55, 95%CI 2.51-12.28) as independent predictors of dengue, while smoking was less likely observed with COVID-19 (OR 0.27, 95%CI 0.09-0.79) and upper respiratory tract infection symptoms were associated with OFIs., Conclusions/significance: Although prone to potential biases, these data suggest that non-severe dengue may be more symptomatic than COVID-19 in a co-epidemic setting with higher dengue attack rates. At clinical presentation, nine basic clinical and epidemiological indicators may help to distinguish COVID-19 or dengue from each other and other febrile illnesses., Competing Interests: The authors have declared that no competing interests exist.

We report the outcome of 68 patients with advanced peripheral T-cell lymphoma receiving transplantation from haploidentical or from conventional donors. The 4-year OS, PFS, 2-year cumulative incidence of relapse and 2-year GRFS was 75%, 70%, 21%, and 51%, respectively. Survival was not affected by donor type. The 2-year NRM was 9%, lower after related or haploidentical donor (21% vs 0% vs 7%; p = 0.06). Grade 2-4 aGVHD cumulative incidence was significantly different after transplantation from haploidentical vs matched sibling vs unrelated donor, and (24% vs 35% vs 58%, p = 0.024). The familial donor cohort was compared to the unrelated cohort. Familial donor induced less grade 2-4 aGVHD, with a trend to less grade 3-4 aGVHD or moderate-severe cGVHD. The OS and PFS were not different, while the relapse risk and NRM were reduced. Allo-SCT is highly effective in T-cell lymphoma, with low NRM and low relapse rate. The incidence of aGVHD was lower after haploidentical transplantation. Related donor may challenge unrelated transplant reducing the risk of relapse and NRM.

Introduction: Double-J ureteral stents are subject to encrustation. Studies have shown that the encrustation onset is linked with indwelling time. In prevention, it is admitted that the Double-J stent indwelt for medium or long term should be replaced periodically. However, in the absence of guidelines, indwelling durations vary with centers' habits, stent indication, and stent materials. Our target was to evaluate the actual ureteral stent medium-/long-term indwelling times and related encrustation rates perceived by urologists in daily practice. Methods: An observational retrospective study was performed over six European centers. All data of all consecutive removed stents of the same material implanted for more than 2 months within a same 2-year referred period were collected. Three stent types of various materials, with/without coating, were evaluated. Encrustation rates were analyzed according to indwelling times and stent indication. Results: Four hundred seventy-three stents were recorded with indwelling times between 60 and 679 days. An unexpected number of long-term indwelling times were noticed: globally one-third more than 6 months, and 9% more than 1 year. In case of malignant indication, these rates were, respectively, 44% and 17%. For nonstone indication, clinically significant encrustation rates stayed extremely low before 4 months (1.3%) and quite low before 6 months (5.2%), increasing with time to reach around 10% in the long term. However, as expected, the rate was higher for stone indication with a marked increase after 4 months (8% before 4 months, nearly 17% after). Conclusion: Our data confirm a higher encrustation risk for stone patients. Long indwelling times in nonstone patients beyond 6 months or even 12 months appear to be still requested and relatively well supported in usual practice by this population.

Eosinophils are granulocytes involved mainly in allergic inflammation and parasitic responses and constitute 1-5% of the circulating leukocytes in human healthy subjects. New immunotherapies targeting eosinophils have been developed and evaluated recently, and the availability of animal models that could mimic human eosinophil responses is important to consider. Differences in eosinophil biology and pathogenesis between humans and murine models have limited their utility in some settings. Isolation of viable eosinophils from rhesus macaque blood suitable for ex vivo and in vitro experimentation could provide a valuable tool for the study of eosinophil-targeted therapies and for the exploration of eosinophilic associated responses. Here, a new technique for the isolation of human eosinophils from rhesus macaque blood by negative selection from whole blood is described.

