Trial of Botulinum Toxin for Isolated or Essential Head Tremor.

BACKGROUND: Local injections of botulinum toxin type A have been used to treat essential head tremor but have not been extensively studied in randomized trials. METHODS: In a multicenter, double-blind, randomized trial, we assigned, in a 1:1 ratio, adult patients with essential or isolated head tremor to receive botulinum toxin type A or placebo. Botulinum toxin or placebo was injected under electromyographic guidance into each splenius capitis muscle on the day of randomization (day 0) and during week 12. The primary outcome was improvement by at least 2 points on the Clinical Global Impression of Change (CGI) scale at week 6 after the second injection (week 18 after randomization). The CGI scale was used to record the patient's assessment of the degree of improvement or worsening of head tremor since baseline; scores range from 3 (very much improved) to -3 (very much worse). Secondary outcomes included changes in tremor characteristics from baseline to weeks 6, 12, and 24. RESULTS: A total of 120 patients were enrolled; 3 patients were excluded during screening, and 117 patients were randomly assigned to receive botulinum toxin (62 patients) or placebo (55 patients) and were included in the intention-to-treat analysis. Twelve patients in the botulinum toxin group and 2 patients in the placebo group did not receive injections during week 12. The primary outcome - improvement by at least 2 points on the CGI scale at week 18 - was met by 31% of the patients in the botulinum toxin group as compared with 9% of those in the placebo group (relative risk, 3.37; 95% confidence interval, 1.35 to 8.42; P = 0.009). Analyses of secondary outcomes at 6 and 12 weeks but not at 24 weeks were generally supportive of the primary-outcome analysis. Adverse events occurred in approximately half the patients in the botulinum toxin group and included head and neck pain, posterior cervical weakness, and dysphagia. CONCLUSIONS: Injection of botulinum toxin into each splenius capitis muscle on day 0 and during week 12 was more effective than placebo in reducing the severity of isolated or essential head tremor at 18 weeks but not at 24 weeks, when the effects of injection might be expected to wane, and was associated with adverse events. (Funded by the French Ministry of Health; Btx-HT ClinicalTrials.gov number, NCT02555982.).

Interhemispheric reactivity of the subthalamic nucleus sustains progressive dopamine neuron loss in asymmetrical parkinsonism.

Parkinson's disease (PD) is characterized by the progressive and asymmetrical degeneration of the nigrostriatal dopamine neurons and the unilateral presentation of the motor symptoms at onset, contralateral to the most impaired hemisphere. We previously developed a rat PD model that mimics these typical features, based on unilateral injection of a substrate inhibitor of excitatory amino acid transporters, L-trans-pyrrolidine-2,4-dicarboxylate (PDC), in the substantia nigra (SN). Here, we used this progressive model in a multilevel study (behavioral testing, in vivo 1H-magnetic resonance spectroscopy, slice electrophysiology, immunocytochemistry and in situ hybridization) to characterize the functional changes occurring in the cortico-basal ganglia-cortical network in an evolving asymmetrical neurodegeneration context and their possible contribution to the cell death progression. We focused on the corticostriatal input and the subthalamic nucleus (STN), two glutamate components with major implications in PD pathophysiology. In the striatum, glutamate and glutamine levels increased from presymptomatic stages in the PDC-injected hemisphere only, which also showed enhanced glutamatergic transmission and loss of plasticity at corticostriatal synapses assessed at symptomatic stage. Surprisingly, the contralateral STN showed earlier and stronger reactivity than the ipsilateral side (increased intraneuronal cytochrome oxidase subunit I mRNA levels; enhanced glutamate and glutamine concentrations). Moreover, its lesion at early presymptomatic stage halted the ongoing neurodegeneration in the PDC-injected SN and prevented the expression of motor asymmetry. These findings reveal the existence of endogenous interhemispheric processes linking the primary injured SN and the contralateral STN that could sustain progressive dopamine neuron loss, opening new perspectives for disease-modifying treatment of PD.

Study of the relationship between psychoactive substance use and pain in cancer patients and cancer survivors: A French nationwide cross-sectional study.

Pain is a prevalent symptom among cancer patients and survivors. Psychoactive substance use (PSU) is associated with both the presence and severity of pain. However, little is known about this association in the context of cancer. The primary objective was to compare the prevalence of PSU and its relationship with pain during and after cancer. PSU was defined as the use of nonmedication substances (alcohol, tobacco, e-cigarettes, cannabidiol, and cannabis), with frequency categorized as at least yearly, monthly, weekly, or daily. Secondary objectives aimed to explore the relationships between PSU and pain characteristics, health-related quality of life, anxiety, depression, deprivation, and individual characteristics. Among the 1041 individuals included, pain prevalence was 44.7% (95% confidence interval [CI] 41.6%-47.8%). The overall prevalence of PSU at least monthly was 67.0% (95% CI 64.0%-69.8%). The proportions of chronic and neuropathic pains were higher for at least monthly use of cannabidiol compared to nonuse (70.0% vs. 39.3% and 55.7% vs. 28.1%, p < .001). In multivariate analysis, the monthly uses of tobacco and cannabidiol were higher in painful individuals than in nonpainful ones (odds ratio: 2.85 [95% CI 1.22-6.64] and 3.76 [95% CI 1.13-12.44], p < .05). From the point of view of the patient care, the study underscores the need for physicians to prioritize smoking cessation and pay attention to the use of cannabidiol during and after cancer.

