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International audience; Ice losses from the Greenland and Antarctic ice sheets have accelerated since the 1990s, accounting for a significant increase in the global mean sea level. Here, we present a new 29-year record of ice sheet mass balance from 1992 to 2020 from the Ice Sheet Mass Balance Inter-comparison Exercise (IMBIE). We compare and combine 50 independent estimates of ice sheet mass balance derived from satellite observations of temporal changes in ice sheet flow, in ice sheet volume, and in Earth's gravity field. Between 1992 and 2020, the ice sheets contributed 21.0±1.9 mm to global mean sea level, with the rate of mass loss rising from 105 Gt yr−1 between 1992 and 1996 to 372 Gt yr−1 between 2016 and 2020. In Greenland, the rate of mass loss is 169±9 Gt yr−1 between 1992 and 2020, but there are large inter-annual variations in mass balance, with mass loss ranging from 86 Gt yr−1 in 2017 to 444 Gt yr−1 in 2019 due to large variability in surface mass balance. In Antarctica, ice losses continue to be dominated by mass loss from West Antarctica (82±9 Gt yr−1) and, to a lesser extent, from the Antarctic Peninsula (13±5 Gt yr−1). East Antarctica remains close to a state of balance, with a small gain of 3±15 Gt yr−1, but is the most uncertain component of Antarctica's mass balance. The dataset is publicly available at https://doi.org/10.5285/77B64C55-7166-4A06-9DEF-2E400398E452 (IMBIE Team, 2021).

Models predicting the risk of adverse pathology (ie, International Society of Urological Pathology [ISUP] grade group ≥3, pT3, and/or pN1) among patients operated by radical prostatectomy (RP) have been proposed to expand active surveillance (AS) inclusion criteria. We aimed to test these models in a set of 1062 low-risk and favorable intermediate-risk prostate cancer (PCa) patients diagnosed by multiparametric magnetic resonance imaging (MRI) and MRI-targeted biopsy. We hypothesized that the inclusion of radiological features into a novel model would improve patient selection. Performance was assessed using discrimination, calibration, and decision curve analysis (DCA). Available models were characterized by poor discrimination (areas under the receiver operating characteristic curve [AUCs] of 59% and 60%), underestimation of predicted risk on calibration plots, and a small amount of net benefit against a probability threshold of 40-50% at the DCA. The development of a novel model slightly improved discrimination (AUC of 63% vs 59%, p = 0.001, and 63% vs 60%, p = 0.07) and net benefit against threshold probabilities of ≥30%. This first multicenter study demonstrated the poor performance of models predicting adverse pathology and that implementation of MRI and MRI-targeted biopsy in this setting was not associated with a clear improvement in patient selection. Patients harboring low-risk or favorable intermediate-risk PCa and candidates for RP cannot be referred accurately to an AS program without a non-negligible risk of misclassification. PATIENT SUMMARY: We tested prediction models that could expand the selection of prostate cancer patients for active surveillance. Models were inaccurate and associated with a high risk of misclassification despite the implementation of multiparametric magnetic resonance imaging and targeted biopsies.

n May 2018, the Mayotte island, located in the Indian Ocean, was affected by an unprecedented seismic crisis, followed by anomalous on-land surface displacements in July 2018. Cumulatively from July 1, 2018 to December 31, 2021, the horizontal displacements were approximately 21 to 25 cm eastward, and subsidence was approximately 10 to 19 cm. The study of data recorded by the on-land GNSS network, and their modeling coupled with data from ocean bottom pressure gauges, allowed us to propose a magmatic origin of the seismic crisis with the deflation of a deep source east of Mayotte, that was confirmed in May 2019 by the discovery of a submarine eruption, 50 km offshore of Mayotte ([Feuillet et al., 2021]). Despite a non-optimal network geometry and receivers located far from the source, the GNSS data allowed following the deep dynamics of magma transfer, via the volume flow monitoring, throughout the eruption., En mai 2018, l’île de Mayotte a été touchée par une crise sismique sans précédent, suivie en juillet 2018 par des déplacements de surface à terre anormaux. En cumulé, du 1er juillet 2018 au 31 décembre 2021, les déplacements horizontaux étaient d’environ 21 à 25 cm vers l’est, et la subsidence d’environ 10 à 19 cm. L’étude des données GNSS à terre, et leur modélisation couplée aux données des capteurs de pression en mer, ont permis de conclure à une origine magmatique de la crise sismique avec la déflation d’une source profonde à l’est de Mayotte, confirmée en mai 2019 par la découverte d’une éruption sous-marine, à 50 km au large de Mayotte ([Feuillet et al., 2021]). Malgré une géométrie de réseau non optimale et des récepteurs éloignés de la source, les données GNSS ont permis de suivre la dynamique profonde du transfert magmatique, via la surveillance des flux volumiques.