Introduction: As the population ages, loss of autonomy is becoming a priority public health issue. "Atout Age Mobility" prevention interventions for seniors aim to limit frailty, which is a predictive and reversible factor in the loss of autonomy and disability., Objectives: The objective of this study is to describe the impact of these interventions on the physical performance and quality of life of a pilot sample of participants., Design: We conducted a prospective study named 5P PILOT with 3 months of follow up., Settings: Subjects were recruited by convenience sampling from participants in the "Atout Age Mobility" workshops at Saint Joseph from 04/09/2017 to 29/01/2019., Participants: Retired people over 55 years old with no contraindications to physical activity recruited from participants in the "Atout Age Mobility" workshops in Saint Joseph. Intervention(s) (for clinical trials) or Exposure(s) (for observational studies): All participants completed 12 weeks of physical exercise called the "Atout Age Mobility" workshop, which lasted 60 minutes each week and was supervised by physical activity coaches. Main Outcome(s) and Measure(s): Physical performance was assessed by Short physical performance battery (SPPB), 10-m gait speed and grip strength measurement. Quality of life through the SF-36 test., Results: Ninety-six patients were included and 55 (57.3%) completed the study. There was a significant improvement in gait speed (1.35±0.26m/s vs. 1.27±0.24m/s; p=0.008). There was no significant change in SF-36, grip strength dominant arm and SPPB at the 0.01 significance level., Conclusion: The "Atout Ages Mobility" workshops seem to significantly improve gait speed but not other aspects of physical performance or quality of life., Competing Interests: The authors stated that there was no conflict of interest.

Glucocorticoids are considered first-line therapy in a variety of eosinophilic disorders. They lead to a transient, profound decrease in circulating human eosinophils within hours of administration. The phenomenon of glucocorticoid-induced eosinopenia has been the basis for the use of glucocorticoids in eosinophilic disorders, and it has intrigued clinicians for 7 decades, yet its mechanism remains unexplained. To investigate, we first studied the response of circulating eosinophils to in vivo glucocorticoid administration in 3 species and found that the response in rhesus macaques, but not in mice, closely resembled that in humans. We then developed an isolation technique to purify rhesus macaque eosinophils from peripheral blood and performed live tracking of zirconium-89-oxine-labeled eosinophils by serial positron emission tomography/computed tomography imaging, before and after administration of glucocorticoids. Glucocorticoids induced rapid bone marrow homing of eosinophils. The kinetics of glucocorticoid-induced eosinopenia and bone marrow migration were consistent with those of the induction of the glucocorticoid-responsive chemokine receptor CXCR4, and selective blockade of CXCR4 reduced or eliminated the early glucocorticoid-induced reduction in blood eosinophils. Our results indicate that glucocorticoid-induced eosinopenia results from CXCR4-dependent migration of eosinophils to the bone marrow. These findings provide insight into the mechanism of action of glucocorticoids in eosinophilic disorders, with implications for the study of glucocorticoid resistance and the development of more targeted therapies. The human study was registered at ClinicalTrials.gov as #NCT02798523.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a valid option in patients with refractory lymphomas. HLA haploidentical stem cell transplantation (haplo-SCT) expanded the accessibility to allogeneic hematopoietic cell transplantation. The aims of study were to retrospectively assess the toxicity and efficacy of haplo-SCT using nonmyeloablative conditioning in patients with advanced lymphoma. In total, 147 patients with advanced lymphoma at 2 partner institutions were included. Patients received a uniform nonmyeloablative conditioning regimen and graft-versus-host disease (GVHD) prophylaxis. The primary endpoints were progression-free survival (PFS), overall survival (OS), GVHD, nonrelapse mortality, and GVHD, relapse-free survival (GRFS). Median follow-up was 39 months (range, 6 to 114 months). The median age was 46 years (range, 19 to 71 years). Sixty-five percent of patients were in complete remission (CR) at transplantation. Cumulative incidence of grade II to IV acute GVHD was 30% (95% confidence interval [Cl], 23% to 38%). Two-year cumulative incidence of all grades of chronic GVHD was 13% (95% CI, 8% to 20%). Two-year cumulative incidence of disease relapse was 19% (95% CI, 14% to 27%), with a higher incidence in patients not being in CR at allo-HCT (CR versus not CR: 12% versus 33%, P = .006). Two-year PFS, OS, and GRFS were 66% (95% CI, 59-75), 73% (95% CI, 66-81), and 56% (95% CI, 48-65), respectively. Haplo-SCT with post-transplantation cyclophosphamide may be considered a valid option for patients with aggressive lymphoma and deserves further evaluation., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Objective : To examine the moderating effect of internalized media messages on ideal body shape and lifestyle in the relationships between physical exercise, self-esteem, physical self-perceptions, and body image satisfaction. Design : pre-test/posttest control group experimental design. Methods : 46 inactive women (mean age = 21.4 ± 2.1 years-old) volunteered to participate in this study and were randomly assigned to Exercise (n = 23) or Wait-list (n = 23) groups. The Exercise group participated in two 50 minutes long exercise sessions per week for six weeks. During this period women in the Wait-list group did not participate in any regular physical activity. The French version of the Physical Self-Perception Profile (ISP-25) and the Body Image Assessment Scale (BIAS-BD) were administered to participants before and after intervention. In addition, the Sociocultural Attitudes Toward Appearance Questionnaire (SATAQ) was completed to assess participants' level of internalization of media standards. Results and Discussion : Women in the Exercise group improved more in outcomes than those in the Wait-list group. Effects were only marginally moderated by levels of media internalization. Potential explanations for these findings are reviewed and discussed.

