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Abstract Richter transformation (RT) is an aggressive lymphoma occurring in patients with chronic lymphocytic leukaemia. Here we investigated the anti-CD3/anti-CD19 T-cell-engager blinatumomab after R-CHOP (i.e. rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in patients with untreated RT of diffuse large B-cell lymphoma histology (NCT03931642). In this multicentre phase 2 study, patients without complete response (CR) after two cycles of R-CHOP were eligible to receive an 8-week blinatumomab induction via continuous vein infusion with stepwise dosing until 112 μg/day. The primary endpoint was the CR rate after blinatumomab induction and secondary endpoint included safety, response duration, progression-free and overall survival. Thirty-nine patients started the first cycle of R-CHOP, 25 of whom received blinatumomab. After blinatumomab induction, five (20%) patients achieved CR, four (16%) achieved partial response, and six (24%) were stable. Considering the entire strategy, the overall response rate in the full-analysis-set was 46% (n = 18), with CR in 14 (36%) patients. The most common treatment-emergent adverse events of all grades in the blinatumomab-safety-set included fever (36%), anaemia (24%), and lymphopaenia (24%). Cytokine release syndrome (grade 1/2) was observed in 16% and neurotoxicity in 20% of patients. Blinatumomab demonstrated encouraging anti-tumour activity (the trial met its primary endpoint) and acceptable toxicity in patients with RT.

The development of leadership skills has been the topic of several position statements over recent decades, and the need of medical leaders for a specific training was emphasized during the COVID-19 crisis, to enable them to adequately collaborate with governments, populations, civic society, organizations, and universities. However, differences persist as to the way such skills are taught, at which step of training, and to whom. From these observations and building on previous experience at the University of Ottawa, a team of medical professors from Lyon (France), Ottawa, and Montreal (Canada) universities decided to develop a specific medical leadership training program dedicated to faculty members taking on leadership responsibilities. This pilot training program was based on a holistic vision of a transformation model for leadership development, the underlying principle of which is that leaders are trained by leaders. All contributors were eminent French and Canadian stakeholders. The model was adapted to French faculty members, following an inner and outer analysis of their specific needs, both contextual and related to their time constraints. This pilot program, which included 10 faculty members from Lyon, was selected to favor interactivity and confidence in older to favor long-term collaborations between them and contribute to institutional changes from the inner; it combined several educational methods mixing interactive plenary sessions and simulation exercises during onescholar year. All the participants completed the program and expressed global satisfaction with it, validating its acceptability by the target. Future work will aim to develop the program, integrate evaluation criteria, and transform it into a graduating training.

Richter syndrome (RS) arising from chronic lymphocytic leukemia (CLL) exemplifies an aggressive malignancy that develops from an indolent neoplasm. To decipher the genetics underlying this transformation, we computationally deconvoluted admixtures of CLL and RS cells from 52 patients with RS, evaluating paired CLL-RS whole-exome sequencing data. We discovered RS-specific somatic driver mutations (including IRF2BP2, SRSF1, B2M, DNMT3A and CCND3), recurrent copy-number alterations beyond del(9p21)(CDKN2A/B), whole-genome duplication and chromothripsis, which were confirmed in 45 independent RS cases and in an external set of RS whole genomes. Through unsupervised clustering, clonally related RS was largely distinct from diffuse large B cell lymphoma. We distinguished pathways that were dysregulated in RS versus CLL, and detected clonal evolution of transformation at single-cell resolution, identifying intermediate cell states. Our study defines distinct molecular subtypes of RS and highlights cell-free DNA analysis as a potential tool for early diagnosis and monitoring.