MALDI-TOF MS is a powerful analytical technique that provides a fast and label-free readout for in vitro assays in the high-throughput screening (HTS) environment. Here, we describe the development of a novel, HTS compatible, MALDI-TOF MS-based drug discovery assay for the endoplasmic reticulum aminopeptidase 1 (ERAP1), an important target in immuno-oncology and auto-immune diseases. A MALDI-TOF MS assay was developed beginning with an already established ERAP1 RapidFire MS (RF MS) assay, where the peptide YTAFTIPSI is trimmed into the product TAFTIPSI. We noted low ionisation efficiency of these peptides in MALDI-TOF MS and hence incorporated arginine residues into the peptide sequences to improve ionisation. The optimal assay conditions were established with these new basic assay peptides on the MALDI-TOF MS platform and validated with known ERAP1 inhibitors. Assay stability, reproducibility and robustness was demonstrated on the MALDI-TOF MS platform. From a set of 699 confirmed ERAP1 binders, identified in a prior affinity selection mass spectrometry (ASMS) screen, active compounds were determined at single concentration and in a dose-response format with the new MALDI-TOF MS setup. Furthermore, to allow for platform performance comparison, the same compound set was tested on the established RF MS setup, as the new basic peptides showed fragmentation in ESI-MS. The two platforms showed a comparable performance, but the MALDI-TOF MS platform had several advantages, such as shorter sample cycle times, reduced reagent consumption, and a lower tight-binding limit.

The ocean engine of NEMO is a primitive equation model adapted to regional and global ocean circulation problems. It is intended to be a flexible tool for studying the ocean and its interactions with the others components of the earth climate system over a wide range of space and time scales. To cite this edition: Madec, G. and the NEMO System Team, 2023.NEMO Ocean Engine Reference Manual, Zenodo, https://doi.org/10.5281/zenodo.8167700

Il est des livres qui font date. Celui de James Clifford en fait partie. Depuis sa publication en 1988, les débats qu’il a suscités furent vifs, et rares sont les publications d’anthropologie qui ne lui font pas référence. Il est donc heureux que ce texte soit disponible en français dans sa version première, sans ajouts ou corrections ultérieurs. […] Lire la suite dans le fac-similé en PDF

Some books are milestones. James Clifford’s is one such. Since its publication in 1988, it has prompted much debate, and anthropological works which make no reference to it are few far between. So its availability in French, in its original version with no addition or later revisions, is more than welcome. […] Read more in the PDF facsimile

Disruptive behavior during instruction is a common problem in elementary classrooms. One intervention to reduce disruptive behavior is the Good Behavior Game (GBG). In this study, the students of 2 early elementary classrooms experienced 3 versions of the GBG: experimenter-implemented, teacher-implemented, and student-implemented. The effects of the GBG on disruptive behavior and peer interactions were evaluated using a combined reversal and multielement design. Student preference for conditions was assessed via a group arrangement of a concurrent-chains preference assessment. All versions of the game reduced disruptive behavior compared to baseline, but the rate of disruptive behavior was slightly higher during the teacher-implemented sessions in Class 1. Few peer interactions occurred during the game; however, negative interactions increased slightly in both classes during the GBG. Students overwhelmingly preferred the student-implemented version of the game. This study provides support for student implementation of the GBG and offers an approach to student shared governance in the classroom.

The present work deals with the study of the damping capacity of b-metastable Ti–(24–26) Nb alloys. In this work, several methods have been used to characterize this damping. The impact tests were carried out using two test benches: high-speed impacts were carried out using a vertical firing pressure gun and low-velocity impacts were studied with a bullet drop test. In addition, an original approach of a dynamic mechanical analysis (DMA) is proposed in order to obtain more in-depth understanding of the relationship between microstructure, deformation mechanisms, and damping capacity. The specimens are studied at different microstructure states: single β, dual-phase β + α″, and martensitic phase. A correlation is established between the evolution of the damping factor as function of the applied strain and the occurrence of the corresponding deformation mechanisms. The stress-in-duced martensite mechanism contributes to the improvement of the damping factor.The highest damping capacity is observed for the dual-phase specimen (β + α″). It is shown that the contribution of both the reorientation martensite variants and stress-induced martensitic transformation lead to a damping capacity higher than a single deformation mechanism one.

