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Une raideur post prothese totale de genou (PTG) peut être définie par un flessum de plus de 15 degrés et/ou une flexion inférieure à 75 degrés mais pour d’autres par un arc de mobilité inférieur à 70°, voire 45° ou 50̊. On pourrait aussi la définir comme une « mobilité inférieure à celle nécessaire au patient pour faire tout ce qu’il souhaite ». La première étape consiste à déterminer ses causes, préopératoires (antécédents de raideur, facteurs de risque liés au patient…), peropératoires (erreur technique : malposition, surdimensionnement, débord d’une pièce…) et postopératoires (gestion de la douleur, défaut de rééducation…). La prise en charge dépend du délai écoulé depuis la PTG ainsi que du type de raideur (de la flexion ou de l’extension) et doit être pluridisciplinaire (rééducation, gestion de la douleur). À moins de 3 mois, une manipulation douce sous anesthésie générale peut être proposée avec de bons résultats sur la flexion. En cas d’échec, la chirurgie doit être envisagée. En l’absence d’erreur technique significative, l’arthrolyse est discutée. L’arthrolyse arthroscopique est la plus pratiquée. Bien que techniquement difficile, son taux de complications est faible. L’arthrolyse à ciel ouvert permet une libération postérieure plus étendue et de remplacer l’insert en place par un insert moins épais. En cas d’anomalie de position ou de taille des implants ou en cas d’échec des autres procédures, la révision prothétique est la seule option, mais avec un risque élevé de complications. Après une exposition souvent difficile, elle doit corriger les erreurs techniques, rétablir la hauteur de l’interligne articulaire et deux espaces en extension et flexion symétriques et équilibrés. Elle peut nécessiter une prothèse semi-contrainte, voire charnière à l’avenir incertain chez un sujet jeune. Dans tous les cas, le patient doit accepter que cette prise en charge puisse être longue, et qu’elle nécessite plus que la seule intervention (gestion de la douleur et rééducation spécifique) et que ses objectifs soient raisonnables compte tenu de ses résultats souvent partiels.

In this article, we present the Predictive Gameplay-based Layered Affect Model (PreGLAM), an affective game spectator model that flexibly integrates into a game design process. PreGLAM combines elements of real-time player experience models and affective nonplayer-character models to output real-time estimated values for a spectator's valence, arousal, and tension during gameplay. Because tension is related to prospective events, PreGLAM attempts to predict future gameplay events. We implement and evaluate PreGLAM in a custom game Galactic Defense, which we also describe. PreGLAM significantly outperforms a random walk time series in how accurately it matches ground-truth annotations and has comparable accuracy to state-of-the-art affect models.

This article studies the ways the coronavirus pandemic impacts on the spirituality of seniors in Quebec. The methodological approach follows two stages: 1- a theoretical and systematized search in databases (integrative review); 2- a field approach, combining a meeting of senior experts, followed by a questionnaire. The results highlighted the recurrence of a feeling of loneliness and confrontation with the unknown, which resulted in a disoriented state of being that challenges the existential meaning. The elders responded to the unknown caused by the pandemic, by regaining control of their disoriented state through awareness-raising work, which led them to discern the importance of reworking in their lives the existential and spiritual level. As a result, a deployment of spiritualities occurs and institutional religion is replaced by intentional spiritualities.

1. Technical advances in radiation therapy enable significant lowering of the doses delivered to sexual structures.

Women with a previous caesarean delivery face a difficult choice in their next pregnancy: planning another caesarean or attempting vaginal delivery, both of which are associated with potential maternal and perinatal complications. This trial aimed to assess whether a multifaceted intervention, which promoted person-centred decision making and best practices, would reduce the risk of major perinatal morbidity among women with one previous caesarean delivery.

The spontaneous ordering of a two-dimensional (2D) SrTiO3-derived film supported on Pt(111)/Al2O3(0001) is investigated by scanning tunneling microscopy. After annealing under ultrahigh vacuum, a 2D reduced wetting layer is formed where oxide quasicrystal approximants are observed. Upon increasing the number of preparation cycles, the Sr content in the film decreases. The structure of the film then evolves into a Ti2O3honeycomb (HC) lattice partially decorated by Sr adatoms. The latter is localized in hollow sites of the network, with several complex structures resulting from the Sr occupation rate. A labyrinth-like phase was identified as well as an ordered (√3 × √3)R30° phase, where only 1/3 of the hollow sites of the HC lattice are occupied. Those results suggest that the phase sequence is driven by a stoichiometry change that is mainly controlled by the Sr/(Ti2O3) ratio.

In this essay, the editorial team for the Journal of Popular Music Education(JPME) introduces the first issue of the journal’s eighth volume (2024). The authors provide a summary of the JPMEcontents from the previous year (2023, volume 7) and highlight the two Special Issues from that volume. One Special Issue was a belated 25th anniversary response to Paul Théberge’s landmark book, Any Sound You Can Imagine, and the other was dedicated to contemporary considerations around music technology pertaining to popular music education. The authors acknowledge the privilege of publishing and of engaging in scholarship amidst a world in turmoil. They then look forward to conferences taking place in 2024, including the first gathering of the Association for Popular Music Education outside of the United States, in Edinburgh, Scotland, in the summer. The editorial closes by outlining the topic foci of two forthcoming JPMESpecial Issues in 2024.