In order to determine the required duration of whole-body exposure to extreme cold (-110 °C) in males and females for achieving the same cold-induced response, a mathematical model of skin cooling kinetics was developed. This modeling is derived from the implementation of a new experimental cryotherapy protocol to obtain continuous skin temperature maps over time. Each 3-min whole-body cryostimulation session was divided into six incremental sessions of 30 s carried out over six consecutive days. Seventeen young, healthy subjects (8 males aged 22.6 ±3.0 years and 9 females aged 23.7 ±4.7 years) agreed to participate in this study. The smallest sex-related difference in temperature was found in the trunk area (2.93 °C after 3 min) while the greatest temperature drop was found in the lower limbs (5.92 °C after 3 min). The largest temperature variation was observed between the trunk and the lower limbs, and peaked at 2.67 °C in males and 6.99 °C in females. For both sexes, skin cooling kinetics showed a strong transient exponential type decrease followed by linear regression behavior. It appeared that for achieving the same cold-induced response, the required duration of cryostimulation is longer for males. For example, a trunk skin cooling of -12 °C could be achieved in 125s for females vs 170s for males (+36% longer); for the lower limbs, the same skin cooling magnitude could be reached after 87s for females vs 140s for males (+62% longer)., Competing Interests: Declaration of competing interest The authors report no conflict of interests regarding the publication of this paper., (Copyright © 2020. Published by Elsevier Inc.)

Objective: Whole-Body Cryotherapy (WBC) has seen a recent surge in popularity with patients with inflammatory conditions, athletes, and even people seeking to improve general health and quality of life. WBC treatment usually requires participation in a dozen of 3-min long sessions. But compliance is considered difficult due to possible cold-induced unpleasant sensations. Based on hedonic psychology assumptions, ratings of pleasure-displeasure experienced during a taks or activity may be important to understand individual differences in attendance., Methods: Two hundred fifty nine customers from two French cryocenters took the Feeling Scale immediately after their first WBC session., Results: End affect appeared to be negatively valenced (M = -1.85, SD = 1.38, 95 % confidence interval: -2.02 to -1.68). Additional statistical analyses revealed a moderating influence of past experience, in women only. Similarly, BMI was found to be negatively associated with displeasure in women, but not in men., Conclusion: These findings are discussed and further research directions are suggested., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

MEdiator of cell MOtility1 (MEMO1) is a ubiquitously expressed redox protein involved in extracellular ligand-induced cell signaling. We previously reported that inducible whole-body Memo1 KO (cKO) mice displayed a syndrome of premature aging and disturbed mineral metabolism partially recapitulating the phenotype observed in Klotho or Fgf23-deficient mouse models. Here, we aimed at delineating the contribution of systemic mineral load on the Memo1 cKO mouse phenotype. We attempted to rescue the Memo1 cKO phenotype by depleting phosphate or vitamin D from the diet, but did not observe any effect on survival. However, we noticed that, by contrast to Klotho or Fgf23-deficient mouse models, Memo1 cKO mice did not present any soft-tissue calcifications and displayed even a decreased serum calcification propensity. We identified higher serum magnesium levels as the main cause of protection against calcifications. Expression of genes encoding intestinal and renal magnesium channels and the regulator epidermal growth factor were increased in Memo1 cKO. In order to check whether magnesium reabsorption in the kidney alone was driving the higher magnesemia, we generated a kidney-specific Memo1 KO (kKO) mouse model. Memo1 kKO mice also displayed higher magnesemia and increased renal magnesium channel gene expression. Collectively, these data identify MEMO1 as a novel regulator of magnesium homeostasis and systemic calcification propensity, by regulating expression of the main magnesium channels., Competing Interests: AP is an inventor of the T50-Test and stock-holder and employee of Calciscon AG, which commercialized the T50-Test (calcification propensity test). MB is an employee of Calciscon AG. This does not affect our adherence to PLOS ONE policies on data or materials sharing.