International audience; Cancer-Associated Fibroblasts (CAFs) represent the most prominent component of the tumor microenvironment (TME). Recent studies demonstrated that CAF are heterogeneous and composed of different subpopulations exerting distinct functions in cancer. CAF populations differentially modulate various aspects of tumor growth, including cancer cell proliferation, extra-cellular matrix remodeling, metastatic dissemination, immunosuppression and resistance to treatment. Among other markers, the Fibroblast Activation Protein (FAP) led to the identification of a specific CAF subpopulation involved in metastatic spread and immunosuppression. Expression of FAP at the surface of CAF is detected in many different cancer types of poor prognosis. Thus, FAP recently appears as an appealing target for therapeutic and molecular imaging applications. In that context, 68 Ga-labeled radiopharmaceutical-FAP-inhibitors (FAPI) have been recently developed and validated for quantitatively mapping FAP expression over the whole-body using Positron Emission Tomography (PET/CT). In this review, we describe the main current knowledge on CAF subpopulations and their distinct functions in solid cancer, as well as the promising diagnostic and therapeutic implications of radionuclides targeting FAP.

Background and ObjectivesTo assess gender disparities in neurology researcher careers in the United States.MethodsA 34-question survey was distributed to 4,644 US-based American Academy of Neurology members who self-identified as researchers in 2020 addressing the following domains: research and funding, scholarly activities, coronavirus disease 2019 (COVID-19) effect, and local institutional climate.ResultsA total of 700 (15%) individuals completed the survey (women, n = 231; men, n = 426), with 71% White and >80% conducting research. Women respondents were significantly younger than men, more likely to be assistant professors (32% vs 21%), and less likely to be full professors (18% vs 39%). Compared with men, women received equivalent grants and research support and had comparable or additional formal research training and mentorship. Women had less middle author publications (mean 5.8 [SD 9.2] vs mean 8.2 [SD 11.8],p= 0.03) compared with men but similar first or last author publications (mean 4.3[5.4] vs 6.1 [9.8],p= 0.05). A lower proportion of women presented research at grand rounds or at a national/international conference compared with men (58% vs 69%,p= 0.01). Women spent more time in nonprofessional responsibilities, were less satisfied with their work-life balance, and were less likely to agree with statements addressing equity/diversity and institutional climate. Respondents shared their concerns regarding how the pandemic was affecting neurology research careers, with a higher proportion of women reporting that family responsibilities affected research activities and lead to delayed submission of non–COVID-19-related manuscripts.DiscussionOur survey of US-based neurology researchers demonstrated continued gender-based disparities in academic rank, manuscript authorship, and invited speaking engagements, although funding opportunities and access to additional training were equivalent. Women were less likely than men to agree that neurology departments support diversity and equity and that the institutional climate was inclusive and transparent. The pandemic had affected both genders in research, but areas were different for women related to family responsibilities. This article also highlights additional areas of research and areas for intervention to improve and reduce gender disparities among neurology researchers.

The present study aims at developing a new Shape Memory Alloy (SMA) autonomous torsion actuator that exhibits Two-Way reversible memory effect Assisted by SuperElasticity. The developed actuator noted hereafter TWASE is composed by a single NiTi compact component having two distinct SMAs parts on one single axis: a SuperElastic part (length L SE ) and a Shape Memory Effect part (length L SME ). The proposed design ensures twisting the actuator when heated, this activates then the superelastic part putting back the actuator into its original shape as a result of a decrease in temperature. Hence, the actuator moves and goes back to the initial position autonomously (self-reversible). It has been established that the actuation efficiency is strongly dependent on the length ratio (k SME ) of the SME part with respect to the total length of the torsion actuator. Experimentally, an actuator with a length ratio of 3/5 has been developed and tested. The actuator’s axis is subjected to a specific heat treatment for obtaining a SMA wire with two distinct zones. A FE analysis using a proper UMAT subroutine into Abaqus software has been performed to predict the kinematics and the thermomechanical response of the actuator and finally to optimize it accordingly. The developed computational model captures the actuator responses and the subsequent optimizations are carried out leading to the improved specifications, which are confirmed experimentally. The experimental validation has been carried out using a prototype set-up of a torsion bench built by 3D printing. The actuation response of TWASE is numerically analyzed for several length ratio configurations. Based on the numerical simulations, the performance of the actuator has been optimized in terms of rotation angle and length ratio. The best ratio of shape memory to superelastic parts in the actuator has been predicted to 1/4 for obtaining the expected two-way reversible memory effect (TWASE).