Variants of uncertain significance (VUS) are a significant issue for the molecular diagnosis of rare diseases. The publication of episignatures as effective biomarkers of certain Mendelian neurodevelopmental disorders has raised hopes to help classify VUS. However, prediction abilities of most published episignatures have not been independently investigated yet, which is a prerequisite for an informed and rigorous use in a diagnostic setting. We generated DNA methylation data from 101 carriers of (likely) pathogenic variants in ten different genes, 57 VUS carriers, and 25 healthy controls. Combining published episignature information and new validation data with a k-nearest-neighbour classifier within a leave-one-out scheme, we provide unbiased specificity and sensitivity estimates for each of the signatures. Our procedure reached 100% specificity, but the sensitivities unexpectedly spanned a very large spectrum. While ATRX, DNMT3A, KMT2D, and NSD1signatures displayed a 100% sensitivity, CREBBP-RSTSand one of the CHD8signatures reached <40% sensitivity on our dataset. Remaining Cornelia de Lange syndrome, KMT2A, KDM5Cand CHD7signatures reached 70–100% sensitivity at best with unstable performances, suffering from heterogeneous methylation profiles among cases and rare discordant samples. Our results call for cautiousness and demonstrate that episignatures do not perform equally well. Some signatures are ready for confident use in a diagnostic setting. Yet, it is imperative to characterise the actual validity perimeter and interpretation of each episignature with the help of larger validation sample sizes and in a broader set of episignatures.

Identifying endocrine disrupting chemicals in order to limit their usage is a priority and required according to the European Regulation. There are no Organization for Economic Co-operation and Development (OECD) test guidelines based on fish available for the detection of Thyroid axis Active Chemicals (TACs). This study aimed to fill this gap by developing an assay at eleuthero-embryonic life stages in a novel medaka (Oryzias latipes) transgenic line. This transgenic line expresses green fluorescent protein (GFP) in thyrocytes, under the control of the medaka thyroglobulingene promoter. The fluorescence expressed in the thyrocytes is inversely proportional to the thyroid axis activity. When exposed for 72 h to activators (triiodothyronine (T3) and thyroxine (T4)) or inhibitors (6-N-propylthiouracil (PTU), Tetrabromobisphenol A (TBBPA)) of the thyroid axis, the thyrocytes can change their size and express lower or higher levels of fluorescence, respectively. This reflects the regulation of thyroglobulin by the negative feedback loop of the Hypothalamic–Pituitary–Thyroid axis. T3, T4, PTU, and TBBPA induced fluorescence changes with the lowest observable effect concentrations (LOECs) of 5 μg/L, 1 μg/L, 8 mg/L, and 5 mg/L, respectively. This promising tool could be used as a rapid screening assay and also to help decipher the mechanisms by which TACs can disrupt the thyroid axis in medaka.

Agricultural producers face multiple risks, including climatic, disease, and market risks, that make crop insurance especially valuable to them. However, risk interactions raise specific issues: The value of prevention efforts in a multiple risk context, risk correlation, and compounded effects (whereby the realization of a risk makes it difficult to prevent another one) all affect the design and effectiveness of insurance. In contrast to the US, the EU-subsidized crop insurance creates different financial conditions for climate and pest risks and increases expertise costs. We discuss how this affects input use and disproportionately disadvantages organic producers because of compounded effects. We report on an experiment bundling a real pest insurance contract with an agronomic protocol aiming at reducing treatments, for vine-growing in the South-West of France. The experiment highlighted the costs to separating risks in insurance contracts, as well as the need for insurance to help transition to greener practices.

Background: The onset of castration-resistance is associated with dismal outcomes in patients with prostate cancer (PCa). Metastasis directed therapy has been investigated in multiple disease settings and may improve outcomes in selected patients. Our systematic review aims to summarize evidence with stereotactic body radiotherapy (SBRT) in castration-resistant prostate cancer (CRPC). Methods: The literature search was performed on March 2024, on Pubmed, using the keywords “SBRT” AND “CRPC”, and “stereotactic ablative radiotherapy (SABR)” AND “CRPC”. This search retrieved a total of 108 articles, 19 were included. Results: The literature is largely dominated by retrospective series. In men with metachronous oligoprogression, SBRT with androgen receptor pathway inhibitor significantly increased progression-free survival (PFS) including biochemical progression-free survival in a randomized phase II trial (hazard ratio of 0.35, p&lt; 0.001). In patients continuing ADT, the bPFS ranged between 9.5 months to 17.9 months, and next systemic treatment-free survival (NEST-FS) reached up to 2 years. In men with induced oligoprogression, SBRT enabled NEST-FS up to 3 years. SBRT was well tolerated, with less than 5% grade 3 toxicity reported across studies. Conclusion: In the population of patients with oligometastatic CRPC, SBRT enables long-term biochemical response and PFS. In the oligoprogressive setting, SBRT could be integrated to prolong the duration and efficacy of systemic therapies. Nevertheless, the level of evidence remains very low and inclusion within prospective trials remain the preferred option for this population of patients.