Introduction: Aneurysms of the splenomesenteric artery variant are extremely rare with an unusual location; making its management approach challenging. Case presentation: We report a case of splenomesenteric artery aneurysms that was managed in an endovascular approach in a 56-year-old gentleman with co-morbidity, obesity and anticoagulation treatment. A computed tomography investigating a left flank pain found a left sub-capsular renal hematoma and an incidental finding of a fusiform splenic artery aneurysm originating from the SMA measuring 3.2 × 3.4 cm. An endovascular intervention was performed by combining an embolization of the aneurysm and emplacement of stent graft at the superior mesenteric artery to isolate the aneurysm and prevent coil migration. The patient was discharged at day 2 post-operatively with excellent clinical and radiographic findings upon follow-ups. Discussion: Splenomesenteric artery aneurysms is rare as there are 47 published cases reported in the literature. They may present with abdominal pain, back pain, flank pain or discovered incidentally. Its open surgical management approach pose various potential difficulties due to its retropancreatic location. Other approaches were proposed in the literature including laparoscopic and endovascular managements. Conclusion: An appropriate endovascular management can be more feasible and suitable approach management of splenomesenteric artery aneurysms in patients with complicated medical condition.

Background:. Arm transplantation has been proposed as a valid therapeutic option for arm amputees. A bilateral arm transplantation including reconstruction of the left shoulder was performed on January 13, 2021 in Lyon (France). Methods:. The recipient was a 48-year-old man with bilateral amputation at proximal arm level on both sides following an electric shock in 1998. He had received a liver transplant in 2002. The donor was a 35-year-old man. On the right side, the donor humerus was fixed on the remaining 9-cm-long proximal stump, and was reinforced with the donor fibula in an intramedullary fashion. On the left side, the whole donor humerus (including the humeral head) was transplanted with reconstruction of the gleno-humeral joint, including a suspension ligamentoplasty. The immunosuppressive protocol was based on antithymocyte globulins as induction therapy, and tacrolimus, steroids and mycophenolate mofetil as maintenance therapy. Results:. Good bone healing and a well-positioned ligamentoplasty on the left side were achieved. At 2 years, the recipient was able to flex both elbows, and wrist extension, finger flexion, and extension were appreciated on both sides. Intrinsic muscle activity was detectable by electromyography during the eighth posttransplant month, and sensitivity was recovered. The patient is satisfied with his autonomy in some daily activities, but his greatest satisfaction is the recovery of his body image. Conclusions:. These results confirm that it is possible to propose this transplantation to proximal-level arm amputees. The patients’ information about risks and limits as well as their compliance and determination remain important prerequisites.

The IELSG38 trial was conducted to investigate the effects of subcutaneous (SC) rituximab on the complete remission (CR) rate and the benefits of SC maintenance in patients with extranodal marginal zone lymphoma (MZL) who received frontline treatment with chlorambucil plus rituximab. Study treatment comprised an induction phase with chlorambucil 6 mg/m2/day orally on weeks 1-6, 9-10, 13-14, 17-18, and 21-22, and rituximab 375 mg/m2 intravenously on day 1 of weeks 1-4, and 1400 mg SC on weeks 9, 13, 17, and 21. Then, a maintenance phase followed with rituximab administered at 1400 mg SC every two months for two years. Of the 112 patients enrolled, 109 were evaluated for efficacy. The CR rates increased from 52% at the end of the induction phase to 70% upon completion of the maintenance phase. With a median follow-up of 5.8 years, the 5-year event-free, progression-free, and overall survival rates were 87% (95% CI, 78-92), 84% (95% CI, 75-89), and 93% (95% CI, 86-96), respectively. The most common grade ≥3 toxicities were neutropenia (33%) and lymphocytopenia (16%). Six patients experienced treatment-related serious adverse events, including fever of unknown origin, sepsis, pneumonia, respiratory failure, severe cerebellar ataxia, and fatal acute myeloid leukemia. The trial showed that subcutaneous rituximab did not improve the complete remission rate at the conclusion of the induction phase, which was the main endpoint. Nevertheless, SC maintenance might have facilitated long-term disease control, potentially contributing to enhanced event-free and progression-free survival.

