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Background: Biliary tract cancers, which arise from the intrahepatic or extrahepatic bile ducts and the gallbladder, generally have a poor prognosis and are rising in incidence worldwide. The standard-of-care treatment for advanced biliary tract cancer is chemotherapy with gemcitabine and cisplatin. Because most biliary tract cancers have an immune-suppressed microenvironment, immune checkpoint inhibitor monotherapy is associated with a low objective response rate. We aimed to assess whether adding the immune checkpoint inhibitor pembrolizumab to gemcitabine and cisplatin would improve outcomes compared with gemcitabine and cisplatin alone in patients with advanced biliary tract cancer. Methods: KEYNOTE-966 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 175 medical centres globally. Eligible participants were aged 18 years or older; had previously untreated, unresectable, locally advanced or metastatic biliary tract cancer; had disease measurable per Response Evaluation Criteria in Solid Tumours version 1.1; and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks (maximum 35 cycles), in combination with gemcitabine (1000 mg/m2 intravenously on days 1 and 8 every 3 weeks; no maximum duration) and cisplatin (25 mg/m2 intravenously on days 1 and 8 every 3 weeks; maximum 8 cycles). Randomisation was done using a central interactive voice-response system and stratified by geographical region, disease stage, and site of origin in block sizes of four. The primary endpoint of overall survival was evaluated in the intention-to-treat population. The secondary endpoint of safety was evaluated in the as-treated population. This study is registered at ClinicalTrials.gov, NCT04003636. Findings: Between Oct 4, 2019, and June 8, 2021, 1564 patients were screened for eligibility, 1069 of whom were randomly assigned to pembrolizumab plus gemcitabine and cisplatin (pembrolizumab group; n=533) or placebo plus gemcitabine and cisplatin (placebo group; n=536). Median study follow-up at final analysis was 25·6 months (IQR 21·7–30·4). Median overall survival was 12·7 months (95% CI 11·5–13·6) in the pembrolizumab group versus 10·9 months (9·9–11·6) in the placebo group (hazard ratio 0·83 [95% CI 0·72–0·95]; one-sided p=0·0034 [significance threshold, p=0·0200]). In the as-treated population, the maximum adverse event grade was 3 to 4 in 420 (79%) of 529 participants in the pembrolizumab group and 400 (75%) of 534 in the placebo group; 369 (70%) participants in the pembrolizumab group and 367 (69%) in the placebo group had treatment-related adverse events with a maximum grade of 3 to 4. 31 (6%) participants in the pembrolizumab group and 49 (9%) in the placebo group died due to adverse events, including eight (2%) in the pembrolizumab group and three (1%) in the placebo group who died due to treatment-related adverse events. Interpretation: Based on a statistically significant, clinically meaningful improvement in overall survival compared with gemcitabine and cisplatin without any new safety signals, pembrolizumab plus gemcitabine and cisplatin could be a new treatment option for patients with previously untreated metastatic or unresectable biliary tract cancer. Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

Purpose:The phase III CELESTIAL study demonstrated improved overall survival (OS) and progression-free survival (PFS) with cabozantinib versus placebo in patients with previously treated, advanced hepatocellular carcinoma (HCC). We analyzed outcomes by baseline alpha-fetoprotein (AFP) and on-treatment AFP changes.Patients and Methods:Serum AFP was measured every 8 weeks by blinded, centralized testing. Outcomes were analyzed by baseline AFP bifurcated at 400 ng/mL and by on-treatment AFP response (≥20% decrease from baseline at Week 8). The optimal cutoff for change in AFP at Week 8 was evaluated using maximally selected rank statistics.Results:Median OS for cabozantinib versus placebo was 13.9 versus 10.3 months [HR, 0.81; 95% confidence interval (CI), 0.62–1.04] for patients with baseline AFP Conclusions:Cabozantinib improved outcomes versus placebo across a range of baseline AFP levels. On-treatment AFP response and control rates were higher with cabozantinib than placebo, and were associated with longer OS and PFS with cabozantinib.

Supplementary Data_Clean File

Figure S3. AFP response cutoff determination for overall survival by maximally selected rank statistics. Cutpoint determination plots showing (A) histogram distribution and (B) rank statistic plot of percent AFP change from baseline at Week 8 for patients in the cabozantinib group with baseline AFP {greater than or equal to}20 ng/mL. *Calculated value of 0.48%, rounded to 0% for all subsequent analyses.