BackgroundMolecular diagnosis of neurodevelopmental disorders (NDDs) is mainly based on exome sequencing (ES), with a diagnostic yield of 31% for isolated and 53% for syndromic NDD. As sequencing costs decrease, genome sequencing (GS) is gradually replacing ES for genome-wide molecular testing. As many variants detected by GS only are in deep intronic or non-coding regions, the interpretation of their impact may be difficult. Here, we showed that integrating RNA-Seq into the GS workflow can enhance the analysis of the molecular causes of NDD, especially structural variants (SVs), by providing valuable complementary information such as aberrant splicing, aberrant expression and monoallelic expression.MethodsWe performed trio-GS on a cohort of 33 individuals with NDD for whom ES was inconclusive. RNA-Seq on skin fibroblasts was then performed in nine individuals for whom GS was inconclusive and optical genome mapping (OGM) was performed in two individuals with an SV of unknown significance.ResultsWe identified pathogenic or likely pathogenic variants in 16 individuals (48%) and six variants of uncertain significance. RNA-Seq contributed to the interpretation in three individuals, and OGM helped to characterise two SVs.ConclusionOur study confirmed that GS significantly improves the diagnostic performance of NDDs. However, most variants detectable by GS alone are structural or located in non-coding regions, which can pose challenges for interpretation. Integration of RNA-Seq data overcame this limitation by confirming the impact of variants at the transcriptional or regulatory level. This result paves the way for new routinely applicable diagnostic protocols.

BackgroundTranexamic acid (TXA) decreases mortality in injured patients and should be administered as soon as possible. Despite international guidelines recommending TXA in the prehospital setting, its use remains low. The aim of this study was to assess the prehospital administration of TXA for injured patients in a Swiss region.MethodsWe conducted a retrospective observational study in Switzerland between 2018 and 2021. Inclusion criteria were injured patients ≥18 years for whom an ambulance or helicopter was dispatched. The exclusion criterion was minor injury defined by a National Advisory Committee for Aeronautics score <3. The primary outcome was the proportion of patients treated with TXA according to guidelines. The European guidelines were represented by the risk of death from bleeding (calculated retrospectively using the Bleeding Audit for Trauma and Triage (BATT) score). Factors impacting the likelihood of receiving TXA were assessed by multivariate analysis.ResultsOf 13 944 patients included in the study, 2401 (17.2%) were considered at risk of death from bleeding. Among these, 257 (11%) received prehospital TXA. This represented 38% of those meeting US guidelines. For European guidelines, the treatment rate increased with the risk of death from bleeding: 6% (95% CI 4.4% to 7.0%) for low risk (BATT score 3–4); 13% (95% CI 11.1% to 15.9%) for intermediate risk (BATT score 5–7); and 21% (95% CI 17.6% to 25.6%) for high risk (BATT score ≥8) (p<0.01). Women and the elderly were treated less often than men and younger patients, irrespective of the risk of death from bleeding and the mechanism of injury.ConclusionThe proportion of injured patients receiving TXA in the prehospital setting of the State of Vaud in Switzerland was low, with even lower rates for women and older patients. The reasons for this undertreatment are probably multifactorial and would require specific studies to clarify and correct them.

BackgroundBlood neurofilament light chain (NfL) is increasingly considered as a key trial biomarker in genetic frontotemporal dementia (gFTD). We aimed to facilitate the use of NfL in gFTD multicentre trials by testing its (1) reliability across labs; (2) reliability to stratify gFTD disease stages; (3) comparability between blood matrices and (4) stability across recruiting sites.MethodsComparative analysis of blood NfL levels in a large gFTD cohort (GENFI) for (1)–(4), with n=344 samples (n=148 presymptomatic, n=11 converter, n=46 symptomatic subjects, with mutations in C9orf72, GRNor MAPT; and n=139 within-family controls), each measured in three different international labs by Simoa HD-1 analyzer.ResultsNfL revealed an excellent consistency (intraclass correlation coefficient (ICC) 0.964) and high reliability across the three labs (maximal bias (pg/mL) in Bland-Altman analysis: 1.12±1.20). High concordance of NfL across laboratories was moreover reflected by high areas under the curve for discriminating conversion stage against the (non-converting) presymptomatic stage across all three labs. Serum and plasma NfL were largely comparable (ICC 0.967). The robustness of NfL across 13 recruiting sites was demonstrated by a linear mixed effect model.ConclusionsOur results underline the suitability of blood NfL in gFTD multicentre trials, including cross-lab reliable stratification of the highly trial-relevant conversion stage, matrix comparability and cross-site robustness.