L1 chimeric transcripts are expressed in healthy brain and their deregulation in glioma follows that of their host locus.

Besides the consequences of retrotransposition, long interspersed element 1 (L1) retrotransposons can affect the host genome through their antisense promoter. In addition to the sense promoter, the evolutionarily recent L1 retrotransposons, which are present in several thousand copies, also possess an anti-sense promoter that can produce L1 chimeric transcripts (LCT) composed of the L1 5' UTR followed by the adjacent genomic sequence. The full extent to which LCT expression occurs in a given tissue and whether disruption of the defense mechanisms that normally control L1 retrotransposons affects their expression and function in cancer cells, remain to be established. By using CLIFinder, a dedicated bioinformatics tool, we found that LCT expression was widespread in normal brain and aggressive glioma samples, and that approximately 17% of recent L1 retrotransposons, from the L1PA1 to L1PA7 subfamilies, were involved in their production. Importantly, the transcriptional activities of the L1 antisense promoters and of their host loci were coupled. Accordingly, we detected LCT-producing L1 retrotransposons mainly in transcriptionally active genes and genomic loci. Moreover, changes in the host genomic locus expression level in glioma were associated with a similar change in LCT expression level, regardless of the L1 promoter methylation status. Our findings support a model in which the host genomic locus transcriptional activity is the main driving force of LCT expression. We hypothesize that this model is more applicable when host gene and LCT are transcribed from the same strand.

Development and validation of a score to assess transmural healing and response in patients with Crohn's disease.

BACKGROUND AND AIMS: As transmural healing (TH) could be the best therapeutic target in Crohn's disease (CD), we aimed to build and validate a score to assess TH and transmural response (TR), and to confirm their association with favorable CD outcomes. METHODS: DEVISE-CD project encompassed two retrospective cohorts (274 and 224 CD patients for development and validation phase, retrospectively) and one multicenter prospective validation cohort (N=46 patients). A step-by-step process was used to build the modified Clermont score (C-score). The primary endpoints were time to bowel damage progression, and steroid-free clinical remission with fecal calprotectin < 250 (CFREM) at one year for retrospective and prospective validation cohorts, respectively. RESULTS: Edema, ulcer, contrast enhancement, diffusion-weighted hyperintensity, fat wrapping, bowel thickening (>3 mm), and enlarged lymph nodes were associated to higher risk of bowel damage progression (p<0.01). Edema, diffusion-weighted hyperintensity, post-gadolinium contrast enhancement, and bowel thickening were highly coexistent (>95%) and collinear (p<0.0001). Bowel thickness had the highest sensitivity to change after treatment (SMD=0.30±1.0)(p=0.001). C-score was calculated as 0.2x(bowel thickness-3mm) + 1.5x enlarged lymph nodes + 2x ulcer. TH (C-score<0.5) (HR=0.28[0.13-0.63],p=0.002; aHR=0.15[0.04-0.53], p=0.003), TR50 (50%-decrease of C-score)(HR=0.30[0.15-0.63], p=0.001; aHR = 0.36[0.14-0.88], p=0.025) or TR25(25%-decrease of C-score)(HR=0.37[0.19-0.71], p=0.003; aHR=0.46[0.23-0.94], p=0.034) prevented bowel damage progression in development and validation cohorts, respectively. In the prospective validation cohort, achieving TH (OR=4.6[1.3-15.6], p=0.016), TR50 (OR=6.9[1.8-26.0], p=0.008) or TR25 (OR=6.0[1.6-22.3], p=0.008) after 12 weeks of anti-TNF therapy led to higher rate of CFREM at one year. CONCLUSION: C-score is a validated, reliable and easy-to-use tool to assess TH and TR in CD patients.

Impact of screening programme to prevent anal cancer in high-risk patients with HIV.