Background and objectives. Sex is an important contributing factor to neuroimaging phenotypes in brain disorders. However, little is known about the contribution of sex differences to the neurodegeneration in dementia with Lewy bodies (DLB). We investigated sex differences in probable DLB patients by using both visual rating scales of lobar atrophy and automated estimations of regional atrophy. Methods. We included 442 probable DLB patients from the European-DLB consortium and the Mayo Clinic who have magnetic resonance imaging (MRI) data available. We assessed sex differences and the sex-by-age interaction in two largely independent samples through visual rating scales of lobar atrophy (n = 333; mean age 73 ± 8 years, 62% males) and automated regional estimations of gray matter (GM) volume and mean cortical thickness (CTh) (n = 165; mean age 69 ± 9 years, 72% males). We used binary logistic regression and ANOVA for statistical analysis. Results. We found a statistically significantly higher likelihood of frontal atrophy measured by the global cortical atrophy-frontal subscale (GCA-F) in males (40% of males had an abnormal GCA-F score versus 29% of females, P-value = 0.006). Using automated estimations, we found smaller GM volumes in 6 cortical regions in males compared with females, as well as smaller GM volume in the entorhinal cortex and thinner olfactory cortices in females, compared with males. The sex-by-age interaction showed statistically significant results in 6 cortical volumes and 7 mean CTh estimations (P-value ≤ 0.05), accentuated in the right middle frontal gyrus (FDR-adjusted P-value = 0.047). These cross-sectional interactions indicated that while females have statistically significantly less atrophy than males at younger ages, differences become non-significant at older ages, with females showing the same level of atrophy than males around the age of 75. Conclusions. This study demonstrates sex differences on brain atrophy in probable DLB. While male DLB patients have a more widespread pattern of cortical atrophy at younger ages, these sex differences tend to disappear with increasing age. Longitudinal studies will help establish these cross-sectional findings and inform on sex and age considerations to the use of MRI in clinical routine, as the field moves towards precision medicine.

BackgroundGenome-wide Association Studies (GWAS) have reshaped our understanding of the genetic bases of complex diseases in general and neurodegenerative diseases in particular. Despite being a common disorder, dementia with Lewy bodies (DLB), which, together with Parkinson’s disease dementia (PDD), comprise the umbrella term Lewy body dementias (LBD), is far from being well-characterized genetically. This is primarily due to a lack of familial cases and difficulty recruiting large, deeply characterized cohorts, given the high rate of misdiagnosis. By performing the largest GWAS in DLB, we aimed to identify novel risk loci to gain a better understanding of this disease’s pathobiology.MethodsHere, we conducted the largest meta-analysis of genome-wide association studies performed in LBD, using a total of 5,119 cases and 20,988 controls, from five independent datasets, aggregating all previously published DLB genome-wide association results to date, as well as two previously undescribed cohorts. Additionally, we performed a sex stratified GWAS using the discovery datasets. We updated the heritability estimates for DLB and, to fine map these estimates, we used local heritability analysis. We calculated genetic correlation estimates between DLB and a range of other diseases and traits to identify potential pleiotropy. We also performed gene-set analysis to identify genes with excess burden of rare variability and pathway analysis. Lastly, we used the UK Biobank data to perform a PheWas using individuals at the extremes of genetic risk for DLB.FindingsBetween November 2018 and September 2022 we analyzed 8.6 million single nucleotide polymorphisms in 3293 DLB cases, 1826 LBD cases and 20,988 controls, as well as phenotypes from the UK Biobank dataset. Despite more than doubling the sample size from the previous GWAS in DLB, we did not identify significant loci in addition to those previously reported atGBA, SNCA, STX1B, andAPOE. However, the sex-stratified analysis revealed that theGBAandSNCAsignals are mainly driven by males, suggesting a sex-specific genetic architecture of disease. Using only clinical and neuropathologically diagnosed cases, we highlight four loci surpassing the significance threshold. Using the largest cohort of DLB we update our heritability estimates to 13% and fine map these results highlighting regions of the genome with high heritability but no genome-wide significant result so far.InterpretationThese data provide the most comprehensive analysis of genetic variability in DLB to date. The fact that no novel risk loci have been identified after doubling the cohort size indicates the potentially significant role of rare variants in the genetic architecture of DLB and stresses the urgent need for larger, well-characterized cohorts of this disease for genetic studies. The sex-stratified analysis shows that males and females have different signatures of genetic risk for DLB. These results have widespread implications for clinical practice and clinical trials’ design in DLB.

