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Abstract Background Interventional trials in amyotrophic lateral sclerosis (ALS) suffer from the heterogeneity of the disease as it considerably reduces statistical power. We asked if blood neurofilament light chains (NfL) could be used to anticipate disease progression and increase trial power. Methods In 125 patients with ALS from three independent prospective studies—one observational study and two interventional trials—we developed and externally validated a multivariate linear model for predicting disease progression, measured by the monthly decrease of the ALS Functional Rating Scale Revised (ALSFRS-R) score. We trained the prediction model in the observational study and tested the predictive value of the following parameters assessed at diagnosis: NfL levels, sex, age, site of onset, body mass index, disease duration, ALSFRS-R score, and monthly ALSFRS-R score decrease since disease onset. We then applied the resulting model in the other two study cohorts to assess the actual utility for interventional trials. We analyzed the impact on trial power in mixed-effects models and compared the performance of the NfL model with two currently used predictive approaches, which anticipate disease progression using the ALSFRS-R decrease during a three-month observational period (lead-in) or since disease onset (ΔFRS). Results Among the parameters provided, the NfL levels (P

The interpretation of the Maintenance Wakefulness Test (MWT) relies on sleep onset detection. However, microsleeps (MSs), i.e., brief periods of sleep intrusion during wakefulness, may occur before sleep onset. We assessed the prevalence of MSs during the MWT and their contribution to the diagnosis of residual sleepiness in patients treated for obstructive sleep apnea (OSA) or hypersomnia. The MWT of 98 patients (89 OSA, 82.6% male) were analyzed for MS scoring. Polysomnography parameters and clinical data were collected. The diagnostic value for detecting sleepiness (Epworth Sleepiness Scale > 10) of sleep onset latency (SOL) and of the first MS latency (MSL) was assessed by the area under the receiver operating characteristic (ROC) curve (AUC, 95% CI). At least one MS was observed in 62.2% of patients. MSL was positively correlated with SOL (r = 0.72, p < 0.0001) but not with subjective scales, clinical variables, or polysomnography parameters. The use of SOL or MSL did not influence the diagnostic performance of the MWT for subjective sleepiness assessment (AUC = 0.66 95% CI (0.56, 0.77) versus 0.63 95% CI (0.51, 0.74)). MSs are frequent during MWTs performed in patients treated for sleep disorders, even in the absence of subjective sleepiness, and may represent physiological markers of the wake-to-sleep transition.

Abstract Background Kennedy’s disease (KD), also known as spinal and bulbar muscular atrophy (SBMA), is a rare, adult-onset, X-linked recessive neuromuscular disease caused by CAG expansions in exon 1 of the androgen receptor gene (AR). The objective of the French national diagnostic and management protocol is to provide evidence-based best practice recommendations and outline an optimised care pathway for patients with KD, based on a systematic literature review and consensus multidisciplinary observations. Results The initial evaluation, confirmation of the diagnosis, and management should ideally take place in a tertiary referral centre for motor neuron diseases, and involve an experienced multidisciplinary team of neurologists, endocrinologists, cardiologists and allied healthcare professionals. The diagnosis should be suspected in an adult male presenting with slowly progressive lower motor neuron symptoms, typically affecting the lower limbs at onset. Bulbar involvement (dysarthria and dysphagia) is often a later manifestation of the disease. Gynecomastia is not a constant feature, but is suggestive of a suspected diagnosis, which is further supported by electromyography showing diffuse motor neuron involvement often with asymptomatic sensory changes. A suspected diagnosis is confirmed by genetic testing. The multidisciplinary assessment should ascertain extra-neurological involvement such as cardiac repolarisation abnormalities (Brugada syndrome), signs of androgen resistance, genitourinary abnormalities, endocrine and metabolic changes (glucose intolerance, hyperlipidemia). In the absence of effective disease modifying therapies, the mainstay of management is symptomatic support using rehabilitation strategies (physiotherapy and speech therapy). Nutritional evaluation by an expert dietician is essential, and enteral nutrition (gastrostomy) may be required. Respiratory management centres on the detection and treatment of bronchial obstructions, as well as screening for aspiration pneumonia (chest physiotherapy, drainage, positioning, breath stacking, mechanical insufflation-exsufflation, cough assist machnie, antibiotics). Non-invasive mechanical ventilation is seldom needed. Symptomatic pharmaceutical therapy includes pain management, endocrine and metabolic interventions. There is no evidence for androgen substitution therapy. Conclusion The French national Kennedy’s disease protocol provides management recommendations for patients with KD. In a low-incidence condition, sharing and integrating regional expertise, multidisciplinary experience and defining consensus best-practice recommendations is particularly important. Well-coordinated collaborative efforts will ultimately pave the way to the development of evidence-based international guidelines.