When a dynamic crack front travels through material heterogeneities, elastic waves are emitted, which perturb the crack and change the morphology of the fracture surface. For asperity-free crystalline materials, crack propagation along preferential cleavage planes is expected to present a smooth crack front and form a mirror-like fracture surface. Surprisingly, we show here that in single crystalline silicon without material asperities, the crack front presents a local kink during high-speed crack propagation. Meanwhile, local oscillations of the crack front, which can move along the crack front, emerge at the front kink position and generate periodic fracture surface corrugations. They grow from angstrom amplitude to a few hundred nanometers and propagate with a long lifetime at a frequency-dependent speed, while keeping a scale-independent shape. In particular, the local front oscillations collide in a particle-like manner rather than proceeding with a linear superposition upon interaction, which presents the characteristic of solitary waves. We propose that such a propagating mode of the crack front, which results from the fracture energy fluctuation at a critical crack speed in the silicon crystal, can be considered as nonlinear elastic waves that we call "corrugation waves.", Competing Interests: The authors declare no competing interest.

Background: We aimed at evaluating the feasibility and effects of intense (i.e. -90°C) whole-body cryostimulation (WBC) on somnolence and psychological well-being in an older-adult patient diagnosed with restless legs syndrome (RLS)., Methods: An interrupted time series approach was used in which the efficacy of cryostimulation was evaluated by measuring self-reported fatigue, wake time sleepiness, and well-being several times prior to, during, and after exposure to treatment (i.e. daily 3-min sessions of intense WBC)., Results: No adverse event occurred. Reported levels of sleepiness decreased immediately following the beginning of the treatment phase. In the same time, self-reported well-being significantly increased. Effects sizes were of large magnitude., Conclusion: In summary, the present study demonstrated that daily exposure to extremely cold air in an enclosed space for 2 weeks was feasible and effective in promoting physical and psychological states in an older patient with sleep disturbances., (© 2019 The International Association of Applied Psychology.)

Water supply, in hydroponic greenhouses, can originate from groundwater, surface water or rainwater stored in open tanks. To limit contamination of water supply, several methods have been used including active and passive methods such as slow filtration techniques which consist in passing the nutrient solutions slowly through filters. The purpose of this study was to describe the microbiota associated with water sampled before entering greenhouses and in recirculating nutrient solutions, either before or after running through a biofiltration system. Metabarcoding analysis revealed that water ecosystems were unique niches for diverse bacterial and fungal communities. Microbial composition varied greatly across storage conditions (groundwater vs. rainwater) and among greenhouses, suggesting that water microbiota is site- and storage-condition-specific. Nonetheless, we found that microbiota structure in open-stored water (either coming from ground or rain) shared a higher degree of similarity than with water directly pumped out of the ground. Open-stored waters were characterized by predominant taxa, notably those involved in aerobic chemoheterotrophy, such as the Sphingomonadaceae and Hyphomicrobiaceae families. Water directly collected from the ground showed the lowest levels of fungal and bacterial richness while also characterized by a significantly higher level of bacterial equitability and an enrichment in taxa involved in N-cycling. Slow filtration allowed reducing cultivable bacterial loads as well Pythium spp. and Fusarium oxysporum propagules, based on culture-dependent results, without compromising microbiota richness and diversity. Although compositional structure was similar following biofiltration, significant differences in bacterial (but not fungal) taxa abundance were reported, with primarily an enrichment of Chelativorans , Mycobacterium , and Gemmata as well as a depletion of Rhodobacter , Aminobacter , and Ellin329 . The exact mechanisms by which such taxa would be favored at the expense of other remained unknown. Besides the accurate description of microbiota found in water at both taxonomical and predicted functional levels, our study allowed comparing the water microbiota between various storage system and following biofiltration. Although preliminary, our results provide a first insight into the potential microbial diversity, which can increase ecosystem functionality., (Copyright © 2020 Picot, Cobo-Díaz, Pawtowski, Donot, Legrand, Le Floch and Déniel.)