Background. Dementia with Lewy bodies (DLB) is a neurodegenerative disorder with a wide heterogeneity of symptoms, which suggests the existence of different subtypes. Objectives. We used data-driven analysis of MRI data to investigate DLB subtypes. Methods. We included 165 probable DLB from the Mayo Clinic and 3 centers from the European DLB consortium and performed a hierarchical cluster analysis to identify subtypes based on gray matter (GM) volumes. To characterize the subtypes, we used demographic and clinical data, as well as β-amyloid and cerebrovascular biomarkers at baseline, and cognitive decline over three years. Results. We identified 3 subtypes: an older subtype with reduced cortical GM volumes, worse cognition, and faster cognitive decline (n=49, 30%); a subtype with low GM volumes in fronto-occipital regions (n=76, 46%); and a subtype of younger patients with the highest cortical GM volumes, proportionally lower GM volumes in basal ganglia and the highest frequency of cognitive fluctuations (n=40, 24%). Conclusions. This study shows the existence of MRI subtypes in DLB, which may have implications for clinical workout, research, and therapeutic decisions.

International audience; Introduction: Approximately 40% of dementia cases could be delayed or prevented acting on modifiable risk factors including hypertension. However, the mechanisms underlying the hypertension-dementia association are still poorly understood.Methods: We conducted a cross-sectional analysis in 2048 patients from the MEMENTO cohort, a French multicenter clinic-based study of outpatients with either isolated cognitive complaints or mild cognitive impairment. Exposure to hypertension was defined as a combination of high blood pressure (BP) status and antihypertensive treatment intake. Pathway associations were examined through structural equation modeling integrating extensive collection of neuroimaging biomarkers and clinical data.Results: Participants treated with high BP had significantly lower cognition compared to the others. This association was mediated by higher neurodegeneration and higher white matter hyperintensities load but not by Alzheimer's disease (AD) biomarkers.Discussion: These results highlight the importance of controlling hypertension for prevention of cognitive decline and offer new insights on mechanisms underlying the hypertension-dementia association.Highlights: Paths of hypertension-cognition association were assessed by structural equation models. The hypertension-cognition association is not mediated by Alzheimer's disease biomarkers. The hypertension-cognition association is mediated by neurodegeneration and leukoaraiosis. Lower cognition was limited to participants treated with uncontrolled blood pressure. Blood pressure control could contribute to promote healthier brain aging.

International audience

Dementia with Lewy Bodies (DLB) is a common form of cognitive neurodegenerative disease. Only one third of patients are correctly diagnosed due to the clinical similarity mainly with Alzheimer’s disease (AD). In this review, we evaluate the interest of different biomarkers: cerebrospinal fluid (CSF), brain MRI, FP-CIT SPECT, MIBG SPECT, PET by focusing more specifically on differential diagnosis between DLB and AD. FP-CIT SPECT is of high interest to discriminate DLB and AD, but not at the prodromal stage (i.e., MCI). MIBG SPECT with decreased cardiac sympathetic activity, perfusion SPECT with occipital hypoperfusion, FDG PET with occipital hypometabolism and cingulate island signs are of interest at the dementia stage but with a lower validity. Brain MRI has shown differences in group study with lower grey matter concentration of the Insula in prodromal DLB, but its interest in clinical routines is not demonstrated. Concerning CSF biomarkers, many studies have already examined the relevance of AD biomarkers but also alpha-synuclein assays in DLB, so we will focus as comprehensively as possible on other biomarkers (especially those that do not appear to be directly related to synucleinopathy) that may be of interest in the differential diagnosis between AD and DLB. Furthermore, we would like to highlight the growing interest in CSF synuclein RT-QuIC, which seems to be an excellent discrimination tool but its application in clinical routine remains to be demonstrated, given the non-automation of the process.