The aim of this study is to assess the effect of a systemic intervention on the evolution of empowering leadership and emotional exhaustion in a university hospital sub-centre compared to a control sub-centre, both being part of a large French university hospital complex.Empowering leadership is a promising strategy for developing hospital team engagement and performance. However, the bureaucratic functioning of large hospitals, characterized by a managerial culture of control and a stratified organization, can be a barrier to empowering leadership.The intervention included empowering leadership training, direct field experimentation of empowering leadership and coaching, involving all the sub-centre hierarchical levels for 12 months. Data were collected before and after the intervention. A total of 441 and 310 participants were, respectively, included in the intervention and control sub-centres.Empowering leadership was decreased, and emotional exhaustion was increased in the control sub-centre, while the scores remained stable in the intervention sub-centre. The increased emotional exhaustion in the control sub-centre could partially be explained by the change in empowering leadership.In a context of decreased empowering leadership and increased emotional exhaustion, the intervention had a protective effect. Implications for the design of future interventions were discussed.This study unequivocally showed the benefit of transforming hospital management towards empowering leadership, to prevent increased emotional exhaustion.This study is registered on ClinicalTrials.gov on 4 July 2019 (NCT04010773).

Dans la zone soudano-sahélienne du Nord-Cameroun, à partir de 1994, le projet Développement paysannal et gestion de terroir a encouragé la restauration des parcs agroforestiers à Faidherbia albida en subventionnant leur régénération naturelle assistée (RNA), en prélevant sur les revenus du coton. Ensuite, les instituts de recherche agronomique camerounais (Irad) et français (Cirad) s’associèrent pour étudier la dynamique de restauration de ces parcs, avec l’appui de l’École nationale du génie rural, des eaux et forêts (Engref) et du projet PRASAC, en réalisant des essais d’émondage des arbres, des inventaires et des enquêtes. Mais depuis la crise sécuritaire de Boko Haram (2015), l’accès au terrain est devenu compliqué. L’étude a pour objet de déterminer si un suivi de l’évolution de la couverture arborée de deux de ces parcs serait possible par une photo-interprétation semi-automatique d’images Google Earth prises en saison sèche, basée sur une analyse orientée-objet, et quel serait son degré de fiabilité. La comparaison entre les données provenant d’un inventaire réalisé dans ces parcs en 2012 et celles provenant de l’interprétation d’images Google Earth de 2013 montre que ces dernières sont très imprécises pour l’estimation du nombre d’arbres, en particulier pour les arbres dont le houppier a une surface de 2 à 100 m2, et pour les F. albida qui perdent une partie de leur feuillage et qui sont émondés de façon très irrégulière. Malgré cela, il est constaté que, sur les terroirs de Sirlawé et Gané, la superficie projetée des houppiers a plus que doublé entre 2009 et 2018, en passant respectivement de 246 à 587 m2/ha (2,5 % à 5,9 %) et de 245 à 575 m2/ha (2,5 % à 5,8 %). Cette augmentation du couvert est essentiellement due aux arbres de petite taille. Cette étude dessine des bases pour : inventorier plus précisément avec d’autres types d’images satellitaires ; comparer l’évolution du couvert arboré des villages bénéficiant ou pas de la politique de RNA subventionnée ; déterminer les perceptions des agriculteurs sur l’intérêt de la politique d’appui à la RNA et sur la gestion durable de ces systèmes agroforestiers.

Palliation is a controversial indication for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Patients with peritoneal carcinomatosis (PC) are living longer, and the roles of palliative CRS and HIPEC are increasingly challenged. The purpose of this study is to evaluate indications, morbidity, and symptom improvement from CRS/HIPEC in advanced PC.A retrospective review of patients undergoing CRS and/or HIPEC with a palliative intent at a single institution from February 2008 to February 2018 was performed. Main end points included symptom improvement, symptom-free interval, and overall survival.Two hundred and seventy seven patients were referred for CRS/HIPEC during the study period and 17 underwent 20 palliative procedures. Appendiceal (n = 6) and colorectal cancers (n = 6) were the most common malignancies. Ascites (n = 8) and bowel obstruction (n = 8) were the most common indications for intervention. The postoperative complication rate was 50% and major complication rate was 20%. Partial symptom improvement or resolution of symptoms was achieved in 18 (90%) cases. A durable symptom control at 90 d was achieved in 13 (65%) cases. The median time to symptom recurrence was 5.1 mo (interquartile range: 2-11.4), and the median overall survival was 11.6 mo (interquartile range: 3.8-28.5).Palliative CRS and/or HIPEC achieve symptom improvement in patients with advanced PC. Risk assessment and expected time to recovery from surgery remain paramount for patient selection.