Background: Candidemia is a major cause of mortality in the intensive care unit (ICU). According to the Infectious Diseases Society of America (IDSA), an echinocandin is recommended as initial therapy and fluconazole as an alternative. In a context of echinocandin resistance development, the question arising is whether azoles are a suitable alternative to echinocandins for the treatment of candidemia in critically ill patients. Methods: A 3-year (2015–2017) retrospective multicentric cohort study was conducted. Adult patients with a diagnosis of candidemia during the ICU stay and treated with echinocandins or azoles were included. Demographic, clinical data, mycological data, and antifungal treatments were collected. Kaplan–Meier survival analysis, univariate analysis, and a multivariate logistic regression analysis using a propensity score with the inverse probability of treatment weighting method were performed. Findings: Seventy-nine patients (n = 79) were analyzed. Treatment success, as well as survival on day 90 (Kaplan–Meier survival analysis, log rank test, p = 0.542), were comparable between patients who received echinocandins (caspofungin (n = 47)) or azoles (fluconazole (n = 29) or voriconazole (n = 3)). A multivariable analysis demonstrated that higher SOFA score on the day of candidemia diagnosis and absence of adequate Candida source control were independently associated with a greater risk of 90-day mortality, whereas azoles treatment was not associated with an excess 90-day mortality. Interpretation: This study confirms that the use of azoles recommended for candidemia, mostly fluconazole, as a first-line therapy is a reasonable alternative to caspofungin for ICU patients in our institution. This needs to be included in local guidelines through antifungal stewardship programs. Keywords: Candidemia, Caspofungin, Fluconazole, Voriconazole, Mortality, Propensity score

Background: The functional reorganization of brain networks sustaining gait is poorly characterized in amyotrophic lateral sclerosis (ALS) despite ample evidence of progressive disconnection between brain regions. The main objective of this fMRI study is to assess gait imagery-specific networks in ALS patients using dynamic causal modeling (DCM) complemented by parametric empirical Bayes (PEB) framework. Method: Seventeen lower motor neuron predominant (LMNp) ALS patients, fourteen upper motor neuron predominant (UMNp) ALS patients and fourteen healthy controls participated in this study. Each subject performed a dual motor imagery task: normal and precision gait. The Movement Imagery Questionnaire (MIQ-rs) and imagery time (IT) were used to evaluate gait imagery in each participant. In a neurobiological computational model, the circuits involved in imagined gait and postural control were investigated by modelling the relationship between normal/precision gait and connection strengths. Results: Behavioral results showed significant increase in IT in UMNp patients compared to healthy controls (Pcorrected

Frontotemporal involvement has been extensively investigated in amyotrophic lateral sclerosis (ALS) but remains relatively poorly characterized in other motor neuron disease (MND) phenotypes such as primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), spinal muscular atrophy (SMA), spinal bulbar muscular atrophy (SBMA), post poliomyelitis syndrome (PPS), and hereditary spastic paraplegia (HSP). This review focuses on insights from structural, metabolic, and functional neuroimaging studies that have advanced our understanding of extra-motor disease burden in these phenotypes. The imaging literature is limited in the majority of these conditions and frontotemporal involvement has been primarily evaluated by neuropsychology and post mortem studies. Existing imaging studies reveal that frontotemporal degeneration can be readily detected in ALS and PLS, varying degree of frontotemporal pathology may be captured in PMA, SBMA, and HSP, SMA exhibits cerebral involvement without regional predilection, and there is limited evidence for cerebral changes in PPS. Our review confirms the heterogeneity extra-motor pathology across the spectrum of MNDs and highlights the role of neuroimaging in characterizing anatomical patterns of disease burden in vivo. Despite the contribution of neuroimaging to MND research, sample size limitations, inclusion bias, attrition rates in longitudinal studies, and methodological constraints need to be carefully considered. Frontotemporal involvement is a quintessential clinical facet of MND which has important implications for screening practices, individualized management strategies, participation in clinical trials, caregiver burden, and resource allocation. The academic relevance of imaging frontotemporal pathology in MND spans from the identification of genetic variants, through the ascertainment of presymptomatic changes to the design of future epidemiology studies.