Background: Isolated subjective cognitive impairment (SCI) and mild neurocognitive impairment (MCI) are prodromal phase of dementia with Lewy bodies (DLB). Memento is a nationwide study of patients with SCI and MCI with clinic, neuropsychology, biology and brain imaging data. We aimed to compare SCI and MCI patients with symptoms of prodromal DLB to others in this study at baseline. Methods: Participants of the French Memento cohort study recruited for either SCI or MCI. Among them, 892 were included in the Lewy sub-study, designed to search specifically for symptoms of DLB. Probable prodromal DLB group (pro-DLB) was done using a two-criteria cut-off score among the four core clinical features of DLB. This Pro-DLB group was compared to two other groups at baseline: one without any core symptoms (NS group), and the one with one core symptom (1S group). A comprehensive cognitive battery, questionnaires on behavior, neurovegetative and neurosensory symptoms, brain 3D volumetric MRI, CSF, FDG PET and amyloid PET were done.Results: The Pro-DLB group comprised 148 patients (16.6%). This group showed more multidomain (59.8%) MCI with slower processing speed and a higher proportion of patients with depression, anxiety, apathy, constipation, rhinorrhea, sicca syndrome, and photophobia. The Pro-DLB group had isolated lower P-Tau and on brain MRI widening of sulci including fronto-insular, occipital, and olfactory sulci (FDR corrected). Conclusions: Patients with symptoms of prodromal DLB are cognitively slower, with more behavioral disorders, autonomic symptoms, and photophobia. Biomarkers confirmed the non-Alzheimer profile. The occipital, fronto-insular, and olfactory bulb involvement on brain MRI was consistent with symptoms and known neuropathology. The next step will be to study the clinical, biological, and imaging evolution of these patients.Trial registration: Clinicaltrials.gov, NCT01926249 .

Background Deregulation of FGF19-FGFR4 signaling is found in several cancers, including hepatocellular carcinoma (HCC), nominating it for therapeutic targeting. FGF401 is a potent, selective FGFR4 inhibitor with antitumor activity in preclinical models. This study was designed to determine the recommended phase 2 dose (RP2D), characterize PK/PD, and evaluate the safety and efficacy of FGF401 alone and combined with the anti-PD-1 antibody, spartalizumab. Methods Patients with HCC or other FGFR4/KLB expressing tumors were enrolled. Dose-escalation was guided by a Bayesian model. Phase 2 dose-expansion enrolled patients with HCC from Asian countries (group1), non-Asian countries (group2), and patients with other solid tumors expressing FGFR4 and KLB (group3). FGF401 and spartalizumab combination was evaluated in patients with HCC. Results Seventy-four patients were treated in the phase I with single-agent FGF401 at 50 to 150 mg. FGF401 displayed favorable PK characteristics and no food effect when dosed with low-fat meals. The RP2D was established as 120 mg qd. Six of 70 patients experienced grade 3 dose-limiting toxicities: increase in transaminases (n = 4) or blood bilirubin (n = 2). In phase 2, 30 patients in group 1, 36 in group 2, and 20 in group 3 received FGF401. In total, 8 patients experienced objective responses (1 CR, 7 PR; 4 each in phase I and phase II, respectively). Frequent adverse events (AEs) were diarrhea (73.8%), increased AST (47.5%), and ALT (43.8%). Increase in levels of C4, total bile acid, and circulating FGF19, confirmed effective FGFR4 inhibition. Twelve patients received FGF401 plus spartalizumab. RP2D was established as FGF401 120 mg qd and spartalizumab 300 mg Q3W; 2 patients reported PR. Conclusions At biologically active doses, FGF401 alone or combined with spartalizumab was safe in patients with FGFR4/KLB-positive tumors including HCC. Preliminary clinical efficacy was observed. Further clinical evaluation of FGF401 using a refined biomarker strategy is warranted. Trial registration NCT02325739.