INTRODUCTION: We assessed the impact of a nationwide screening programme to reduce the risk of anal cancer in a large cohort of high-risk patients with HIV. METHODS: From a large database from one referral centre, all high-risk patients with HIV (men who have sex with men, history of anal or genital warts, or previous cervix human papillomavirus-related lesions) who were eligible to enter the French anal cancer screening programme (2011-2020) were retrospectively included. Adherence to the screening programme was defined as no interval >18 months between two visits. Standardized management included perianal visualization and standard anoscopy with biopsies of macroscopic abnormalities. RESULTS: Overall, 700 patients with HIV were included (median follow-up 8.4 years [interquartile range 4.3-9.2] and 1491.6 patient-years), and 336 had one or more proctology visit. A total of 13 patients were diagnosed with anal squamous cell carcinomas. The risk of anal cancer was higher with anal intra-epithelial neoplasia grade 3 (AIN3; hazard ratio [HR] 44.5 [95% confidence interval {CI} 11.2-176.6], p < 0.001), AIN2 (HR 11.9 [95% CI 2.1-66.9], p = 0.005), or high-grade dysplasia (HR 23.4 [95% CI 7.9-69.1], p < 0.001) than with low-grade dysplasia or no lesion. Among the patients who were strictly adherent to the screening programme (4.6% [32/700]), we did not report any AIN or anal cancer, but we also did not observe any significant reduction in the risk of anal cancer (p = 0.51), AIN3 (p = 0.28), high-grade dysplasia (p = 0.19), or any AIN lesions (p = 0.10) compared with non-adherent patients. In contrast, screened patients were more likely to be diagnosed with anal warts (HR 3.71 [95% CI 2.14-6.42], p < 0.001). CONCLUSION: Macroscopic high-grade dysplasia lesions are associated with a higher risk of developing anal cancer. Despite finding no cases of cancer during the screening programme, we also did not demonstrate a clear benefit from our screening programme for the prevention of anal cancer in high-risk patients with HIV.

Total Versus Subtotal Gastrectomy for Distal Gastric Poorly Cohesive Carcinoma.

BACKGROUND: Gastric poorly cohesive carcinoma (PCC) in advanced stages has a poor prognosis. Total gastrectomy (TG) remains the common treatment for distal gastric PCC, but subtotal gastrectomy (SG) may improve quality of life without compromising outcomes. Currently, no clear recommendation on the best surgical strategy for distal PCC is available. This study aimed to compare overall survival (OS) and disease-free survival (DFS) at 5 years for patients with antropyloric PCC treated by total versus subtotal gastrectomy. METHODS: A large retrospective European multicenter cohort study analyzed 2131 patients treated for gastric cancer between 2007 and 2017 by members of the French Association of Surgery (AFC). The study compared a group of patients who underwent TG with a group who underwent SG for antropyloric PCC. The primary outcomes were 5 year OS and DFS. RESULTS: The study enrolled 269 patients: 140 (52.0%) in the TG group and 129 (48.0%) in the SG group. The baseline characteristics and pTNM stage were similar between the two groups. According to Dindo-Claven classification, the patients treated with TG had more postoperative complications than the patients treated with SG (p < 0.001): grades I to IIIa (77.1% vs 59.5%) and grades IIIb to IVb (14.4% vs 9.0%). No difference in 5-year OS was observed between TG (53.8%; 95 % confidence interval [CI], 43.2-63.3%) and SG (53.0%; 95% CI, 41.4-63.3%) (hazard ratio [HR], 0.94; 95% CI, 0.68-1.29). The same was observed for 5-year DFS: TG (46.0%; 95% CI, 35.9-55.5%) versus SG (45.3%; 95% CI, 34.3-55.6%) (HR, 0.97; 95% CI, 0.70-1.34). CONCLUSIONS: At 5 years, SG was not associated with worse OS and DFS than TG for distal PCC. Surgical morbidity was higher after TG. Subtotal gastrectomy is a valuable option for distal PCC gastric cancer.

Neoadjuvant Chemotherapy Does Not Improve Survival in cT2N0M0 Gastric Adenocarcinoma Patients: A Multicenter Propensity Score Analysis.

BACKGROUND: According to current international guidelines, stage cT2N0M0 gastric adenocarcinoma warrants preoperative chemotherapy followed by surgery. However, upfront surgery is often preferred in clinical practice, depending on patient clinical status and local treatment preferences. OBJECTIVE: The aim of the present study was to assess the impact of neoadjuvant chemotherapy in overall survival (OS) and disease-free survival (DFS) of cT2N0M0 patients. METHODS: A retrospective analysis was performed among 32 centers, including gastric adenocarcinoma patients operated between January 2007 and December 2017. Patients with cT2N0M0 stage were divided into upfront surgery (S) and neoadjuvant chemotherapy followed by surgery (CS) groups. Inverse probability of treatment weighting (IPTW) was used to compensate for baseline differences between the groups. RESULTS: Among the 202 patients diagnosed with cT2N0M0 stage, 68 (33.7%) were in the CS group and 134 (66.3%) were in the S group. CS patients were younger (mean age 62.7 ± 12.8 vs. 69.8 ± 12.1 years for S patients; p < 0.001) and had a better health status (World Health Organization performance status = 0 in 60.3% of CS patients vs. 34.5% of S patients; p = 0.006). During follow-up, recurrence occurred in 27.2% and 19.6% of CS and S patients, respectively, after IPTW (p = 0.32). Five-year OS was similar between CS and S patients (78.9% vs. 68.3%; p = 0.42), as was 5-year DFS (70.4% vs. 68.5%; p = 0.96). Neoadjuvant chemotherapy was associated with neither OS nor DFS in multivariable analysis after IPTW. CONCLUSIONS: Patients with cT2N0M0 gastric adenocarcinoma did not present a survival or recurrence benefit if treated with perioperative chemotherapy followed by surgery as opposed to surgery alone.