Familial amyloid polyneuropathy is a rare autosomal dominant disorder caused by mutations in the transthyretin gene, TTR. More than 100 mutations in the TTR gene are known. p.Val30Met was identified first as a cause of FAP and is the most common mutation worldwide. p.Val30Met is associated with peripheral neuropathy while p.Val142lle (C.424G>A) (also known as p.Val122lle) is associated with cardiac amyloidosis [1, 2, 3] . In this context, we report a patient harboring p.Val142lle mutation with exclusive small fiber neuropathy and absence of any cardiac involvement representing genotypic-phenotypic heterogenicity.

International audience

The COVID-19 pandemic has been an unprecedented disruption in students' academic development. Using reading test scores from 5 million U.S. students in grades 3-8, we tracked changes in achievement across the first two years of the pandemic. Average fall 2021 reading test scores in grades 3-8 were .09 to .17 standard deviations lower relative to same-grade peers in fall 2019, with the largest impacts in grades 3-5. Students of color attending high-poverty elementary schools saw the largest test score declines in reading. Our results suggest that many upper elementary students are at-risk for reading difficulties and will need targeted supports to build and strengthen foundational reading skills.The online version contains supplementary material available at 10.1007/s11145-022-10345-8.

In Niger, literature from the years 1990–2020 shows a rapid regression in the surface areas of forest, an abundant regeneration of trees in some cultivated areas, and a sharp increase in the consumption of wood energy in cities and the countryside, with this wood increasingly coming from parklands. This study, carried out in 2015–2019 on the outskirts of Niamey, aimed to assess the economic benefits for households of parkland fuelwood production and the ecological state of the parklands. Surveys were carried out among 90 farmers to assess the contribution of fuelwood to their household income. Semi-structured interviews with focus groups were conducted in 3 villages to determine farmers' strategies and practices. The inventory of the trees in the parklands was carried out in 3 villages (5000 ha per village). Most rural households have an income diversification strategy to cope with the vagaries of agricultural production. Among these revenues, the sale of fuelwood occupies on average a small place (4 to 10%). To explain their reduced use of assisted natural regeneration (ANR) for the restoration of parklands, farmers point to the difficulty in exploiting wood pruned from their trees due to conflicts of use with livestock herders, taxes and fines from environmental services agencies. Trees and shrubs in parklands have a low diversity (24 species) and low density (5–8 trees/ha). The low density of young trees indicates that during the past decade, there have been fewer efforts to enrich parklands compared to the 1980s, when ANR projects were first implemented. The 3 parklands studied are in the process of becoming severely degraded because dead old trees are no longer replaced through ANR. The Economic importance of fuelwod in family resources is not a sufficient trigger factor for farmers to restore their parklands but could support village's interest for sustainable management of natural forests. These results should serve to alert public authorities and aid organizations that research and development actions must be launched to reverse this deterioration trend in parklands.

Ibrutinib is a first-in-class Bruton’s tyrosine kinase inhibitor approved for the treatment of various B-cell malignancies and chronic graft-versus-host disease. We evaluated the safety and efficacy of ibrutinib, alone or combined with standard-of-care regimens, in adults with advanced urothelial carcinoma (UC). Once-daily ibrutinib was administered orally at 840 mg (single-agent or with paclitaxel) or at 560 mg (with pembrolizumab). Phase 1b determined the recommended phase 2 dose (RP2D) of ibrutinib, and phase 2 assessed progression-free survival (PFS), overall response rate (ORR), and safety. Thirty-five, eighteen, and fifty-nine patients received ibrutinib, ibrutinib plus pembrolizumab, and ibrutinib plus paclitaxel at the RP2D, respectively. Safety profiles were consistent with those of the individual agents. The best-confirmed ORRs were 7% (two partial responses) with single-agent ibrutinib and 36% (five partial responses) with ibrutinib plus pembrolizumab. Median PFS was 4.1 months (range, 1.0–37.4+) with ibrutinib plus paclitaxel. The best-confirmed ORR was 26% (two complete responses). In previously treated patients with UC, ORR was higher with ibrutinib plus pembrolizumab than with either agent alone (historical data in the intent-to-treat population). ORR with ibrutinib plus paclitaxel was greater than historical values for single-agent paclitaxel or ibrutinib. These data warrant further evaluation of ibrutinib combinations in UC.