Measures of social cognition have now become central in neuropsychology, being essential for early and differential diagnoses, follow-up, and rehabilitation in a wide range of conditions. With the scientific world becoming increasingly interconnected, international neuropsychological and medical collaborations are burgeoning to tackle the global challenges that are mental health conditions. These initiatives commonly merge data across a diversity of populations and countries, while ignoring their specificity.In this context, we aimed to estimate the influence of participants' nationality on social cognition evaluation. This issue is of particular importance as most cognitive tasks are developed in highly specific contexts, not representative of that encountered by the world's population.Through a large international study across 18 sites, neuropsychologists assessed core aspects of social cognition in 587 participants from 12 countries using traditional and widely used tasks.Age, gender, and education were found to impact measures of mentalizing and emotion recognition. After controlling for these factors, differences between countries accounted for more than 20% of the variance on both measures. Importantly, it was possible to isolate participants' nationality from potential translation issues, which classically constitute a major limitation.Overall, these findings highlight the need for important methodological shifts to better represent social cognition in both fundamental research and clinical practice, especially within emerging international networks and consortia. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Introduction: Cabozantinib, an inhibitor of MET, AXL, and VEGF receptors, significantly improved overall survival (OS) and progression-free survival (PFS) versus placebo in patients with previously treated advanced hepatocellular carcinoma (HCC). In this exploratory analysis, outcomes were evaluated according to plasma biomarker levels. Methods: Baseline plasma levels were evaluated for MET, AXL, VEGFR2, HGF, GAS6, VEGF-A, PlGF, IL-8, EPO, ANG2, IGF-1, VEGF-C, and c-KIT for 674/707 randomized patients; and Week 4 levels were evaluated for MET, AXL, VEGFR2, HGF, GAS6, VEGF-A, PlGF, IL-8, and EPO for 614 patients. OS and PFS were analyzed by baseline levels as dichotomized or continuous variables and by on-treatment changes at Week 4 as continuous variables; biomarkers were considered potentially prognostic if p < 0.05 and predictive if p < 0.05 for the interaction between treatment and the biomarker. Multivariable analyses adjusting for clinical covariates were also performed. Results: In the placebo group, high levels of MET, HGF, GAS6, IL-8, and ANG2 and low levels of IGF-1 were associated with shorter OS in univariate and multivariable analyses; these associations were also observed for MET, IL-8, and ANG2 in the cabozantinib group. Hazard ratios for OS and PFS favored cabozantinib over the placebo at low and high baseline levels for all biomarkers. No baseline biomarkers were predictive of a treatment benefit. Cabozantinib promoted pharmacodynamic changes in several biomarkers, including increases in VEGF-A, PlGF, AXL, and GAS6 levels and decreases in VEGFR2 and HGF levels; these changes were not associated with OS or PFS. Conclusion: Cabozantinib improved OS and PFS versus placebo at high and low baseline concentrations for all biomarkers analyzed. Low baseline levels of MET, HGF, GAS6, IL-8, and ANG2 and high levels of IGF-1 were identified as potential favorable prognostic biomarkers for survival in previously treated advanced HCC. Although cabozantinib promoted pharmacodynamic changes in several biomarkers, these changes were not associated with survival.

IntroductionSoccer is the most popular sport in the world. This contact sport carries the risk of exposure to repeated head impacts in the form of subconcussions, defined as minimal brain injuries following head impact, with no symptom of concussion. While it has been suggested that exposure to repetitive subconcussive events can result in long-term neurophysiological modifications, and the later development of chronic traumatic encephalopathy, the consequences of these repeated impacts remain controversial and largely unexplored in the context of soccer players.Methods and analysisThis is a prospective, single-centre, exposure/non-exposure, transverse study assessing the MRI and neuropsychological abnormalities in professional retired soccer players exposed to subconcussive impacts, compared with high-level athletes not exposed to head impacts. The primary outcome corresponds to the results of MRI by advanced MRI techniques (diffusion tensor, cerebral perfusion, functional MRI, cerebral volumetry and cortical thickness, spectroscopy, susceptibility imaging). Secondary outcomes are the results of the neuropsychological tests: number of errors and time to complete tests. We hypothesise that repeated subconcussive impacts could lead to morphological lesions and impact on soccer players’ cognitive skills in the long term.Ethics and disseminationEthics approval has been obtained and the study was approved by the Comité de Protection des Personnes (CPP) No 2021-A01169-32. Study findings will be disseminated by publication in a high-impact international journal. Results will be presented at national and international imaging meetings.Trial registration numberNCT04903015.