Therapeutic drug monitoring (TDM) is essential for voriconazole to ensure optimal drug exposure, mainly in critically ill patients for whom voriconazole demonstrated a large variability. The study aimed at describing factors associated with trough voriconazole concentrations in critically ill patients and evaluating the impact of voriconazole concentrations on adverse effects. A 2-year retrospective multicenter cohort study (NCT04502771) was conducted in six intensive care units. Adult patients who had at least one voriconazole TDM were included. Univariable and multivariable linear regression analyses were performed to identify predictors of voriconazole concentrations, and univariable logistic regression analysis, to study the relationship between voriconazole concentrations and adverse effects. During the 2-year study period, 70 patients were included. Optimal trough voriconazole concentrations were reported in 37 patients (52.8%), subtherapeutic in 20 (28.6%), and supratherapeutic in 13 (18.6%). Adverse effects were reported in six (8.6%) patients. SOFA score was identified as a factor associated with an increase in voriconazole concentration (p = 0.025), mainly in the group of patients who had SOFA score ≥ 10. Moreover, an increase in voriconazole concentration was shown to be a risk factor for occurrence of adverse effects (p = 0.011). In that respect, critically ill patients who received voriconazole treatment must benefit from a TDM, particularly if they have a SOFA score ≥ 10. Indeed, identifying patients who are overdosed will help to prevent voriconazole related adverse effects. This result is of utmost importance given the recognized COVID-19-associated pulmonary aspergillosis in ICU patients for whom voriconazole is among the recommended first-line treatment.

Background: Amyotrophic Lateral Sclerosis (ALS) is a relentlessly progressive neurodegenerative condition with limited therapeutic options at present. Survival from symptom onset ranges from 3 to 5 years depending on genetic, demographic, and phenotypic factors. Despite tireless research efforts, the core etiology of the disease remains elusive and drug development efforts are confounded by the lack of accurate monitoring markers. Disease heterogeneity, late-stage recruitment into pharmaceutical trials, and inclusion of phenotypically admixed patient cohorts are some of the key barriers to successful clinical trials. Machine Learning (ML) models and large international data sets offer unprecedented opportunities to appraise candidate diagnostic, monitoring, and prognostic markers. Accurate patient stratification into well-defined prognostic categories is another aspiration of emerging classification and staging systems.Methods: The objective of this paper is the comprehensive, systematic, and critical review of ML initiatives in ALS to date and their potential in research, clinical, and pharmacological applications. The focus of this review is to provide a dual, clinical-mathematical perspective on recent advances and future directions of the field. Another objective of the paper is the frank discussion of the pitfalls and drawbacks of specific models, highlighting the shortcomings of existing studies and to provide methodological recommendations for future study designs.Results: Despite considerable sample size limitations, ML techniques have already been successfully applied to ALS data sets and a number of promising diagnosis models have been proposed. Prognostic models have been tested using core clinical variables, biological, and neuroimaging data. These models also offer patient stratification opportunities for future clinical trials. Despite the enormous potential of ML in ALS research, statistical assumptions are often violated, the choice of specific statistical models is seldom justified, and the constraints of ML models are rarely enunciated.Conclusions: From a mathematical perspective, the main barrier to the development of validated diagnostic, prognostic, and monitoring indicators stem from limited sample sizes. The combination of multiple clinical, biofluid, and imaging biomarkers is likely to increase the accuracy of mathematical modeling and contribute to optimized clinical trial designs.

BackgroundDespite direct-acting antivirals (DAA), aims to "eradicate" viral hepatitis by 2030 remain unlikely. In Nepal, an expert consortium was established to treat HCV through Nepal earthquakes aftermath offering a model for HCV treatment expansion in a resource-poor setting.Methodology/principal findingsIn 2015, we established a network of hepatologists, laboratory experts, and community-based leaders at 6 Opioid Substitution Treatment (OST) sites from 4 cities in Nepal screening 838 patients for a treatment cohort of 600 individuals with HCV infection and past or current drug use. During phase 1, patients were treated with interferon-based regimens (n = 46). During phase 2, 135 patients with optimal predictors (HIV controlled, without cirrhosis, low baseline HCV viral load) were treated with DAA-based regimens. During phase 3, IFN-free DAA treatment was expanded, regardless of HCV disease severity, HIV viremia or drug use. Sustained virologic response (SVR) was assessed at 12 weeks. Median age was 37 years and 95.5% were males. HCV genotype was 3 (53.2%) or 1a (40.7%) and 32% had cirrhosis; 42.5% were HIV-HCV coinfected. The intention-to-treat (ITT) SVR rates in phase 2 and 3 were 97% and 81%, respectively. The overall per-protocol and ITT SVR rates were 97% and 85%, respectively. By multivariable analysis, treatment at the Kathmandu site was protective and substance use, treatment during phase 3 were associated with failure to achieve SVR.Conclusions/significanceVery high SVR rates may be achieved in a difficult-to-treat, low-income population whatever the patient's profile and disease severity. The excellent treatment outcomes observed in this real-life community study should prompt further HCV treatment initiatives in Nepal.