IMPORTANCE: Mechanisms contributing to disability accumulation in multiple sclerosis (MS) are poorly understood. Blood neurofilament light chain (NfL) level, a marker of neuroaxonal injury, correlates robustly with disease activity in people with MS (MS); however, data on the association between NfL level and disability accumulation have been conflicting. OBJECTIVE: To determine whether and when NfL levels are elevated in the context of confirmed disability worsening (CDW). DESIGN, SETTING, AND PARTICIPANTS: This study included 2 observational cohorts: results from the Expression, Proteomics, Imaging, Clinical (EPIC) study at the University of California San Francisco (since 2004) were confirmed in the Swiss Multiple Sclerosis Cohort (SMSC), a multicenter study in 8 centers since 2012. Data were extracted from EPIC in April 2022 (sampling July 1, 2004, to December 20, 2016) and SMSC in December 2022 (sampling June 6, 2012, to September 2, 2021). The study included 2 observational cohorts in tertiary MS centers. All participants of both cohorts with available NfL results were included in the study, and no eligible participants were excluded or declined to participate. EXPOSURE: Association between NfL z scores and CDW. MAIN OUTCOME MEASURES: CDW was defined as Expanded Disability Status Scale (EDSS) worsening that was confirmed after 6 or more months and classified into CDW associated with clinical relapses (CDW-R) or independent of clinical relapses (CDW-NR). Visits were classified in relation to the disability worsening events into CDW(−2) for 2 visits preceding event, CDW(−1) for directly preceding event, CDW(event) for first diagnosis of EDSS increase, and the confirmation visit. Mixed linear and Cox regression models were used to evaluate NfL dynamics and to assess the association of NfL with future CDW, respectively. RESULTS: A total of 3906 EPIC visits (609 participants; median [IQR] age, 42.0 [35.0-50.0] years; 424 female [69.6%]) and 8901 SMSC visits (1290 participants; median [IQR] age, 41.2 [32.5-49.9] years; 850 female [65.9%]) were included. In CDW-R (EPIC, 36 events; SMSC, 93 events), NfL z scores were 0.71 (95% CI, 0.35-1.07; P &lt; .001) units higher at CDW-R(−1) in EPIC and 0.32 (95% CI, 0.14-0.49; P &lt; .001) in SMSC compared with stable MS samples. NfL elevation could be detected preceding CDW-NR (EPIC, 191 events; SMSC, 342 events) at CDW-NR(−2) (EPIC: 0.23; 95% CI, 0.01-0.45; P = .04; SMSC: 0.28; 95% CI, 0.18-0.37; P &lt; .001) and at CDW-NR(−1) (EPIC: 0.27; 95% CI, 0.11-0.44; P &lt; .001; SMSC: 0.09; 95% CI, 0-0.18; P = .06). Those findings were replicated in the subgroup with relapsing-remitting MS. Time-to-event analysis confirmed the association between NfL levels and future CDW-R within approximately 1 year and CDW-NR (in approximately 1-2 years). CONCLUSIONS AND RELEVANCE: This cohort study documents the occurrence of NfL elevation in advance of clinical worsening and may hint to a potential window of ongoing dynamic central nervous system pathology that precedes the diagnosis of CDW.

In this contemporary study integrating functional imaging data, we found potential efficacy of salvage radiotherapy with dose escalation for macroscopic relapse in the prostate bed, with an acceptable toxicity profile.

Review of: Contemporary Black Urban Music: The Revolution of Hip-Hop, Ron Westray (2023)London: First Hill Books, 250 pp.,ISBN 978-1-83998-527-0, h/bk, $49.95

•In adult KMT2A-r BCP-ALL, TP53and IKZF1alterations are associated with very poor outcome.•KMT2Agenomic fusion should be the preferred MRD marker over IG/TRto assess early treatment response and predict long-term outcome.

Recently, a holistic approach to oncology that integrates a whole-body understanding of the etiology and dynamics of cancer and the development of new therapies has been proposed. Herein we discuss how this concept is also relevant to pediatric oncology, with the caveat of specificities that must be considered.

Understanding the genetic and nongenetic determinants of tumor protein 53 (TP53)-mutation-driven clonal evolution and subsequent transformation is a crucial step toward the design of rational therapeutic strategies. Here we carry out allelic resolution single-cell multi-omic analysis of hematopoietic stem/progenitor cells (HSPCs) from patients with a myeloproliferative neoplasm who transform to TP53-mutant secondary acute myeloid leukemia (sAML). All patients showed dominant TP53‘multihit’ HSPC clones at transformation, with a leukemia stem cell transcriptional signature strongly predictive of adverse outcomes in independent cohorts, across both TP53-mutant and wild-type (WT) AML. Through analysis of serial samples, antecedent TP53-heterozygous clones and in vivo perturbations, we demonstrate a hitherto unrecognized effect of chronic inflammation, which suppressed TP53WT HSPCs while enhancing the fitness advantage of TP53-mutant cells and promoted genetic evolution. Our findings will facilitate the development of risk-stratification, early detection and treatment strategies for TP53-mutant leukemia, and are of broad relevance to other cancer types.

A small number of military severe trauma patients injured during recent military operations presented with near complete resolution of almost all initial organ failures upon arrival at the national territory hospital but developed further complications during their hospital stay.

Purpose: The efficacy of noninvasive ventilation (NIV) during procedures that require sedation and analgesia has not been established. We evaluated whether NIV reduces the incidence of respiratory events. Methods: In this randomized controlled trial, we included 195 patients with an American Society of Anesthesiologists Physical Status of III or IV during electrophysiology laboratory procedures. We compared NIV with face mask oxygen therapy for patients under sedation. The primary outcome was the incidence of respiratory events determined by a computer-driven blinded analysis and defined by hypoxemia (peripheral oxygen saturation &lt; 90%) or apnea/hypopnea (absence of breathing for 20 sec on capnography). Secondary outcomes included hemodynamic variables, sedation, patient safety (composite scores of major or minor adverse events), and adverse outcomes at day 7. Results: A respiratory event occurred in 89/98 (95%) patients in the NIV group and in 69/97 (73%) patients with face masks (risk ratio [RR], 1.29; 95% confidence interval [CI], 1.13 to 1.47; P&lt; 0.001). Hypoxemia occurred in 40 (42%) patients in the NIV group and in 33 (34%) patients with face masks (RR, 1.21; 95% CI, 0.84 to 1.74; P= 0.30). Apnea/hypopnea occurred in 83 patients (92%) in the NIV group vs65 patients (70%) with face masks (RR, 1.32; 95% CI, 1.14 to 1.53; P&lt; 0.001). Hemodynamic variables, sedation, major or minor safety events, and patient outcomes were not different between the groups. Conclusions: Respiratory events were more frequent among patients receiving NIV without any safety or outcome impairment. These results do not support the routine use of NIV intraoperatively. Study registration: ClinicalTrials.gov (NCT02779998); registered 4 November 2015.