International audience; PurposeThe purpose of this study was to evaluate the capabilities of radiomics using magnetic resonance imaging (MRI) data in the assessment of treatment response to 90yttrium transarterial radioembolization (TARE) in patients with locally advanced hepatocellular carcinoma (HCC) by comparison with predictions based on European Association for the Study of the Liver (EASL) criteria.Patients and methodsTwenty-two patients with HCC (19 men, 3 women; mean age: 66.7 ± 9.8 [SD]; age range: 37–82 years) who underwent contrast-enhanced MRI 4 ± 1 weeks before and 4 ± 4 weeks after TARE, were enrolled in this retrospective study. Regions of interest were placed manually along the contours of the treated tumor on each axial slice of arterial and portal phase images using the ITK-SNAP post-processing software. For each MRI, the Pyradiomics Python package was used to extract 107 radiomics features on both arterial and portal phases, and resulting delta-features were computed. The Mann-Whitney U test with Bonferroni correction was used to select statistically different features between responders and non-responders (i.e., those with progressive or stable disease) at 6-month follow-up, according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Finally, for each selected feature, univariable logistic regression with leave-one-out cross validation procedure was used to perform receiver operating characteristic (ROC) curve analysis and compare radiomics parameters with MRI variables.ResultsAccording to mRECIST, 14 patients (14/22; 64%) were non-responders and 8 (8/22; 36%) were responders. Four radiomics parameters (long run emphasis, minor axis length, surface area, and gray level non-uniformity on arterial phase images) were the only predictors of early response. ROC curve analysis showed that long run emphasis was the best parameter for predicting early response, with 100% sensitivity (95% CI: 68–100) and 100% specificity (95% CI: 78–100). EASL morphologic criteria yielded 75% sensitivity (95% CI: 41–96%) and 93% specificity (95% CI: 69–100%).ConclusionRadiomics allows identify marked differences between responders and non-responders, and could aid in the prediction of early treatment response following TARE in patients with HCC.

e16194 Background: Fibrolamellar carcinomas (FLC) are rare hepatic malignancies affecting young patients without chronic liver disease, often diagnosed at an advanced stage. Few data are available regarding efficacy of systemic anti-tumor treatments. Main objective was to explore response according to RECIST 1.1 criteria in the first line setting in advanced FLC patients. Methods: This retrospective multicentric French cohort included 44 patients with advanced FLC who received at least one systemic treatment and had one morphological evaluation, performed every 2-3 months. Results: Median age at diagnosis was 24 years (range 13-62), 59.1% were female, 38% were at stage IVa (lymph node involvement) and 42% at stage IVb (metastatic involvement). Responses were analyzed in 42 patients, 7 receiving neoadjuvant treatment and 35 patients receiving a first line palliative treatment. There was no complete response, 14.3% (n = 5) had a partial response (PR), 37.1% (n = 13) had stable disease (SD) and 48.6% (n = 17) had progressive disease. GEMOX was the most prescribed regimen (n = 8) with a disease control rate (PR+SD) at 25% (PR = 12.5% and SD = 12.5%). Doxorubicine-platine was the second most prescribed association (n = 5) with a disease control rate at 80% (PR = 40% and SD = 40%). Tyrosine kinase inhibitors, i.e. sorafenib (n = 10) and sunitinib (n = 3) showed no response and a rate of SD of 40% and 33% respectively. The association of doxorubicine-platine plus sorafenib was used in 4 patients, with one PR and three SD. Only one patient received immunotherapy (nivolumab and ipilimumab), but progressed at first evaluation at two months. Median overall survival was 3.3 years. Five years overall survival was 35% (95%CI = 0.23-0.54). Patients who underwent surgery had a better prognosis (55 months vs 15.5 months). Unfortunately, disease relapsed quickly after surgery, with a median relapse-free survival of 11 months. Conclusions: Advanced fibrolamellar carcinomas have a low chemosensitivity to either cytotoxic chemotherapy or tyrosine kinase inhibitors. Larger studies are warranted to define a standard of care for these rare tumors requiring treatment in an expert centre, either with a molecular screening.