Music-based therapy for rehabilitation induces neuromodulation at the brain level and improves the functional recovery. In line with this, musical rhythmicity improves post-stroke gait. Moreover, an external distractor also helps stroke patients to improve locomotion. We raised the question whether music with irregular tempo (arrhythmic music), and its possible influence on attention would induce neuromodulation and improve the post-stroke gait. We tested music-induced neuromodulation at the level of a propriospinal reflex, known to be particularly involved in the control of stabilized locomotion; after stroke, the reflex is enhanced on the hemiparetic side. The study was conducted in 12 post-stroke patients and 12 controls. Quadriceps EMG was conditioned by electrical stimulation of the common peroneal nerve, which produces a biphasic facilitation on EMG, reflecting the level of activity of the propriospinal reflex between ankle dorsiflexors and quadriceps (CPQ reflex). The CPQ reflex was tested during treadmill locomotion at the preferred speed of each individual, in 3 conditions randomly alternated: without music vs. 2 arrhythmic music tracks, including a pleasant melody and unpleasant aleatory electronic sounds (AES); biomechanical and physiological parameters were also investigated. The CPQ reflex was significantly larger in patients during walking without sound, compared to controls. During walking with music, irrespective of the theme, there was no more difference between groups. In controls, music had no influence on the size of CPQ reflex. In patients, CPQ reflex was significantly larger during walking without sound than when listening to the melody or AES. No significant differences have been revealed concerning the biomechanical and the physiological parameters in both groups. Arrhythmic music listening modulates the spinal excitability during post-stroke walking, restoring the CPQ reflex activity to normality. The plasticity was not accompanied by any clear improvement of gait parameters, but the patients reported to prefer walking with music than without. The role of music as external focus of attention is discussed. This study has shown that music can modulate propriospinal neural network particularly involved in the gait control during the first training session. It is speculated that repetition may help to consolidate plasticity and would contribute to gait recovery after stroke.

PurposeTo investigate the efficacy and tolerance of systemic treatments for the prevention of HLA-B27-associated acute uveitis (AU) recurrence.MethodsRetrospective review of patients with HLA-B27-associated uveitis followed in our tertiary center over a 15-year period. Systemic treatments were prescribed to patients with frequent (more than 2 flares per year) or severe uveitis, according to a step-up strategy.Results101 patients (51.5% of men, 88.1% of white Europeans) with a median age of 37 years. AU was mostly recurrent (68.3%) and associated with spondyloarthritis (60.4%). After a median follow-up duration of 22 months (3-73), 37.6% of the patients have received systemic treatment. 88.5% of the patients have been treated with sulfasalazine (SSZ) for ophthalmologic purposes (23/26). Methotrexate (MTX) and anti-TNFα agents have been initiated for a rheumatologic indication in 81.8% (9/11) and 100% of the patients (13/13), respectively. The annual uveitis relapse rate significantly decreased on SSZ (0.37 recurrences/year versus baseline 2.46 recurrences/year; pConclusionWe report an open-label strategy to prevent the recurrences of HLA-B27-associated AU. First-line sulfasalazine reduced uveitis relapses. The use of anti-TNFα agents for ophthalmologic purposes was unnecessary with rare exceptions.

Extracellular vesicles can mediate communication between tissues, affecting the physiological conditions of recipient cells. They are increasingly investigated in Amyotrophic Lateral Sclerosis, the most common form of Motor Neurone Disease, as transporters of misfolded proteins including SOD1, FUS, TDP43, or other neurotoxic elements, such as the dipeptide repeats resulting from C9orf72 expansions. EVs are classified based on their biogenesis and size and can be separated by differential centrifugation. They include exosomes, released by the fusion of multivesicular bodies with the plasma membrane, and ectosomes, also known as microvesicles or microparticles, resulting from budding or pinching of the plasma membrane. In the current study, EVs were obtained from the myotube cell culture medium of ALS patients or healthy controls. EVs of two different sizes, separating at 20,000 or 100,000 g, were then compared in terms of their effects on recipient motor neurons, astrocytes, and myotubes. Compared to untreated cells, the smaller, exosome-like vesicles of ALS patients reduced the survival of motor neurons by 31% and of myotubes by 18%, decreased neurite length and branching, and increased the proportion of stellate astrocytes, whereas neither those of healthy subjects, nor larger EVs of ALS or healthy subjects, had such effects.