Research has shown the potential of social media to disseminate important information as well as transform citizen engagement with government. However, implementation proves difficult, especially in public sector organizations. The success, impact and performance of these new forms of networked interactions are yet to be fully explored, especially at the local level. Many municipalities are experimenting with social media use, but few actively measure their performance on these platforms and their interactions with users. Different frameworks have been proposed to describe government communication types and activity on social media. They are addressed here through three phases that refer to forms of government‐citizen communication on social media. The original assessment method developed here contributes to the existing literature and provides guidance to practitioners. Empirically, our research relies on a database of cities that have between 100,000 and 500,000 inhabitants in European Union member states located in Central and Eastern Europe. It provides social media metrics for these cities (N=82 and compares various indicators on Facebook, Twitter and Instagram. This contributes to a better assessment ofhow social media platforms are used by local governments in the region.

La majorité des Services d’incendie et de secours (SIS) disposent de cellules mobiles d’intervention radiologique (CMIR) dont les moyens en équipements de protection, de détection, de prélèvement, d’identification et de décontamination permettent d’évaluer les risques, de localiser et confiner une source radioactive, et d’en limiter les effets sur l’homme et son environnement. Les risques radiologiques les plus courants auxquels les sapeurs-pompiers font face comprennent la découverte fortuite de matières radioactives et les accidents de transport. L’utilisation malveillante de produits radioactifs est aussi prise en compte par les services d’intervention qui, en cas de plan d’urgence, s’appuieront notamment sur l’expertise de l’Institut de radioprotection et de sûreté nucléaire (IRSN). Certains SIS sont dotés de moyens nationaux, par exemple des portiques de contrôle de contamination, permettant de répondre à des accidents d’ampleur. La prise en charge médicochirurgicale de victimes radio-contaminées catégorisées UA est prioritaire sur la décontamination. La décontamination d’urgence ciblera en priorité les plaies et les muqueuses afin d’éviter que la contamination externe ne devienne interne. Des dispositifs spécifiquement développés telles que la crème Calixarene (CEVIDRA) et les lingettes imprégnées DECPOL®RAD (OUVRY) complètent les moyens de décontamination d’urgence mis à disposition des intervenants. L’information et la préparation des populations à la gestion des risques radiologiques et nucléaires sont cruciales pour améliorer l’efficience de la réponse.

La syphilis congénitale est rare mais son incidence est en augmentation dans le monde depuis les dix dernières années y compris en Europe. Le diagnostic précoce est difficile. Il est primordial de pouvoir poser un diagnostic rapide pour prévenir le risque de séquelles ultérieures. Nous rapportons le cas d’une patiente de 2 mois qui présentait des lésions inflammatoires croûteuses du cuir chevelu.

Reproductive genetic carrier screening (RGCS) for hundreds of different genetic conditions is technically available for prospective parents, but these tests have not been integrated in a public health policy except for specific sub-groups. We aimed to provide an overview of the perspectives of multiple professional stakeholder groups in order to enhance a responsible implementation of population-based reproductive genetic carrier screening. We conducted a systematic literature search using eight online databases focussing on studies that were published from January 2009 to January 2021. We selected articles dealing with attitudes and opinions from different professional stakeholders, in particular healthcare professionals and policymakers, on how to implement a policy about carrier screening for a reproductive purpose. We identified 18 studies that met our inclusion criteria. Based on our inductive analysis, we identified ten themes categorized in both clinical and program management challenges: ensuring availability of RGCS to all couples who request the test, embedding RGCS as a test offer before pregnancy, providing clear and reliable information, ensuring voluntary participation, developing genetic counselling pre- and post-testing (after positive or negative result), avoiding psychological harm, ensuring equal access, avoiding social pressure, educating and involving a broad spectrum of non-genetic health care professionals, and promoting an independent non-commercial organisational structure. We highlight one major stumbling block on how to responsibly inform couples about hundreds different genetic conditions within constraints regarding time and ability of non-genetic professionals. We promote further research to tackle the issues brought up by this systematic review through pilot studies. Trial Registration: PROSPERO International Prospective Register of Systematic Reviews PROSPERO 2021 # CRD42021233762; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=233762.

To investigate the relationship between the number of oocytes and both the live birth rate (LBR) after fresh embryo transfer and the cumulative live birth rate (CLBR).

Although antibiotic is a major contributor to shifts in the intestinal flora that may persist for up to several months after cessation, it is now increasingly recognized that its prescription may differentially influence clinical outcome of different anticancer treatments. Intense clinical and basic research efforts aim then at gaining sufficient insights about how the cooperative action between the intestinal ecosystem and immune surveillance modulates the efficacy of anticancer treatments. In this review, we summarize multiple levels of knowledge between vancomycin exposure, the gut microbiota, and a meaningful therapeutic response. Furthermore, we discuss the mode of action of antibiotic therapy that is prescribed for prophylaxis of bacteremia and neutropenia and outline the opportunity for judiciously improving the efficacy of anticancer drugs.