Mixed anion materials and anion doping are very promising strategies to improve solid-state electrolyte properties by enabling an optimized balance between good electrochemical stability and high ionic conductivity. In this work, we present the discovery of a novel lithium aluminum sulfide-chloride phase. The structure is strongly affected by the presence of chloride anions on the sulfur site, as this stabilizes a higher symmetry phase presenting a large degree of cationic site disorder, as well as disordered octahedral lithium vacancies, in comparison with Li-Al-S ternaries. The effect of disorder on the lithium conductivity properties was assessed by a combined experimental-theoretical approach. In particular, the conductivity is increased by a factor 103 compared to the pure sulfide phases. Although it remains moderate (10−6 S·cm-1), Ab Initio Molecular Dynamics and Maximum Entropy (applied to neutron diffraction data) methods show that disorder leads to a 3D diffusion pathway, where Li atoms move thanks to a concerted mechanism. An understanding of the structure-property relationships is developed to determine the limiting factor governing lithium ion conductivity. This analysis, added to the strong step forward obtained in the determination of the dimensionality of diffusion paves the way for accessing even higher conductivity in materials comprising an hcp anion arrangement.

Background: Few patients with a normal cerebrospinal fluid (CSF) biomarker profile fulfill the clinical criteria for Alzheimer disease (AD). Objective: The aim of this study was to test the hypothesis of misdiagnoses for these patients. Method: Patients from the e-PLM centers fulfilling the core clinical criteria for probable AD dementia or mild cognitive impairment due to AD (AD-MCI), with normal CSF Aβ1-42, T-tau and P-tau biomarkers and clinical follow-up, were included. Clinical and imaging data were reviewed by an independent board, from baseline (visit with clinical evaluation and CSF analysis) to the end of the follow-up, for a final diagnosis. Results: In the e-PLM cohort of 1098 AD patients with CSF analysis, 37 (3.3%) patients (20 with AD dementia core clinical criteria and 17 with AD-MCI core clinical criteria) had normal CSF biomarker profile and a clinical follow-up. All patients presented with episodic memory impairment and 27 (73%) had medial temporal lobe atrophy on MRI-scan. After a median follow-up of 36 months (range 7-74), the final diagnosis was AD MCI or dementia for 9 (24%) patients, and unlikely due to AD for 28 (76%) patients. A misdiagnosis was corrected in 18 (49%) patients (mood disorders, non-AD degenerative dementia, vascular cognitive impairment, alcohol cognitive disorders, temporal epilepsy and hippocampal sclerosis), and 10 (27%) patients had cognitive disorders of undetermined etiology. Conclusion: AD diagnosis (MCI or dementia) with normal CSF biomarkers is a rare condition. A clinical follow- up is particularly recommended to consider an alternative diagnosis.

Cytoplasmic aminoacyl-tRNA synthetases (ARSs) are emerging as a cause of numerous rare inherited diseases. Recently, biallelic variants in tyrosyl-tRNA synthetase 1 (YARS1) have been described in ten patients of three families with multi-systemic disease (failure to thrive, developmental delay, liver dysfunction, and lung cysts). Here, we report an additional subject with overlapping clinical findings, heterozygous for two novel variants in tyrosyl-tRNA synthetase 1 (NM_003680.3(YARS1):c.176T>C; p.(Ile59Thr) and NM_003680.3(YARS1):c.237C>G; p.(Tyr79*) identified by whole exome sequencing. The p.Ile59Thr variant is located in the highly conserved aminoacylation domain of the protein. Compared to subjects previously described, this patient presents a much more severe condition. Our findings support implication of two novel YARS1 variants in these disorders. Furthermore, we provide evidence for a reduced protein abundance in cells of the patient, in favor of a partial loss-of-function mechanism.