Abstract Background The majority of patients undergoing hepatectomy for hepatocellular carcinoma (HCC) suffer from underlying liver disease and are exposed to the risk of postoperative ascites, which is favored by an imbalance between portal venous inflow and a diminished hepatic volume. Finding a reversible, non-invasive method for modulating the portal inflow would be of interest as it could be used temporarily during the early postoperative course. Somatostatin, a well-known drug already used in several indications, may limit the risk of postoperative ascites and liver failure by decreasing portal pressure after hepatectomy for HCC in patients with underlying liver disease. We aimed to evaluate the impact of somatostatin postoperative infusion on the incidence of ascites following hepatectomy by laparotomy for HCC in patients with underlying liver disease. Methods/design The SOMAPROTECT study is a multicenter randomized double-blind placebo controlled phase III trial comparing two arms of patients with underlying liver disease undergoing hepatectomy for HCC by open approach. All patients will have primary abdominal drainage before closure. Patients in the experimental arm will receive a postoperative intravenous infusion of somatostatin during 6 days. Patients in the control group will receive a placebo infusion for the same duration. The primary endpoint will be the presence or absence of postoperative ascites occurring during the 90-day postoperative course, defined as ≥500 ml/24 h of fluid in the drains during at least 3 days or any ascites requiring an invasive procedure comprising percutaneous puncture or drainage. Secondary endpoints will be duration and total volume of ascites, postoperative 90-day mortality and morbidity, liver failure, acute renal failure, length of stay in intensive care unit and hospital stay. The total number of patients to be enrolled was calculated to be 152. Discussion Postoperative ascites remains a major issue after hepatectomy for HCC as it is associated with increased morbidity, liver and renal failure, the need for specific treatments and prolonged hospital stay. This study represents the first randomized controlled trial to assess the benefits of somatostatin on the risk of postoperative ascites after surgery for HCC. Trial registration NCT02799212 (ClinicalTrials.gov identifier). Registered prior to conducting the research on 9 June 2016.

The research on the site of the urban development zone “Saint Eutrope”, Escrennes, some kilometers south of Pithiviers, allowed the discovering of a first Iron age settlement. The main remains are around thirty silos with complex fills, as well as nine houses or granaries. The many ceramic furniture give evidences of the continuation of the occupation from Hallstatt D1 to Hallstatt D3, and its developpment. The archéozoologic study brings a lot of information concerning the agro-pastoral practices and allow to follow partially the evolution of the breeding. The increase of the meat-based consumption and a more important implication of the pork are two examples of these variations. Finally, the carpological study complete the information already collected regionally for the end of first Iron age and the beginning of la Tène, allowing to place the site of Escrennes in a homogeneous regional dynamic.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder causing a progressive motor weakness of all voluntary muscles, whose progression challenges communication modalities such as handwriting or speech. The current study investigated whether ALS subjects can use Eye-On-Line (EOL), a novel eye-operated communication device allowing, after training, to voluntarily control smooth-pursuit eye-movements (SPEM) so as to eye-write in cursive. To that aim, ALS participants (n = 12) with preserved eye-movements but impaired handwriting were trained during six on-site visits. The primary outcome of the study was the recognition of eye-written digits (0–9) from ALS and healthy control subjects by naïve “readers.” Changes in oculomotor performance and the safety of EOL were also evaluated. At the end of the program, 69.4% of the eye-written digits from 11 ALS subjects were recognized by naïve readers, similar to the 67.3% found for eye-written digits from controls participants, with however, large inter-individual differences in both groups of “writers.” Training with EOL was associated with a transient fatigue leading one ALS subject to drop out the study at the fifth visit. Otherwise, itching eyes was the most common adverse event (3 subjects). This study shows that, despite the impact of ALS on the motor system, most ALS participants could improve their mastering of eye-movements, so as to produce recognizable eye-written digits, although the eye-traces sometimes needed smoothing to ease digit legibility from both ALS subjects and control participants. The capability to endogenously and voluntarily generate eye-traces using EOL brings a novel way to communicate for disabled individuals, allowing creative personal and emotional expression.

Purpose: People with traumatic brain injury are frequently involved in a litigation because another person was at fault for causing the accident. A compensation amount will often be settled to compensate the victim for the past, present, future damages and losses suffered. We report descriptive data about the full and final personal compensation amount and investigated its association with patient's outcomes.Methods: We used a longitudinal prospective study of severe TBI patients injured in 2005–2007 (PariS-TBI). Questions regarding involvement in a litigation were asked concurrently with 4 and 8-year outcomes.Results: Among 160 participants assessed 4 and/or 8 years post-injury, a total of 67 persons declared being involved in a litigation, among which 38 people reported a compensation amount of a mean €292,653 (standard deviation = 436,334; interquartile 25–50–75 = 37,000–100,000–500,000; minimum = 1,500-maximum = 2,000,000). A higher compensation amount was associated with more severe disability and cognitive impairment in patients, and with more informal care time provided by caregivers. However, no significant association related to patient's gender, age, years of education, motor/balance impairment, return to work status, mood and related to caregiver's subjective burden was found.Conclusion: Financial compensation was related to victims' long-term severity of impairment, although some extreme cases with severe disability were granted very poor compensation.