Abstract Graft-versus-leukemia (GvL) reactions are responsible for the effectiveness of allogeneic hematopoietic cell transplantation as a treatment modality for myeloid neoplasia, whereby donor T- effector cells recognize leukemia neoantigens. However, a substantial fraction of patients experiences relapses because of the failure of the immunological responses to control leukemic outgrowth. Here, through a broad immunogenetic study, we demonstrate that germline and somatic reduction of human leucocyte antigen (HLA) heterogeneity enhances the risk of leukemic recurrence. We show that preexistent germline-encoded low evolutionary divergence of class II HLA genotypes constitutes an independent factor associated with disease relapse and that acquisition of clonal somatic defects in HLA alleles may lead to escape from GvL control. Both class I and II HLA genes are targeted by somatic mutations as clonal selection factors potentially impairing cellular immune responses and response to immunomodulatory strategies. These findings define key molecular modes of post-transplant leukemia escape contributing to relapse.

Between 2011 and 2012, a phase II trial evaluated the use of the RiBVD (rituximab, bendamustine, velcade and dexamethasone) combination as first-line treatment for mantle cell lymphoma (MCL) patients over the age of 65. We have now re-examined the classic prognostic factors, adding an assessment of TP53 mutation status. Patients (N=74; median age 73 years) were treated with the RiBVD combination. Median progression-free survival (mPFS) was 79 months and median overall survival (mOS) was 111 months. TP53 mutation status was available for 54/74 (73%) patients. TP53 mutations (TP53mt) were found in 12 patients (22.2%). In multivariate analysis, among the prognostic factors (PF) evaluated, only TP53mt and an albumin level (Alb) 3.6 g/dL were independently associated with a shorter mPFS. A hazard ratio (HR) of 3.16 (1.3-9.9, P=0.014) was obtained for TP53mt versus TP53 wild-type (wt), and 3.6 (1.39-9.5, P=0.009) for Alb

Richter syndrome (RS) is the transformation of chronic lymphocytic leukaemia (CLL) into aggressive lymphoma, in most cases diffuse large B-cell lymphoma (DLBCL). Here, the authors characterize the DNA methylation and transcriptomic profiles of RS samples, find a clonally-related CLL epigenetic imprint, and develop classifiers for “RS-type” de novo DLBCLs.

Because our civilization has relied on pesticides to fight weeds, insects, and diseases since antiquity, the use of these chemicals has become natural and exclusive. Unfortunately, the use of pesticides has progressively had alarming effects on water quality, biodiversity, and human health. This paper proposes to improve farming practices by replacing pesticides with a laser-based robotic approach. This study focused on the neutralization of aphids, as they are among the most harmful pests for crops and complex to control. With the help of deep learning, we developed a mobile robot that spans crop rows, locates aphids, and neutralizes them with laser beams. We have built a prototype with the sole purpose of validating the localization-neutralization loop on a single seedling row. The experiments performed in our laboratory demonstrate the feasibility of detecting different lines of aphids (50% detected at 3 cm/s) and of neutralizing them (90% mortality) without impacting the growth of their host plants. The results are encouraging since aphids are one of the most challenging crop pests to eradicate. However, enhancements in detection and mainly in targeting are necessary to be useful in a real farming context. Moreover, robustness regarding field conditions should be evaluated.