IMPORTANCE: There is a lack of validated biomarkers for disability progression independent of relapse activity (PIRA) in multiple sclerosis (MS). OBJECTIVE: To determine how serum glial fibrillary acidic protein (sGFAP) and serum neurofilament light chain (sNfL) correlate with features of disease progression vs acute focal inflammation in MS and how they can prognosticate disease progression. DESIGN, SETTING, AND PARTICIPANTS: Data were acquired in the longitudinal Swiss MS cohort (SMSC; a consortium of tertiary referral hospitals) from January 1, 2012, to October 20, 2022. The SMSC is a prospective, multicenter study performed in 8 centers in Switzerland. For this nested study, participants had to meet the following inclusion criteria: cohort 1, patients with MS and either stable or worsening disability and similar baseline Expanded Disability Status Scale scores with no relapses during the entire follow-up; and cohort 2, all SMSC study patients who had initiated and continued B-cell–depleting treatment (ie, ocrelizumab or rituximab). EXPOSURES: Patients received standard immunotherapies or were untreated. MAIN OUTCOMES AND MEASURES: In cohort 1, sGFAP and sNfL levels were measured longitudinally using Simoa assays. Healthy control samples served as the reference. In cohort 2, sGFAP and sNfL levels were determined cross-sectionally. RESULTS: This study included a total of 355 patients (103 [29.0%] in cohort 1: median [IQR] age, 42.1 [33.2-47.6] years; 73 female patients [70.9%]; and 252 [71.0%] in cohort 2: median [IQR] age, 44.3 [33.3-54.7] years; 156 female patients [61.9%]) and 259 healthy controls with a median [IQR] age of 44.3 [36.3-52.3] years and 177 female individuals (68.3%). sGFAP levels in controls increased as a function of age (1.5% per year; P &lt; .001), were inversely correlated with BMI (−1.1% per BMI unit; P = .01), and were 14.9% higher in women than in men (P = .004). In cohort 1, patients with worsening progressive MS showed 50.9% higher sGFAP levels compared with those with stable MS after additional sNfL adjustment, whereas the 25% increase of sNfL disappeared after additional sGFAP adjustment. Higher sGFAP at baseline was associated with accelerated gray matter brain volume loss (per doubling: 0.24% per year; P &lt; .001) but not white matter loss. sGFAP levels remained unchanged during disease exacerbations vs remission phases. In cohort 2, median (IQR) sGFAP z scores were higher in patients developing future confirmed disability worsening compared with those with stable disability (1.94 [0.36-2.23] vs 0.71 [−0.13 to 1.73]; P = .002); this was not significant for sNfL. However, the combined elevation of z scores of both biomarkers resulted in a 4- to 5-fold increased risk of confirmed disability worsening (hazard ratio [HR], 4.09; 95% CI, 2.04-8.18; P &lt; .001) and PIRA (HR, 4.71; 95% CI, 2.05-9.77; P &lt; .001). CONCLUSIONS AND RELEVANCE: Results of this cohort study suggest that sGFAP is a prognostic biomarker for future PIRA and revealed its complementary potential next to sNfL. sGFAP may serve as a useful biomarker for disease progression in MS in individual patient management and drug development.

•Mutant CALR proteins are secreted in complex with sTFR1 to the plasma of MPN patients and activate the TpoR in a rogue cytokine fashion.•TpoR-expressing cells with a CALRmutation are uniquely sensitive to the levels of circulating mutant CALR proteins seen in patients.

Mutant calreticulin (CALR) proteins resulting from a −1/+2 frameshifting mutation of the CALR exon 9 carry a novel C-terminal amino acid sequence and drive the development of myeloproliferative neoplasms (MPNs). Mutant CALRs were shown to interact with and activate the thrombopoietin receptor (TpoR/MPL) in the same cell. We report that mutant CALR proteins are secreted and can be found in patient plasma at levels up to 160 ng/mL, with a mean of 25.64 ng/mL. Plasma mutant CALR is found in complex with soluble transferrin receptor 1 (sTFR1) that acts as a carrier protein and increases mutant CALR half-life. Recombinant mutant CALR proteins bound and activated the TpoR in cell lines and primary megakaryocytic progenitors from patients with mutated CALR in which they drive thrombopoietin-independent colony formation. Importantly, the CALR-sTFR1 complex remains functional for TpoR activation. By bioluminescence resonance energy transfer assay, we show that mutant CALR proteins produced in 1 cell can specifically interact in trans with the TpoR on a target cell. In comparison with cells that only carry TpoR, cells that carry both TpoR and mutant CALR are hypersensitive to exogenous mutant CALR proteins and respond to levels of mutant CALR proteins similar to those in patient plasma. This is consistent with CALR-mutated cells that expose TpoR carrying immature N-linked sugars at the cell surface. Thus, secreted mutant CALR proteins will act more specifically on the MPN clone. In conclusion, a chaperone, CALR, can turn into a rogue cytokine through somatic mutation of its encoding gene.

PurposeIn this study, we describe the phenotype and genotype of the largest cohort of patients with Joubert syndrome (JS) carrying pathogenic variants on one of the most frequent causative genes, CC2D2A.MethodsWe selected 53 patients with pathogenic variants on CC2D2A, compiled and analysed their clinical, neuroimaging and genetic information and compared it to previous literature.ResultsDevelopmental delay (motor and language) was nearly constant but patients had normal intellectual efficiency in 74% of cases (20/27 patients) and 68% followed mainstream schooling despite learning difficulties. Epilepsy was found in only 13% of cases. Only three patients had kidney cysts, only three had genuine retinal dystrophy and no subject had liver fibrosis or polydactyly. Brain MRIs showed typical signs of JS with rare additional features. Genotype–phenotype correlation findings demonstrate a homozygous truncating variant p.Arg950* linked to a more severe phenotype.ConclusionThis study contradicts previous literature stating an association between CC2D2A-related JS and ventriculomegaly. Our study implies that CC2D2A-related JS is linked to positive neurodevelopmental outcome and low rate of other organ defects except for homozygous pathogenic variant p.Arg950*. This information will help modulate patient follow-up and provide families with accurate genetic counselling.