Amyotrophic lateral sclerosis (ALS) is the most common adult onset motor neuron disease with no effective disease modifying therapies at present. Spinal cord degeneration is a hallmark feature of ALS, highlighted in the earliest descriptions of the disease by Lockhart Clarke and Jean-Martin Charcot. The anterior horns and corticospinal tracts are invariably affected in ALS, but up to recently it has been notoriously challenging to detect and characterize spinal pathology in vivo. With recent technological advances, spinal imaging now offers unique opportunities to appraise lower motor neuron degeneration, sensory involvement, metabolic alterations, and interneuron pathology in ALS. Quantitative spinal imaging in ALS has now been used in cross-sectional and longitudinal study designs, applied to presymptomatic mutation carriers, and utilized in machine learning applications. Despite its enormous clinical and academic potential, a number of physiological, technological, and methodological challenges limit the routine use of computational spinal imaging in ALS. In this review, we provide a comprehensive overview of emerging spinal cord imaging methods and discuss their advantages, drawbacks, and biomarker potential in clinical applications, clinical trial settings, monitoring, and prognostic roles.

Objective: Limitations with manual dexterity are an important problem for patients suffering from hemiparesis post stroke. Sensorimotor deficits, compensatory strategies and the use of alternative grasping configurations may influence the efficiency of prehensile motor behavior. The aim of the present study is to examine how different grasp configurations affect patient ability to regulate both grip forces and object orientation when lifting, holding and placing an object.Methods: Twelve stroke patients with mild to moderate hemiparesis were recruited. Each was required to lift, hold and replace an instrumented object. Four different grasp configurations were tested on both the hemiparetic and less affected arms. Load cells from each of the 6 faces of the instrumented object and an integrated inertial measurement unit were used to extract data regarding the timing of unloading/loading phases, regulation of grip forces, and object orientation throughout the task.Results: Grip forces were greatest when using a palmar-digital grasp and lowest when using a top grasp. The time delay between peak acceleration and maximum grip force was also greatest for palmar-digital grasp and lowest for the top grasp. Use of the hemiparetic arm was associated with increased duration of the unloading phase and greater difficulty with maintaining the vertical orientation of the object at the transitions to object lifting and object placement. The occurrence of touch and push errors at the onset of grasp varied according to both grasp configuration and use of the hemiparetic arm.Conclusion: Stroke patients exhibit impairments in the scale and temporal precision of grip force adjustments and reduced ability to maintain object orientation with various grasp configurations using the hemiparetic arm. Nonetheless, the timing and magnitude of grip force adjustments may be facilitated using a top grasp configuration. Conversely, whole hand prehension strategies compound difficulties with grip force scaling and inhibit the synchrony of grasp onset and object release.

Background and aims: Severe traumatic brain injury is a leading cause of acquired persistent disabilities, and represents an important health and economic burden. However, the determinants of long-term outcome have rarely been systematically studied in a prospective longitudinal study of a homogeneous group of patients suffering exclusively from severe TBIMethods: Prospective observational study of an inception cohort of adult patients with severe traumatic brain injury in the Parisian area (PariS-TBI). Outcome was assessed with face-to-face interview 8 years after Traumatic Brain Injury, focusing on impairments, activity limitations, and participation restriction.Results: Five hundred and four patients were included between 2005 and 2007. At 8-year follow-up, 261 patients were deceased, 128 were lost to follow-up, 22 refused to participate, and 86 were finally evaluated. Age, gender, initial injury severity did not significantly differ between evaluated patients and lost to follow-up, but the latter were more frequently students or unemployed. Mean age was 41.9 (SD 13.6), 79% were male, median initial Glasgow Coma Scale Score was 6. The most frequent somatic complaints concerned balance (47.5%), motricity (31%), and headaches (36%), but these were less frequent than cognitive complaints (Memory 71%, Slowness 68%, Concentration 67%). According to the Hospital Anxiety and Depression Scale (HADS), 25 % had a score >8 for anxiety and 23.7% for depression. According to the Extended Glasgow Outcome Scale, 19.8% remained severely disabled, 46.5% moderately disabled, 33.7% had a good recovery. Older age, longer education duration, lower functional status upon intensive care discharge, and more severe 8-year dysexecutive problems were significantly associated with a lower Extended Glasgow Outcome Scale score in multivariable analysis. At 8 years, 48.7% of patients were employed in a productive job. Of those, 38% declared a salary loss since traumatic brain injury. Unemployment was significantly associated with lower 1-year GOSE score and more severe 8-year dysexecutive problems.Conclusions: These results from an inception cohort study highlight the fact that long-term outcome after severe TBI is determined by a complex combination of injury-related, demographic and neuropsychological factors. Long after the injury, persisting impairments still interfere with social integration, and participation.