Abstract Chitin-glucan (CG), an insoluble dietary fiber, has been shown to improve cardiometabolic disorders associated with obesity in mice. Its effects in healthy subjects has recently been studied, revealing its interaction with the gut microbiota. In this double-blind, randomized, cross-over, twice 3-week exploratory study, we investigated the impacts of CG on the cardiometabolic profile and gut microbiota composition and functions in 15 subjects at cardiometabolic risk. They consumed as a supplement 4.5 g of CG daily or maltodextrin as control. Before and after interventions, fasting and postprandial metabolic parameters and exhaled gases (hydrogen [H2] and methane [CH4]) were evaluated. Gut microbiota composition (16S rRNA gene sequencing analysis), fecal concentrations of bile acids, long- and short-chain fatty acids (LCFA, SCFA), zonulin, calprotectin and lipopolysaccharide binding protein (LBP) were analyzed. Compared to control, CG supplementation increased exhaled H2 following an enriched-fiber breakfast ingestion and decreased postprandial glycemia and triglyceridemia response to a standardized test meal challenge served at lunch. Of note, the decrease in postprandial glycemia was only observed in subjects with higher exhaled H2, assessed upon lactulose breath test performed at inclusion. CG decreased a family belonging to Actinobacteria phylum and increased 3 bacterial taxa: Erysipelotrichaceae UCG.003, Ruminococcaceae UCG.005 and Eubacterium ventriosum group. Fecal metabolites, inflammatory and intestinal permeability markers did not differ between groups. In conclusion, we showed that CG supplementation modified the gut microbiota composition and improved postprandial glycemic response, an early determinant of cardiometabolic risk. Our results also suggest breath H2 production as a non-invasive parameter of interest for predicting the effectiveness of dietary fiber intervention.

The development of leadership skills has been the topic of several position statements over recent decades, and the need of medical leaders for a specific training was emphasized during the COVID-19 crisis, to enable them to adequately collaborate with governments, populations, civic society, organizations, and universities. However, differences persist as to the way such skills are taught, at which step of training, and to whom. From these observations and building on previous experience at the University of Ottawa, a team of medical professors from Lyon (France), Ottawa, and Montreal (Canada) universities decided to develop a specific medical leadership training program dedicated to faculty members taking on leadership responsibilities. This pilot training program was based on a holistic vision of a transformation model for leadership development, the underlying principle of which is that leaders are trained by leaders. All contributors were eminent French and Canadian stakeholders. The model was adapted to French faculty members, following an inner and outer analysis of their specific needs, both contextual and related to their time constraints. This pilot program, which included 10 faculty members from Lyon, was selected to favor interactivity and confidence in older to favor long-term collaborations between them and contribute to institutional changes from the inner; it combined several educational methods mixing interactive plenary sessions and simulation exercises during onescholar year. All the participants completed the program and expressed global satisfaction with it, validating its acceptability by the target. Future work will aim to develop the program, integrate evaluation criteria, and transform it into a graduating training. [ABSTRACT FROM AUTHOR]

Introduction: Metabolic flexibility (MetF), defined as the ability to switch between fat and glucose oxidation, is increasingly recognised as a critical marker for assessing responses to dietary interventions. Previously, we showed that the consumption of multifibre bread improved insulin sensitivity and reduced low‐density lipoprotein cholesterol (LDLc) levels in overweight and obese individuals. As a secondary objective, we aimed to explore whether our intervention could also improve MetF. Methods: In this study, 39 subjects at cardiometabolic risk participated in a double‐blind, randomised, crossover trial lasting 8 weeks, repeated twice. During each phase, participants consumed either 150 g of standard bread daily or bread enriched with a mixture of seven dietary fibres. MetF response was assessed using a mixed‐meal tolerance test (MMTT), analysing changes in respiratory quotient (∆RQ) measured using indirect calorimetry. Results: Although there were no significant differences in ∆RQ changes induced by dietary fibre between the two diets, these changes were positively correlated with postprandial triglyceride excursion (∆TG) at baseline. Subgroup analysis of baseline fasting and postprandial plasma metabolites was conducted to characterise MetF responders. These responders exhibited higher baseline fasting LDLc levels and greater post‐MMTT ∆TG. Conclusion: In conclusion, although dietary fibres did not directly impact MetF in this study, our findings highlight potential determinants of MetF response, warranting further investigation in dedicated future interventions. Highlights: The term 'metabolic flexibility' (MetF) was initially used to describe the ability of helminths to generate energy through either aerobic respiration or anaerobic respiration, enabling them to adapt to environmental changes. This concept was later applied to human metabolism, emphasising the body's capacity to switch between different energy sources, such as carbohydrates and fats, based on energy requirements.MetF has been studied in the context of transitions between fasting and fed states, or in response to insulin stimulation. It refers to the body's ability to adapt its energy utilisation in response to changing metabolic demands.Research has shown that insulin resistance, often linked to type 2 diabetes and obesity, may be associated with reduced MetF, characterised by altered patterns of carbohydrate and fat oxidation. [ABSTRACT FROM AUTHOR]