BRAT1biallelic variants are associated with rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL), and neurodevelopmental disorder associating cerebellar atrophy with or without seizures syndrome (NEDCAS). To date, forty individuals have been reported in the literature. We collected clinical and molecular data from 57 additional cases allowing us to study a large cohort of 97 individuals and draw phenotype-genotype correlations. Fifty-nine individuals presented with BRAT1-related RMFSL phenotype. Most of them had no psychomotor acquisition (100%), epilepsy (100%), microcephaly (91%), limb rigidity (93%), and died prematurely (93%). Thirty-eight individuals presented a non-lethal phenotype of BRAT1-related NEDCAS phenotype. Seventy-six percent of the patients in this group were able to walk and 68% were able to say at least a few words. Most of them had cerebellar ataxia (82%), axial hypotonia (79%) and cerebellar atrophy (100%). Genotype-phenotype correlations in our cohort revealed that biallelic nonsense, frameshift or inframe deletion/insertion variants result in the severe BRAT1-related RMFSL phenotype (46/46; 100%). In contrast, genotypes with at least one missense were more likely associated with NEDCAS (28/34; 82%). The phenotype of patients carrying splice variants was variable: 41% presented with RMFSL (7/17) and 59% with NEDCAS (10/17).

Heterozygous mutation targeting proline 95 in Serine/Arginine-rich Splicing Factor 2 (SRSF2) is associated with V617F mutation in Janus Activated Kinase 2 (JAK2) in some myeloproliferative neoplasms (MPNs), most commonly primary myelofibrosis. To explore the interaction of Srsf2P95Hwith Jak2V617F, we generated Cre-inducible knock-in mice expressing these mutants under control of the stem cell leukemia (Scl)gene promoter. In transplantation experiments, Srsf2P95Hunexpectedly delayed myelofibrosis induced by Jak2V617Fand decreased TGFβ1 serum level. Srsf2P95Hreduced the competitiveness of transplanted Jak2V617Fhematopoietic stem cells while preventing their exhaustion. RNA sequencing of sorted megakaryocytes identified an increased number of splicing events when the two mutations were combined. Focusing on JAK/STAT pathway, Jak2exon 14 skipping was promoted by Srsf2P95H, an event detected in patients with JAK2V617Fand SRSF2P95co-mutation. The skipping event generates a truncated inactive JAK2 protein. Accordingly, Srsf2P95Hdelays myelofibrosis induced by the thrombopoietin receptor agonist Romiplostim in Jak2wild-type animals. These results unveil JAK2exon 14 skipping promotion as a strategy to reduce JAK/STAT signaling in pathological conditions.

BackgroundCurrent clinical rating scales in frontotemporal dementia (FTD) often do not incorporate neuropsychiatric features and may therefore inadequately measure disease stage.Methods832 participants from the Genetic FTD Initiative (GENFI) were recruited: 522 mutation carriers and 310 mutation-negative controls. The standardised GENFI clinical questionnaire assessed the frequency and severity of 14 neuropsychiatric symptoms: visual, auditory, and tactile hallucinations, delusions, depression, anxiety, irritability/lability, agitation/aggression, euphoria/elation, aberrant motor behaviour, hypersexuality, hyperreligiosity, impaired sleep, and altered sense of humour. A principal component analysis (PCA) was performed to identify key groupings of neuropsychiatric and behavioural items in order to create a new neuropsychiatric module that could be used as an addition to the Clinical Dementia Rating (CDR) plus National Alzheimer’s Coordinating Center Behaviour and Language Domains (NACC FTLD) rating scale.ResultsOverall, 46.4% of mutation carriers had neuropsychiatric symptoms (51.6% C9orf72, 40.8% GRN, 46.6% MAPT) compared with 24.5% of controls. Anxiety and depression were the most common in all genetic groups but fluctuated longitudinally and loaded separately in the PCA. Hallucinations and delusions loaded together, with the remaining neuropsychiatric symptoms loading with the core behavioural features of FTD. These results suggest using a single ‘psychosis’ neuropsychiatric module consisting of hallucinations and delusions. Adding this to the CDR plus NACC FTLD, called the CDR plus NACC FTLD-N, leads to a number of participants being scored more severely, including those who were previously considered asymptomatic now being scored as prodromal.ConclusionsNeuropsychiatric symptoms occur in mutation carriers at all disease stages across all three genetic groups. However, only psychosis features provided additional staging benefit to the CDR plus NACC FTLD. Inclusion of these features brings us closer to optimising the rating scale for use in trials.

L’instabilité fémoro-tibiale est une cause de reprise précoce des arthroplasties de genou. Elle peut être la conséquence d’une laxité fémoro-tibiale notamment dans le plan frontal avec une décoaptation fémoro-tibiale. Les radiographies standards postopératoires avec une décoaptation (lift-off) fémoro-tibiale peuvent-elles faire craindre une laxité ou une possible instabilité ? À notre connaissance, cette relation n’a jamais été testée. Aussi nous avons mené une étude rétrospective pour évaluer : (1) la fréquence du lift-offsur les radiographies postopératoires, (2) la relation entre lift-offet laxité à court terme, (3) les conséquences fonctionnelles.