Is large for gestational age in singletons born after frozen embryo transfer associated with freezing technique or endometrial preparation protocol? A longitudinal national French study.

STUDY QUESTION: Is large for gestational age (LGA) observed in babies born after frozen embryo transfer (FET) associated with either the freezing technique or the endometrial preparation protocol? SUMMARY ANSWER: Artificial cycles are associated with a higher risk of LGA, with no difference in rate between the two freezing techniques (vitrification versus slow freezing) or embryo stage (cleaved embryo versus blastocyst). WHAT IS KNOWN ALREADY: Several studies have compared neonatal outcomes after fresh embryo transfer (ET) and FET and shown that FET is associated with improved neonatal outcomes, including reduced risks of preterm birth, low birthweight, and small for gestational age (SGA), when compared with fresh ET. However, these studies also revealed an increased risk of LGA after FET. The underlying pathophysiology of this increased risk remains unclear; parental infertility, laboratory procedures (including embryo culture conditions and freezing-thawing processes), and endometrial preparation treatments might be involved. STUDY DESIGN, SIZE, DURATION: A multicentre epidemiological data study was performed through a retrospective analysis of the standardized individual clinical records of the French national register of IVF from 2014 to 2018, including single deliveries resulting from fresh ET or FET that were prospectively collected in fertility centres. Complementary data were collected from the participating fertility centres and included the vitrification media and devices, and the endometrial preparation protocols. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data were collected from 35 French ART centres, leading to the inclusion of a total of 72 789 fresh ET, 10 602 slow-freezing FET, and 39 062 vitrification FET. Main clinical outcomes were presented according to origin of the transferred embryos (fresh, slow frozen, or vitrified embryos) and endometrial preparations for FET (ovulatory or artificial cycles), comparing five different groups (fresh, slow freezing-ovulatory cycle, slow freezing-artificial cycle, vitrification-ovulatory cycle, and vitrification-artificial cycle). Foetal growth disorders were defined in live-born singletons according to gestational age and sex-specific weight percentile distribution: SGA and LGA if <10th and ≥90th percentiles, respectively. Analyses were performed using linear mixed models with the ART centres as random effect. MAIN RESULTS AND THE ROLE OF CHANCE: Transfers led to, respectively, 19 006, 1798, and 9195 deliveries corresponding to delivery rates per transfer of 26.1%, 17.0%, and 23.5% after fresh ET, slow-freezing FET, and vitrification FET, respectively. FET cycles were performed in either ovulatory cycles (n = 21 704) or artificial cycles (n = 34 237), leading to 5910 and 10 322 pregnancies, respectively, and corresponding to pregnancy rates per transfer of 31.6% and 33.3%. A significantly higher rate of spontaneous miscarriage was observed in artificial cycles when compared with ovulatory cycles (33.3% versus 21.4%, P < 0.001, in slow freezing groups and 31.6% versus 21.8%, P < 0.001 in vitrification groups). Consequently, a lower delivery rate per transfer was observed in artificial cycles compared with ovulatory cycles both in slow freezing and vitrification groups (15.5% versus 18.9%, P < 0.001 and 22.8% versus 24.9%, P < 0.001, respectively). Among a total of 26 585 live-born singletons, 16 413 babies were born from fresh ET, 1644 from slow-freezing FET, and 8528 from vitrification FET. Birthweight was significantly higher in the FET groups than in the fresh ET group, with no difference between the two freezing techniques. Likewise, LGA rates were higher and SGA rates were lower in the FET groups compared with the fresh ET group whatever the method used for embryo freezing. In a multivariable analysis, the risk of LGA following FET was significantly increased in artificial compared with ovulatory cycles. In contrast, the risk of LGA was not associated with either the freezing procedure (vitrification versus slow freezing) or the embryo stage (cleaved embryo versus blastocyst) at freezing. Regarding the vitrification method, the risk of LGA was not associated with either the vitrification medium used or the embryo stage. LIMITATIONS, REASONS FOR CAUTION: No data were available on maternal context, such as parity, BMI, infertility cause, or maternal comorbidities, in the French national database. In particular, we cannot exclude that the increased risk of LGA observed following FET with artificial cycles may, at least partially, be associated with a confounding effect of some maternal factors. No information about embryo culture and incubation conditions was available. Most of the vitrification techniques were performed using the same device and with two main vitrification media, limiting the validity of a comparison of risk for LGA according to the device or vitrification media used. WIDER IMPLICATIONS OF THE FINDINGS: Our results seem reassuring, since no potential foetal growth disorders following embryo vitrification in comparison with slow freezing were observed. Even if other factors are involved, the endometrial preparation treatment seems to have the greatest impact on LGA risk following FET. FET during ovulatory cycles could minimize the risk for foetal growth disorders. STUDY FUNDING/COMPETING INTEREST(S): This work has received funding from the French Biomedicine Agency (Grant number: 19AMP002). None of the authors has any conflict of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

The initial molecular response predicts the deep molecular response but not treatment-free remission maintenance in a real-world chronic myeloid leukemia cohort.