Spinal muscular atrophy (SMA) type III and IV are autosomal recessive, slowly progressive lower motor neuron syndromes. Nevertheless, wider cerebral involvement has been consistently reported in mouse models. The objective of this study is the characterisation of spinal and cerebral pathology in adult forms of SMA using multimodal quantitative imaging. Methods: Twenty-five type III and IV adult SMA patients and 25 age-matched healthy controls were enrolled in a spinal cord and brain imaging study. Structural measures of grey and white matter involvement and diffusion parameters of white matter integrity were evaluated at each cervical spinal level. Whole-brain and region-of-interest analyses were also conducted in the brain to explore cortical thickness, grey matter density and tract-based white matter alterations. Results: In the spinal cord, considerable grey matter atrophy was detected between C2-C6 vertebral levels. In the brain, increased grey matter density was detected in motor and extra-motor regions of SMA patients. No white matter pathology was identified neither at brain and spinal level. Conclusions: Adult forms of SMA are associated with selective grey matter degeneration in the spinal cord with preserved white matter integrity. The observed increased grey matter density in the motor cortex may represent adaptive reorganisation. Keywords: Spinal muscular atrophy, SMA, Multimodal MRI, Spinal cord MRI, Grey matter and white matter degeneration

Biomarkers research in amyotrophic lateral sclerosis (ALS) holds the promise of improving ALS diagnosis, follow-up of patients, and clinical trials outcomes. Metabolomics have a big impact on biomarkers identification. In this mini-review, we provide the main findings of metabolomics studies in ALS and discuss the most relevant therapeutics attempts that targeted some prominent alterations found in ALS, like glutamate excitotoxicity, oxidative stress, alterations in energetic metabolism, and creatinine levels. Metabolomics studies have reported putative diagnosis or prognosis biomarkers, but discrepancies among these studies did not allow validation of metabolic biomarkers for clinical use in ALS. In this context, we wonder whether metabolomics knowledge could improve ALS therapeutics. As metabolomics identify specific metabolic pathways modified by disease progression and/or treatment, we support that adjuvant or combined treatment should be used to rescue these pathways, creating a new perspective for ALS treatment. Some ongoing clinical trials are already trying to target these pathways. As clinical trials in ALS have been disappointing and considering the heterogeneity of the disease presentation, we support the application of a pharmacometabolomic approach to evaluate the individual response to drug treatments and their side effects, enabling the development of personalized treatments for ALS. We suggest that the best strategy to apply metabolomics for ALS therapeutics progress is to establish a metabolic signature for ALS patients in order to improve the knowledge of patient metabotypes, to choose the most adequate pharmacological treatment, and to follow the drug response and side effects, based on metabolomics biomarkers.

Background: Fortification of human milk (HM) increases its osmolality, which is associated with an increased risk of necrotizing enterocolitis. The impact of new fortifiers on osmolality is not well-known, nor are the kinetics regarding the increase in osmolality.Aim: To determine the optimum fortifier composition for HM fortification by measuring the osmolality of fortified HM made with three powder multicomponent fortifiers (MCFs) and a protein fortifier (PF).Methods: The osmolality of HM was assessed at 2 (H2) and 24 (H24) h after fortification to compare the effects of MCF (MCF1–3) and PF used in quantities that ensured that infants' nutrient needs would be met (MCF: 4 g/100 ml HM; PF: 0.5 g or 1 g/100 ml HM). To evaluate the early kinetics associated with the osmolality increase, the osmolality of HM fortified with MCF1 or MCF2 was also measured at 0, 1, 5, 10, 15, 20, 30, 40, 50, 60, 90, and 120 min after fortification.Results: The osmolality increased significantly immediately after fortification, depending on the type of fortification used and the quantity of MCF and PF used, rather than the time elapsed after fortification. The maximum value at H24 was 484 mOsm/kg. The mean increase in osmolality between H2 and H24 was 3.1% (p < 0.01) (range: 0.2–10.8%). Most of the increase (>70%) occurred immediately after fortification.Conclusion: When choosing a fortifier, its effect on HM osmolality should be considered. As most of the increase in osmolality occurred immediately, bedside fortification is not useful to prevent the increase in osmolality, and further research should focus on improving fortifier composition.