(1) Background: The European Association of Urology (EAU) biochemical recurrence (BCR) risk grouping relies on data from historical cohorts that used conventional imaging techniques. In the era of PSMA PET/CT, we compared the patterns of positivity in the two risk groups and provided insight into positivity predictive factors. (2) Methods: Data from 1185 patients who underwent 68Ga-PSMA-11PET/CT for BCR was analyzed, out of which 435 patients treated initially treated by radical prostatectomy were included in the final analysis. (3) Results: A significantly higher rate of positivity in the BCR high-risk group was observed (59% vs. 36%, p < 0.001). BCR low-risk group demonstrated more local (26% vs. 6%, p < 0.001) and oligometastatic (100% vs. 81%, p < 0.001) recurrences. The BCR risk group and PSA level at the time of PSMA PET/CT were independent predictive factors of positivity. (4) Conclusions: This study confirms that the EAU BCR risk groups have different rates of PSMA PET/CT positivity. Even with a lower rate in the BCR low-risk group, oligometastatic disease was 100% in those with distant metastases. Given the presence of discordant positivity and risk classification, integrating PSMA PET/CT positivity predictors into risk calculators for BCR might improve patient classification for subsequent treatment options. Future prospective studies are still needed to validate the above findings and assumptions.

Background. Patients with schizophrenia show abnormal gaze processing, which is associated with social dysfunction. These abnormalities are associated with aberrant connectivity among brain regions associated with visual processing, social cognition, and cognitive control. In this study, we investigated 1) how effective connectivity during gaze processing is disrupted in schizophrenia, and 2) how this might contribute to social dysfunction and clinical symptoms.Methods. Thirty-nine patients with schizophrenia/schizoaffective disorder (SZ) and 33 healthy controls (HC) completed an eye gaze processing task during fMRI. Participants viewed faces with different gaze angles and performed explicit and implicit gaze processing. Four brain regions—the secondary visual cortex (Vis), posterior superior temporal sulcus (pSTS), inferior parietal lobule (IPL), and posterior medial frontal cortex (pMFC)—were identified as nodes for dynamic causal modeling analysis. Results. SZ and HC showed similar model structures for general gaze processing. Explicit gaze discrimination led to changes in effective connectivity, including stronger excitatory, bottom-up connections from Vis to pSTS and IPL and inhibitory, top-down connections from pMFC to Vis. Group differences in top-down modulation from pMFC to pSTS and IPL were noted, such that these inhibitory connections were attenuated in HC while further strengthened in SZ. Connectivity was associated with social dysfunction and symptom severity.Discussion. SZ showed notably stronger top-down inhibition during explicit gaze discrimination, which was associated with more social dysfunction but less severe symptoms among patients. Findings help pinpoint neural mechanisms of aberrant gaze processing and may serve as future targets for interventions that combine neuromodulation with social-cognitive training.

Clostridioides difficile(CD) is a sporulating and toxin-producing nosocomial pathogen that opportunistically infects the gut, particularly in patients with depleted microbiota after antibiotic exposure. Metabolically, CD rapidly generates energy and substrates for growth from Stickland fermentations of amino acids, with proline being a preferred reductive substrate. To investigate thein vivoeffects of reductive proline metabolism onC. difficile’svirulence in an enriched gut nutrient environment, we evaluated wild-type and isogenicΔprdBstrains of ATCC43255 on pathogen behaviors and host outcomes in highly susceptible gnotobiotic mice. Mice infected with theΔprdBmutant demonstrated extended survival via delayed colonization, growth and toxin production but ultimately succumbed to disease.In vivotranscriptomic analyses demonstrated how the absence of proline reductase activity more broadly disrupted the pathogen’s metabolism including failure to recruit oxidative Stickland pathways, ornithine transformations to alanine, and additional pathways generating growth-promoting substrates, contributing to delayed growth, sporulation, and toxin production. Our findings illustrate the central role for proline reductase metabolism to support early stages ofC. difficilecolonization and subsequent impact on the pathogen’s ability to rapidly expand and cause disease.