In chronic myeloid leukemia, the identification of early molecular predictors of stable treatment-free remission (TFR) after tyrosine kinase inhibitor (TKI) discontinuation is challenging. The predictive values of residual disease (BCR::ABL1 quantification) at months 3 and 6 and more recently, BCR::ABL1 transcript halving time (HT) have been described, but no study compared the predictive value of different early parameters. Using a real-world cohort of 408 patients, we compared the performance of the ELTS score, BCR::ABL1 HT, and residual disease at month 3 and 6 to predict the molecular response, achievement of the TKI discontinuation criteria, and TFR maintenance. The performances of BCR::ABL1 HT and residual disease at month 3 were similar. Residual disease at month 6 displayed the best performance for predicting the optimal response (area under the ROC curve between 0.81 and 0.92; cut-off values: 0.11% for MR4 at month 24 and 0.12% for MR4.5 at month 48). Conversely, no early parameter predicted reaching the TKI discontinuation criteria and TFR maintenance. We obtained similar results when patients were divided in subgroups by first-line treatment (imatinib vs second generation TKI, 2G-TKI). We identified a relationship between ELTS score, earlier milestones and TFR maintenance only in the 2G-TKI group. In conclusion, this first comparative study of early therapeutic response parameters showed that they are excellent indicators of TKI efficacy (BCR::ABL1 transcript reduction) and best responders. Conversely, they did not predict the achievement of the TKI discontinuation criteria and TFR maintenance, suggesting that other parameters are involved in TFR maintenance.

Value of combining biological age with assessment of individual frailty to optimize management of cancer treated with targeted therapies: model of chronic myeloid leukemia treated with tyrosine kinase inhibitors (BIO-TIMER trial).

BACKGROUND: In the era of targeted therapies, the influence of aging on cancer management varies from one patient to another. Assessing individual frailty using geriatric tools has its limitations, and is not appropriate for all patients especially the youngest one. Thus, assessing the complementary value of a potential biomarker of individual aging is a promising field of investigation. The chronic myeloid leukemia model allows us to address this question with obvious advantages: longest experience in the use of tyrosine kinase inhibitors, standardization of therapeutic management and response with minimal residual disease and no effect on age-related diseases. Therefore, the aim of the BIO-TIMER study is to assess the biological age of chronic myeloid leukemia or non-malignant cells in patients treated with tyrosine kinase inhibitors and to determine its relevance, in association or not with individual frailty to optimize the personalised management of each patient. METHODS: The BIO-TIMER study is a multi-center, prospective, longitudinal study aiming to evaluate the value of combining biological age determination by DNA methylation profile with individual frailty assessment to personalize the management of chronic myeloid leukemia patients treated with tyrosine kinase inhibitors. Blood samples will be collected at diagnosis, 3 months and 12 months after treatment initiation. Individual frailty and quality of life will be assess at diagnosis, 6 months after treatment initiation, and then annually for 3 years. Tolerance to tyrosine kinase inhibitors will also be assessed during the 3-year follow-up. The study plans to recruit 321 patients and recruitment started in November 2023. DISCUSSION: The assessment of individual frailty should make it possible to personalize the treatment and care of patients. The BIO-TIMER study will provide new data on the role of aging in the management of chronic myeloid leukemia patients treated with tyrosine kinase inhibitors, which could influence clinical decision-making. TRIAL REGISTRATION: ClinicalTrials.gov , ID NCT06130787; registered on November 14, 2023.

Robot-assisted gait training improves walking and cerebral connectivity in children with unilateral cerebral palsy.

BACKGROUND: Robot-assisted gait training (RAGT) is promising to help walking rehabilitation in cerebral palsy, but training-induced neuroplastic effects have little been investigated. METHODS: Forty unilateral cerebral palsy children aged 4-18 years were randomly allocated in a monocentric study to ten 20-minute RAGT sessions with the G-EO system, five days a week (n = 20) or to a control group (who continued conventional care with six 30-minute physiotherapy sessions, three days a week) (n = 20), two weeks running, from September 2020 to December 2021. Clinical and MRI outcomes were compared before and one month after therapy. The primary outcome was gait speed. Secondary outcomes were a 6-minute walking test distance, Gross Motor Function Measure-88 (GMFM-88) dimensions D and E, Patient Global Impression of Improvement, resting-state functional connectivity within the sensorimotor network, and structural connectivity in the corticospinal tracts. RESULTS: Gait speed and the 6-minute walking test distance improved more after RAGT. Resting-state functional connectivity increased after RAGT but decreased in controls between superior and lateral healthy or lateral injured sensorimotor networks. GMFM-88 and structural connectivity in corticospinal tracts were unchanged. Impression of improvement in children was better after RAGT. CONCLUSION: Short-term benefit of repetitive RAGT on walking abilities and functional cerebral connectivity was found in unilateral cerebral palsy children. IMPACT STATEMENT: Short-term repetitive robot-assisted gait training improves gait speed and walking resistance and increases cerebral functional connectivity in unilateral cerebral palsy. GMFM dimensions D and E were unchanged after short-term repetitive robot-assisted gait training in unilateral cerebral palsy.