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is a rare, X-linked, late onset neuromuscular disorder. The disease is caused by a CAG trinucleotide repeat expansion in the first exon of the androgen receptor gene. It is characterized by slowly progressive lower motor neurons degeneration, primary myopathy and widespread multisystem involvement. Respiratory involvement is rare, and the condition is associated with a normal life expectancy. Despite a plethora of therapeutic studies in mouse models, no effective disease-modifying therapy has been licensed for clinical use to date. The development of sensitive monitoring markers for the particularly slowly progressing pathology of SBMA is urgently required to aid future clinical trials. A small number of outcome measures have been proposed recently, including promising biochemical markers, which show correlation with clinical disability and disease-stage and progression. Nevertheless, a paucity of SBMA-specific biomarker studies persists, delaying the development of monitoring markers for pharmaceutical trials. Collaborative efforts through international consortia and multicenter registries are likely to contribute to the characterization of the natural history of the condition, the establishment of disease-specific biomarker panels and ultimately contribute to the development of disease-modifying drugs.

In 2010, a rescue excavation in advance of road widening took place at Neuvy-Pailloux (Indre) over a 5 745 square yards area. Roman rural settlement with necroplis was partially uncovered. Ditches and fences delimiting narrow plots are the main finds. Buildings identified are related to both housing and agricultural activities. The plan of one of these buildings is very similar to those of barns located in the Villa’s pars rustica. Several built enclosures with cremations illustrate the burial ground.The archaeological environment of the site is peculiar as, in a radius of 100 m, a late La Tène moated enclosure, an aristocratic burial circa 40-50 AD attached to the Fléré-La-Riviere’s group, and a Villa with peristyle of the 2nd and 3rd century AD have been identified. The study of these remains confirms that they are related. Results from the excavation specify the chronology of human settlements in this area and complete the data concerning the exploitation of the land attached to the Villa.

Hepatitis delta virus (HDV) increases morbidity in Hepatitis B virus (HBV)-infected patients. In the mid-eighties, an outbreak of HDV fulminant hepatitis (FH) in the Central African Republic (CAR) killed 88% of patients hospitalized in Bangui. We evaluated infections with HBV and HDV among students and pregnant women, 25 years after the fulminant hepatitis (FH) outbreak to determine (i) the prevalence of HBV and HDV infection in this population, (ii) the clinical risk factors for HBV and/or HDV infections, and (iii) to characterize and compare the strains from the FH outbreak in the 1980s to the 2010 HBV-HDV strains. We performed a cross sectional study with historical comparison on FH-stored samples (n = 179) from 159 patients and dried blood-spots from volunteer students and pregnant women groups (n = 2172). We analyzed risk factors potentially associated with HBV and HDV. Previous HBV infection (presence of anti-HBc) occurred in 345/1290 students (26.7%) and 186/870 pregnant women (21.4%)(p = 0.005), including 110 students (8.8%) and 71 pregnant women (8.2%), who were also HBsAg-positive (p = 0.824). HDV infection occurred more frequently in pregnant women (n = 13; 18.8%) than students (n = 6; 5.4%) (p = 0.010). Infection in childhood was probably the main HBV risk factor. The risk factors for HDV infection were age (p = 0.040), transfusion (p = 0.039), and a tendency for tattooing (p = 0.055) and absence of condom use (p = 0.049). HBV-E and HDV-1 were highly prevalent during both the FH outbreak and the 2010 screening project. For historical samples, due to storage conditions and despite several attempts, we could only obtain partial HDV amplification representing 25% of the full-length genome. The HDV-1 mid-eighties FH-strains did not form a specific clade and were affiliated to two different HDV-1 African subgenotypes, one of which also includes the 2010 HDV-1 strains. In the Central African Republic, these findings indicate a high prevalence of previous and current HBV-E and HDV-1 infections both in the mid-eighties fulminant hepatitis outbreak and among asymptomatic young adults in 2010, and reinforce the need for universal HBV vaccination and the prevention of HDV transmission among HBsAg-positive patients through blood or sexual routes.

There is an urgent and unmet need for accurate biomarkers in Amyotrophic Lateral Sclerosis. A pharmaco-metabolomics study was conducted using plasma samples from the TRO19622 (olesoxime) trial to assess the link between early metabolomic profiles and clinical outcomes. Patients included in this trial were randomized into either Group O receiving olesoxime (n = 38) or Group P receiving placebo (n = 36). The metabolomic profile was assessed at time-point one (V1) and 12 months (V12) after the initiation of the treatment. High performance liquid chromatography coupled with tandem mass spectrometry was used to quantify 188 metabolites (Biocrates® commercial kit). Multivariate analysis based on machine learning approaches (i.e. Biosigner algorithm) was performed. Metabolomic profiles at V1 and V12 and changes in metabolomic profiles between V1 and V12 accurately discriminated between Groups O and P (p