Background: Superior mesenteric artery (SMA) pseudoaneurysm is a very rare condition, typically associated with trauma, inflammation, and infection, and as a post-operative complication. If left untreated it can lead to serious consequences such as rupture and fatal haemorrhage. Report: A 17 year old male presented to the emergency department with a history of intermittent progressive epigastric pain with no preceding significant symptoms of a possible cause. He was initially treated conservatively until the intensity of pain was so severe an abdominal computed tomography (CT) scan was justified. A pseudoaneurysm of the SMA was found. Full inflammatory and immunological workup was unremarkable. Repeat CT scan showed the SMA pseudoaneurysm was larger, mandating surgical intervention; the vascular surgeon suggested an exploratory laparotomy. Intra-operatively, unexpectedly, a wooden foreign body measuring 5.0 × 0.3 × 0.5 cm was seen once the aneurysm sac was opened. The pseudoaneurysm was repaired and the abdomen closed after ascertaining that all other organs were intact. The patient had a simple recovery with no complications and was discharged home. The follow up CT scans were unremarkable. Conclusion: Pseudoaneurysm of the SMA in the paediatric age group is an extremely rare and life threatening phenomenon. The clinical presentation may be subtle, leading to delayed diagnosis. Early surgical intervention may be lifesaving and prevent further complications.

Pesticide-free agricultural strategies need new tools for disease prevention. Better than early detection of disease, detection of conditions favorable to their appearance can be a progress. In the case of fungal diseases, the presence of water on the plant surface is necessary. In order to detect remotely this presence early and at the scale of a crop field, we propose a low-cost solution based on laser reflection. Here, experimental results in a controlled environment are presented on both hydrophobic and hydrophilic leaves (rapeseed Brassica Napus and grapevine Vitis Vinifera, respectively). We first assess the water detection on a leaf surface by recreating the dew formation process. We next evaluate the influence of the scanning measurement and leaf inclination on the detection to get closer to in-field conditions. Results show that this method is very sensitive on both types of leaves. Water detection is possible from a low surface coverage with a high temporal precision at 1 m. In the hydrophobic case, water on a leaf surface leads to an increase of the detected signal up to three times compared to a dry leaf. The corresponding minimum surface coverage detectable at 1 m is evaluated at 1.6% thanks to 2D ray-tracing numerical simulations. In the hydrophilic case, on the contrary, water on a leaf surface leads to a decrease of the detected signal by almost half. For both types, the dew detection delay is contained under 5 min and can be improved. Finally, the presented results pave the way to a field application. [ABSTRACT FROM AUTHOR]

Some cardiometabolic risk factors such as dyslipidemia and insulin resistance are known to be associated with low gut microbiota richness. A link between gut microbiota richness and the diversity of consumed dietary fibers (DF) has also been reported. We introduced a larger diversity of consumed DF by using a daily consumed bread in subjects at cardiometabolic risk and assessed the impacts on the composition and functions of gut microbiota as well as on cardiometabolic profile. Thirty-nine subjects at cardiometabolic risk were included in a double-blind, randomized, cross-over, twice 8-week study, and consumed daily 150 g of standard bread or enriched with a 7-dietary fiber mixture (5.55 g and 16.05 g of fibers, respectively). Before and after intervention, stool samples were collected for gut microbiota analysis from species determination down to gene-level abundance using shotgun metagenomics, and cardiometabolic profile was assessed. Multi-fiber bread consumption significantly decreased Bacteroides vulgatus, whereas it increased Parabacteroides distasonis, Fusicatenibacter saccharivorans, an unclassified Acutalibacteraceae and an unclassified Eisenbergiella (q