Psychobehavioural profile in narcolepsy type 1 with and without REM sleep behaviour disorder.

REM sleep behaviour disorder (RBD) is common in narcolepsy type 1 (NT1). Abnormalities in the reward system have been observed in NT1, possibly related to impaired orexin projections towards the mesolimbic reward system, but also in RBD when associated with Parkinson's disease. Our study aimed to explore the psychobehavioural profile of NT1 patients with and without RBD compared with healthy controls (HC). Forty patients with NT1 were compared with 20 sex- and age-matched HC. All patients with NT1 underwent a video-polysomnography including a measure of REM sleep without atonia (RSWA). The following neuropsychobehavioural variables were assessed: apathy, impulsivity, depression, cognition, subjective and objective attention, sensation-seeking, and behavioural addictions. The patient population included 22 patients with NT1-RBD and 18 patients with NT1-noRBD. Compared with the healthy controls, patients with NT1 had higher scores of apathy, impulsivity, and depression; a lower score on global cognition, and poorer self-perceived attention. No differences were found between patients with NT1 with and without RBD in all neuropsychological variables, except for impaired objective attention in patients with NT1-RBD. In patients with NT1, a positive correlation was observed between RSWA and both apathy and impulsivity subscale. Moreover, in patients with NT1-RBD, RSWA was positively correlated with depression. Patients with NT1 showed higher depression, apathy, and impulsivity compared with controls. These measures correlate with the severity of RSWA, suggesting a transdiagnostic association between RBD and abnormalities of the reward system at least for patients with NT1.

Augmented Reality Guided Laparoscopic Liver Resection: A Phantom Study With Intraparenchymal Tumors.

INTRODUCTION: Augmented reality (AR) in laparoscopic liver resection (LLR) can improve intrahepatic navigation by creating a virtual liver transparency. Our team has recently developed Hepataug, an AR software that projects the invisible intrahepatic tumors onto the laparoscopic images and allows the surgeon to localize them precisely. However, the accuracy of registration according to the location and size of the tumors, as well as the influence of the projection axis, have never been measured. The aim of this work was to measure the three-dimensional (3D) tumor prediction error of Hepataug. METHODS: Eight 3D virtual livers were created from the computed tomography scan of a healthy human liver. Reference markers with known coordinates were virtually placed on the anterior surface. The virtual livers were then deformed and 3D printed, forming 3D liver phantoms. After placing each 3D phantom inside a pelvitrainer, registration allowed Hepataug to project virtual tumors along two axes: the laparoscope axis and the operator port axis. The surgeons had to point the center of eight virtual tumors per liver with a pointing tool whose coordinates were precisely calculated. RESULTS: We obtained 128 pointing experiments. The average pointing error was 29.4 ± 17.1 mm and 9.2 ± 5.1 mm for the laparoscope and operator port axes respectively (P = 0.001). The pointing errors tended to increase with tumor depth (correlation coefficients greater than 0.5 with P < 0.001). There was no significant dependency of the pointing error on the tumor size for both projection axes. CONCLUSIONS: Tumor visualization by projection toward the operating port improves the accuracy of AR guidance and partially solves the problem of the two-dimensional visual interface of monocular laparoscopy. Despite a lower precision of AR for tumors located in the posterior part of the liver, it could allow the surgeons to access these lesions without completely mobilizing the liver, hence decreasing the surgical trauma.

Comparing ethanol lock therapy versus vancomycin lock in a salvation strategy for totally implantable vascular access device infections due to coagulase-negative staphylococci (the ETHALOCK study): a prospective double-blind randomized clinical trial.

OBJECTIVES: Little is known about efficacy and safety of ethanol lock therapy (ELT) to treat totally implantable venous access device (TIVAD) infections. The objective of this trial was to evaluate the effectiveness and safety profile of a local treatment with ELT without removal for TIVAD infection due to coagulase-negative staphylococci. METHODS: We performed a prospective, multicenter, double-blind, randomized clinical trial comparing the efficacy of 40% ELT versus vancomycin lock therapy (VLT) in TIVAD infections due to coagulase-negative staphylococci, complicated or not by bloodstream infection. RESULTS: Thirty-one patients were assigned to the ELT group and 30 to the VLT arm. Concomitant bacteremia was present in 41 patients (67.2%). Treatment success was 58.1 % (18 of 31) for the ELT arm and 46.7% (14 of 30) for the VLT arm (p = 0.37). The overall treatment success was 52.5% (32). The risk of treatment failure due to uncontrolled infections, superinfections, and mechanical complications did not differ significantly between participants receiving ELT (13 out of 31 [42%]) and those receiving VLT (16 out of 30 [53%]) with a hazard ratio of 0.70 (p = 0.343; 95% CI [0.34-1.46], Cox model). Catheter malfunctions were significantly more frequent in the ELT arm (11 patients versus 2 in the VLT group, p = 0.01). CONCLUSIONS: We found an overall high rate of treatment failure that did not differ between the ELT arm and the VLT arm. TIVAD removal must be prioritized to prevent complications (uncontrolled infections, superinfections, and catheter malfunctions) except in exceptional situations.