We aimed to investigate the molecular basis of a novel recognizable neurodevelopmental syndrome with scalp and enamel anomalies caused by truncating variants in the last exon of the gene FOSL2, encoding a subunit of the AP-1 complex.

•Multiple sclerosis is strongly influenced by environmental parameters.•Higher markers of central obesity were observed among patients with MS.•Food processing and physical activity should be targeted in MS.•The metabolic burden in MS is still under-addressed.

Ocean deoxygenation is an important consequence of climate change that poses an imminent threat to marine life and global food security. However, our understanding of the complex interactions between changes in circulation, solubility, and respiration that drive global‐scale deoxygenation is incomplete. Here, we consider idealized biogeochemical steady states in equilibrium with perpetually slower and warmer oceans constructed from climate‐model simulations of the 2090s that we hold constant in time. In contrast to simulations of the end‐of‐century transient state, our idealized states are intensely deoxygenated in the abyss, consistent with perpetually reduced ventilation and throttled Antarctic Bottom Water formation. We disentangle the effects of the deoxygenation drivers on preformed oxygen and true oxygen utilization (TOU) using the novel concept of upstream exposure time, which precisely connects TOU to oxygen utilization rates and preformed oxygen to ventilation. For our idealized steady states, deoxygenation below 2,000 m depth is due to increased TOU, driven dominantly by slower circulations that allow respiration to act roughly 2–3 times longer thereby overwhelming the effects of reduced respiration rates. Above 500 m depth, decreased respiration and slower circulation closely compensate, resulting in little expansion of upper‐ocean hypoxia. The bulk of preformed oxygen loss is driven by ventilation shifting equatorward to where warmer surface waters hold less oxygen. Warming‐driven declines in solubility account for less than 10% of the total oxygen loss. Although idealized, our analysis suggests that long‐term changes in the marine oxygen cycle could be driven dominantly by changes in circulation rather than by thermodynamics or biology. Climate change is driving oxygen out of the ocean, threatening marine life and global food security. However, the precise contributions of the chemical, physical, and biological processes that control oxygen levels are not well known because of their complex interactions. To better understand these interactions, we consider idealized simulations of a global oxygen cycle that is fully equilibrated with a perpetually warmer and slower ocean constructed from climate‐model simulations of the 2090s but held constant in time for our analyses. Compared to typical predictions, these idealized states exhibit intense deep‐ocean deoxygenation, for which we precisely quantify the contributions from changes in solubility, respiration, and ocean circulation. We find that deep‐ocean deoxygenation is driven by the slower circulation allowing respiration to act for 2–3 times longer thereby overcoming lower respiration rates. The surface origin of oxygen shifts away from cold high‐latitude waters toward warmer waters, in which atmospheric oxygen is less soluble, further reducing oxygen levels. Warming‐driven decreases in solubility alone only account for a mere 10% of the total oxygen loss. The upper ocean remains well oxygenated because changes in respiration and circulation compensate almost perfectly. Our results highlight the central importance of circulation in controlling oxygen in the ocean. Key drivers of deoxygenation are quantified for oxygen cycles idealized by being in equilibrium with perpetually slower oceansWidespread intense abyssal ocean deoxygenation is driven predominantly by slower circulations allowing respiration to act over longer timesMost of the reduction in preformed oxygen is driven by changes in ventilation patterns and not by warming‐driven reduced solubility Key drivers of deoxygenation are quantified for oxygen cycles idealized by being in equilibrium with perpetually slower oceans Widespread intense abyssal ocean deoxygenation is driven predominantly by slower circulations allowing respiration to act over longer times Most of the reduction in preformed oxygen is driven by changes in ventilation patterns and not by warming‐driven reduced solubility

Information on bladder cancer (BC) according to the risk scoring for recurrence or progression in a general population is scarce despite its clinical relevance. The objective was to describe the characteristics of incident BC in a general population, with a focus on the initial management of high-risk non-muscle invasive BC (HR-NMIBC).

La région Auvergne-Rhône-Alpes dispose d’un écosystème des plus innovants en France dans les domaines de l’optique et de la photonique. Le territoire regroupe plusieurs centaines d’entreprises, de start-ups, de plateformes de transfert technologiques et d’organismes de recherche sur cette filière et se positionne en seconde position en termes de R&D avec 25 % de l’activité nationale Photonique.

Unlike familial Alzheimer’s disease, we have been unable to accurately predict symptom onset in presymptomatic familial frontotemporal dementia (f-FTD) mutation carriers, which is a major hurdle to designing disease prevention trials. We developed multimodal models for f-FTD disease progression and estimated clinical trial sample sizes in C9orf72, GRNand MAPTmutation carriers. Models included longitudinal clinical and neuropsychological scores, regional brain volumes and plasma neurofilament light chain (NfL) in 796 carriers and 412 noncarrier controls. We found that the temporal ordering of clinical and biomarker progression differed by genotype. In prevention-trial simulations using model-based patient selection, atrophy and NfL were the best endpoints, whereas clinical measures were potential endpoints in early symptomatic trials. f-FTD prevention trials are feasible but will likely require global recruitment efforts. These disease progression models will facilitate the planning of f-FTD clinical trials, including the selection of optimal endpoints and enrollment criteria to maximize power to detect treatment effects.