In this paper we examined the aerodynamic drag and the resulting decrease of power output associated with the drafting positions used by Kenenisa Bekele at the 2019 Berlin marathon. Examination of videos of the race revealed three different positions adopted by Bekele directly behind a frontline of three runners. These drafting positions were numerically studied using CFD simulations performed with the RANS equations and the SST k-ω model. Depending on his position behind the pacers, our analyses indicated that Bekele's drafting strategy resulted in reductions of 38.5-57.3% of the drag resistance and aerodynamic power. In terms of metabolic power, Bekele's drafting positions yielded an estimated 1.91-2.84% reduction compared to the calculated metabolic power of 1427.89 W (or equivalent metabolic power relative to body mass of 25.50 W/kg) that Bekele would have developed if he had run alone at the same speed of 5.75 m.s -1 ., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest in this work., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

A new photon-counting camera based on hybrid pixel technology has been developed at the SOLEIL synchrotron, making it possible to implement pump-probe-probe hard X-ray diffraction experiments for the first time. This application relies on two specific advantages of the UFXC32k readout chip, namely its high frame rate (50 kHz) and its high linear count rate (2.6 × 10 6  photons s -1  pixel -1 ). The project involved the conception and realization of the chips and detector carrier board, the data acquisition system, the server with its specific software, as well as the mechanical and cooling systems. This article reports on in-laboratory validation tests of the new detector, as well as on tests performed at the CRISTAL beamline within the targeted experimental conditions. A benchmark experiment was successfully performed, showing the advantages of the pump-probe-probe scheme in correcting for drifts of the experimental conditions.

Posttransplant cyclophosphamide (PT-Cy) is an efficient GVHD prophylaxis but has not been extensively evaluated in mismatched unrelated donor (MMUD) allo-HSCT, for which antithymocyte globulin (ATG) is still considered as a standard. Thus, we evaluated the outcome of MMUD allo-HSCT with PT-Cy (n = 22) and performed a historical comparison with a control group receiving ATG (n = 40) in a single center experience. Compared with the ATG group, the risk of grade 2-4 acute GVHD was significantly lower in the PT-Cy group (HR = 0.12, 95% CI = [0.03-0.48], p = 0.002). No difference was observed in the cumulative incidence of chronic GVHD. The risk of both NRM and relapse was significantly lower in the PT-Cy group (NRM: HR = 0.05, 95% CI = [0.00-0.63], p = 0.021; relapse: HR = 0.31; 95% CI = [0.09-1.10], p = 0.07). Thus, we observed significantly better PFS (HR = 0.22, 95% CI = (0.07-0.65); p = 0.006), OS (HR = 0.24, 95% CI = (0.07-0.84); p = 0.026), and GRFS (HR = 0.37, 95% CI = (0.17-0.80); p = 0.011) in the PT-Cy group. We conclude that PT-Cy is an effective GVHD prophylaxis in the setting of MMUD allo-HSCT, resulting in a better outcome compared with standard prophylaxis using ATG. This suggests that as it was shown in the setting of haploidentical allo-HSCT, the use of PT-Cy can overcome the impact of HLA disparity, leading to promising survivals that approach those observed after HLA matched allo-HSCT.

Zeta potential of nanomaterials designed to be used in nanomedicine is an important parameter to evaluate as it influences in vivo behaviour hence biological activity, efficacy and safety. As mentioned by the International Organization for Standardization (ISO), electrophoretic light scattering is a relevant method for evaluating zeta potential. The present work aimed to validate a new protocol based on the application of Fast Field Reversal mode and to explore its scope with nanomaterials investigated as nanomedicines. Its scope was then compared with that of an already validated protocol which uses both Fast Field Reversal and Slow Field Reversal modes. The new protocol was validated within the framework of the application of the Smoluchowski approximation. Its performances complied with the ISO standard. The protocol could be applied to evaluate mean zeta potential of soft nanomaterials including polymer-based nanoparticles and liposomes. However, it appeared unsuitable to evaluate zeta potential of dense nanomaterials including rutile titanium dioxide nanoparticles. Compared with the previously validated protocol which only applied to the determination of zeta potential of polymer nanoparticles, this new validated protocol gives access to the determination of zeta potential to a wider range of nanomedicines under conditions complying with quality control assessments., (Copyright © 2019 Elsevier B.V. All rights reserved.)