Higher energy flux may improve short-term appetite control in adolescents with obesity: the NEXT study.

Recent evidence suggests better appetite control in states of high-energy flux (HEF) in adults and lean children. Nevertheless, it is unknown whether this extends to youth with obesity. This study compares the effects of low, moderate or HEF on short-term appetitive control in adolescents with obesity. Sixteen adolescents with obesity (12-16 years, Tanner stages 3-5, 11 females) randomly completed three conditions: (i) low-energy flux (LEF); (ii) moderate energy flux (MEF; + 250 kcal) and (iii) HEF (HEF; + 500 kcal). Energy flux was achieved in MEF and HEF through elevated energy intake (EI) and concomitant increase in energy expenditure using cycling exercise (65 % VO2peak). Ad libitum EI, macronutrient intake and relative EI were assessed at dinner, subjective appetite sensations taken at regular intervals and food reward measured before dinner. Ad libitum EI at dinner was greater in LEF compared with HEF (P = 0·008), and relative EI (REI) was higher in LEF compared with MEF (P = 0·003) and HEF (P < 0·001). The absolute consumption of carbohydrates was lower in LEF compared with MEF (P = 0·047) and HEF (P < 0·001). Total AUC for hunger and desire to eat was lower in HEF compared with LEF (P < 0·001) and MEF (P = 0·038). Total AUC for prospective food consumption was lower on HEF compared with LEF (P = 0·004). Food choice sweet bias was higher in HEF (P = 0·005) compared with LEF. To conclude, increasing energy flux may improve short-term appetite control in adolescents with obesity.

Immunohistochemical expression of DnaJ homolog subfamily B member 9 in immunoglobulin G4-related disease: a pilot study.

OBJECTIVES: DnaJ homolog subfamily B member 9 (DNAJB9) is a co-chaperone protein that governs the functions and integrity of cells. In immunoglobulin G4-related disease (IgG4-RD), DNAJB9 was shown to be upregulated in plasma cells, but its immunohistochemical expression has never been explored. This pilot study aims to investigate the immunohistochemical distribution and intensity of DNAJB9 in IgG4-RD tissue specimens. METHODS: Patients with definite IgG4-RD and normal tissue controls were selected for anti-DNAJB9 immunohistochemistry, applying a semi-quantitative staining intensity score. RESULTS: We studied the tissue slides of 9 IgG4-RD patients and 15 controls, including salivary gland, pancreatic, pulmonary, pleural, and retroperitoneal fibrosis tissue. Median immunohistochemical intensity was 0 for IgG4-RD patients vs. 2 for controls for endothelial cells (ES=1.58, p<0.01), 2 in each group for glandular epithelial cells (ES 0.70, p=0.26), and 2 for IgG4-RD vs. 3 for controls for inflammatory cells regarding salivary glands alone (ES=0.90, p=0.11). Endothelial staining intensity was negatively correlated with serum IgG4 concentrations (r= -0.72, p=0.03) and the number of treatments required to achieve disease remission (r= -0.70, p=0.04). CONCLUSIONS: Our findings evidenced reduced immunohistochemical expression of DNAJB9 in IgG4-RD endothelial cells, and suggested loss of expression in other cell types, possibly correlating with disease severity and risk of relapse. Although DNAJB9 may not serve as a marker for IgG4-RD, it may be part of a pathophysiological pathway involved in the disease and the onset of fibrosis.

S100B vs. "GFAP and UCH-L1" assays in the management of mTBI patients.