International audience; BACKGROUND:Renal transplantation is the best available therapeutic option for end-stage renal failure in both children and adults. However, little is known about anesthetic practice during pediatric renal transplantation.MATERIAL AND METHODS:The study consisted of a national survey about anesthetic practice during pediatric renal transplantation in France. French tertiary pediatric centers performing renal transplants were targeted, and one physician from each team was asked to complete the survey. The survey included patient data, preoperative assessment and optimization data, and intraoperative anesthesia data (drugs, ventilation, and hemodynamic interventions).RESULTS:Twenty centers performing kidney transplantation were identified and contacted to complete the survey, and eight responded. Surveyed centers performed 96 of the 122 pediatric kidney transplantations performed in France in 2017 (79%). Centers consistently performed echocardiography and ultrasound examinations of the great veins preoperatively and consistently employed esophageal Doppler cardiac output estimation and vasopressors intraoperatively. All other practices were found to be heterogeneous. Central venous pressure was monitored in six centers, and dopamine was administered perioperatively in two centers.CONCLUSIONS:The current study provides a snapshot of the perioperative management of pediatric kidney transplantation in France. Results emphasize the need for both standardization of practice and awareness of recent evidence against the use of CVP monitoring and dopamine infusions.

We report a very rare case of complex upper extralobar pulmonary sequestration, detected during pregnancy and resected early because the diagnosis was uncertain (possibility of a teratoma). At 2 months, the upper left pulmonary lesion was completely removed by thoracoscopy. Pathology concluded an extralobar sequestration associated with a duplication cyst of mixed bronchogenic and esophageal type. The postoperative course was uneventful. The early thoracoscopic approach in this type of antenatally diagnosed lesion was a good option.

Background: Radiologically isolated syndrome (RIS) is characterized by patients with asymptomatic T2 hypersignals detected by brain MRI fulfilling dissemination in space criteria and is suggestive of subclinical multiple sclerosis (MS). In previous studies, it was demonstrated that visual evoked potential and cerebrospinal fluid help to identify pejorative markers in converting to MS. Objective: To date the cognitive function has never been investigated in a cohort of RIS. The objective of this study was to investigate cognitive function in a cohort of 26 RIS patients. Methods: We prospectively assessed the BCcogSEP (a French adaptation of the Brief Repeatable Battery (BRB) including eight cognitive tests) of 26 patients with RIS, compared with 26 MS patients and 26 healthy subjects matched for age, sex and level of education. Results: When comparing the three groups, the cognitive performance was significantly lower in the RIS and MS groups compared with healthy subjects for the Paced Auditory Serial Addition Test (PASAT) 3 seconds ( p = 0.002), phonemic fluencies ( p = 0.02), the code of the WAIS ( p = 0.05), the direct ( p = 0.002) or indirect ( p = 0.007) digit span test, the cross-taping test ( p = 0.019) and Go—No-Go ( p = 0.001). When we compared RIS and MS, the cognitive performance was significantly lower in MS patients for the direct span number ( p = 0.003) and cross-tapping test ( p = 0.05). We did not find significant differences between the three groups for the other tests. We did not find a correlation between clinical, biological and MRI results and cognitive dysfunctions. Conclusions: This study confirms the recently developed concept of RIS patients who present similar features to MS patients. Further studies are necessary to confirm these initial results and to correlate cognitive disorders with MRI surrogate markers.

Lyme borreliosis (LB) is a systemic disease called neuroborreliosis (NB) when neurological symptoms are pre-eminent. LB is a zoonosis caused by Borrelia bacteria transmitted by Ixodes tick-bite. Because of the absence of a national registry, epidemiology of LB in France is not well known. Moreover, diagnosis of NB may be difficult because of the various clinical forms. Acute meningoradiculitis is the most common presentation, but pauci-symptomatic meningitis, encephalitis, myelitis, polyneuropathy, cerebrovascular involvement, and rarely chronic encephalomyelitis are also described. The vector Ixodes ricinus (I. ricinus) is found throughout metropolitan France excepting border areas of the Mediterranean seaside and in regions with an altitude above 1500 meters. In France, the Borrelia infestation rate of Ixodes is 7% with wide disparity between administrative districts. Prospective work in 1999-2000 by 875 general practitioners participating in the "Sentinel" network established the estimated incidence of BL (9.4/100 000) and of NB (0.6/100 000) in France. Incidence is higher in certain regions: in Alsace, prospective work by 419 general practitioners and specialists in cooperation with the national surveillance agency (Institut national de veille sanitaire), estimated BL incidence at 86 to 200/100 000 inhabitants and NB at 10/100 000. Thus, although globally France is a country with a moderate risk for LB, some regions such as Limousin, Auvergne, Lorraine and Alsace, have a high risk of LB, comparable to countries in the northeastern Europe such as Germany and Sweden.