OBJECTIVES: To compare for the first time the performance of "GFAP and UCH-L1" vs. S100B in a cohort of patients managed for mild traumatic brain injury (mTBI) according to actualized French guidelines. METHODS: A prospective study was recently carried at the Emergency Department of Clermont-Ferrand University Hospital in France. Patients with mTBI presenting a medium risk of complications were enrolled. Blood S100B and "GFAP and UCHL-1" were sampled and measured according to French guidelines. S100B was measured in patients with samples within 3 h of trauma (Cobas®, Roche Diagnostics), while GFAP and UCHL-1 were measured in all patients (samples <3 h and 3-12 h) using another automated assay (i-STAT® Alinity, Abbott). RESULTS: For sampling <3 h, serum S100B correctly identifies intracranial lesions with a specificity of 25.7 % (95 % CI; 19.5-32.6 %), a sensitivity of 100 % (95 % CI; 66.4-100 %), and a negative predictive value of 100 % (95 % CI; 92.5-100 %). For sampling <12 h, plasma "GFAP and UCH-L1" levels correctly identify intracranial lesions with a specificity of 31.7 % (95 % CI; 25.7-38.2 %), a sensitivity of 100 % (95 % CI; 73.5-100 %), and a negative predictive value of 100 % (95 % CI; 95-100 %). Comparison of specificities (25.7 vs. 31.7 %) did not reveal a statistically significant difference (p=0.16). CONCLUSIONS: We highlight the usefulness of measuring plasma "GFAP and UCH-L1" levels to target mTBI patients (sampling within 12 h post-injury) and optimize the reduction of CT scans.

CX3CL1/Fractalkine as a biomarker for early pregnancy prediction of preterm premature rupture of membranes.

OBJECTIVES: The objective of our study was to evaluate serum CX3CL1/Fractalkine, a monocyte/macrophage chemoattractant expressed in cytotrophoblasts and decidual cells, as a predictive biomarker for the occurrence of preterm premature rupture of membranes (PPROM). METHODS: A case-control study of 438 pregnancies including 82 PPROM cases and 64 preterm labor with intact membranes cases with blood samples collected at first trimester, second trimester and delivery was conducted. The predictive ability of CX3CL1 and maternal risk factors for the occurrence of PPROM was assessed by receiver operating characteristic curve analysis. A second, independent cohort was prospectively constituted to confirm the case-control study results. RESULTS: First trimester CX3CL1 was significantly increased in PPROM cases when compared to matched controls. Multivariate regression analysis highlighted a significant difference for CX3CL1 measured during the first trimester (p<0.001). Alone, CX3CL1 predicts PPROM with a 90 % sensitivity and a specificity around 40 %. The area under the receiver operating characteristic curve for PPROM prediction were 0.64 (95% confidence interval: 0.57-0.71) for first trimester CX3CL1, and 0.61 (95% confidence interval: 0.54-0.68) for maternal risk factors (body mass index<18.5 kg/m2, nulliparity, tobacco use and the absence of high school diploma). The combination of CX3CL1 and maternal risk factors significantly improved the area under the curve: 0.72 (95% confidence interval: 0.66-0.79) (p<0.001). The results were confirmed on a second independent cohort. CONCLUSIONS: CX3CL1 is a promising blood biomarker in the early (first trimester) prediction of PPROM.

The association between obesity severity and food reward in adolescents with obesity: a one-stage individual participant data meta-analysis.

BACKGROUND: Food reward and cue reactivity have been linked prospectively to problematic eating behaviours and excess weight gain in adults and children. However, evidence to date in support of an association between degree of adiposity and food reward is tenuous. A non-linear relationship between reward sensitivity and obesity degree has been previously proposed, suggesting a peak is reached in mild obesity and decreases in more severe obesity in a quadratic fashion. OBJECTIVE: To investigate and characterise in detail the relationship between obesity severity, body composition, and explicit and implicit food reward in adolescents with obesity. METHODS: Data from seven clinical trials in adolescents with obesity were aggregated and analysed in an independent participant data meta-analysis. Linear and curvilinear relationships between the degree of obesity and explicit and implicit reward for sweet and high fat foods were tested in fasted and fed states with BMI-z score as a continuous and discrete predictor using clinically recognised partitions. RESULTS: Although positive associations between obesity severity and preference for high-fat (i.e. energy dense) foods were observed when fasted, none reached significance in either analysis. Conversely, adiposity was reliably associated with lower reward for sweet, particularly when measured as implicit wanting (p = 0.012, ηp2 = 0.06), independent of metabolic state. However, this significant association was only observed in the linear model. Fat distribution was consistently associated with explicit and implicit preference for high-fat foods. CONCLUSIONS: A limited relationship was demonstrated between obesity severity and food reward in adolescents, although a lower preference for sweet could be a signal of severe obesity in a linear trend. Obesity is likely a heterogenous condition associated with multiple potential phenotypes, which metrics of body composition may help define. CLINICAL TRIAL REGISTRATIONS: NCT02925572: https://classic. CLINICALTRIALS: gov/ct2/show/NCT02925572 . NCT03807609: https://classic. CLINICALTRIALS: gov/ct2/show/NCT03807609 . NCT03742622: https://classic. CLINICALTRIALS: gov/ct2/show/NCT03742622 . NCT03967782: https://classic. CLINICALTRIALS: gov/ct2/show/NCT03967782 . NCT03968458: https://classic. CLINICALTRIALS: gov/ct2/show/NCT03968458 . NCT04739189: https://classic. CLINICALTRIALS: gov/ct2/show/NCT04739189 . NCT05365685: https://www. CLINICALTRIALS: gov/study/NCT05365685?tab=history .