Patterns of ketamine use among people with substance use disorder in France: Multisource analysis of the data from the French Addictovigilance Network.

BACKGROUND: Due to its psychoactive effects, ketamine has become a drug used for non-medical purpose. OBJECTIVES: To assess the latest trends in ketamine use among people with substance use disorder and to characterize its clinical complications using complementary health data sources of the French Addictovigilance Network. METHODS: First, we extracted all reports involving ketamine from 2012 to 2021 from the database of the OPPIDUM program (i.e., a multicentric program conducted in collaboration with hundreds of substance abuse treatment facilities that collects data on drugs used by subjects with substance use disorders). We described the reports globally and the changes from 2012 to 2021. Second, we extracted all cases involving ketamine from July 2020 to December 2022 from the French National Pharmacovigilance Database (BNPV). We identified the cases related to ketamine use among people with substance use disorder and described them. RESULTS: There was a 2.5-fold increase in the number of ketamine users with substance use disorder in the OPPIDUM program, from 35 (0.7%) subjects in 2012 to 89 (1.7%) subjects in 2021. There was an increase in the proportion of subjects who were daily users, had distress upon discontinuation, and presented addiction. There were 238 cases related to ketamine use among people with substance use disorder in the French National Pharmacovigilance Database from July 2020 to December 2022. Among them, 94 (39.5%) cases involved ketamine use disorder, 20 (8.4%) cases involved urinary tract and kidney symptoms, and 13 (5.5%) cases involved hepatobiliary symptoms. CONCLUSION: The trend observed over 10 years reflects the growth in ketamine use among people with substance use disorder, although it does not allow to estimate the rates of non-medical use of ketamine in the general population. Ketamine-induced uropathy and cholangiopathy are reported in ketamine users with substance use disorder, especially in case of repeated and/or prolonged use of high doses.

ß-Lactam Pharmacokinetic/Pharmacodynamic Target Attainment in Intensive Care Unit Patients: A Prospective, Observational, Cohort Study.

BACKGROUND: The aims of this study were to describe pharmacokinetic/pharmacodynamic target attainment in intensive care unit (ICU) patients treated with continuously infused ß-lactam antibiotics, their associated covariates, and the impact of dosage adjustment. METHODS: This prospective, observational, cohort study was performed in three ICUs. Four ß-lactams were continuously infused, and therapeutic drug monitoring (TDM) was performed at days 1, 4, and 7. The primary pharmacokinetic/pharmacodynamic target was an unbound ß-lactam plasma concentration four times above the bacteria's minimal inhibitory concentration during the whole dosing interval. The demographic and clinical covariates associated with target attainment were evaluated. RESULTS: A total of 170 patients were included (426 blood samples). The percentages of empirical ß-lactam underdosing at D1 were 66% for cefepime, 43% for cefotaxime, 47% for ceftazidime, and 14% for meropenem. Indexed creatinine clearance was independently associated with treatment underdose if increased (adjusted odds ratio per unit, 1.01; 95% CI, 1.00 to 1.01; p = 0.014) or overdose if decreased (adjusted odds ratio per unit, 0.95; 95% CI, 0.94 to 0.97; p < 0.001). Pharmacokinetic/pharmacodynamic target attainment was significantly increased after ß-lactam dosage adjustment between day 1 and day 4 vs. no adjustment (53.1% vs. 26.2%; p = 0.018). CONCLUSIONS: This study increases our knowledge on the optimization of ß-lactam therapy in ICU patients. A large inter- and intra-patient variability in plasmatic concentrations was observed, leading to inadequate exposure. A combined indexed creatinine clearance and TDM approach enables adequate dosing for better pharmacokinetic/pharmacodynamic target attainment.

Is increased myocardial triglyceride content associated with early changes in left ventricular function? A 1H-MRS and MRI strain study.

Background: Type 2 diabetes (T2D) and obesity induce left ventricular (LV) dysfunction. The underlying pathophysiological mechanisms remain unclear, but myocardial triglyceride content (MTGC) could be involved. Objectives: This study aimed to determine which clinical and biological factors are associated with increased MTGC and to establish whether MTGC is associated with early changes in LV function. Methods: A retrospective study was conducted using five previous prospective cohorts, leading to 338 subjects studied, including 208 well-phenotyped healthy volunteers and 130 subjects living with T2D and/or obesity. All the subjects underwent proton magnetic resonance spectroscopy and feature tracking cardiac magnetic resonance imaging to measure myocardial strain. Results: MTGC content increased with age, body mass index (BMI), waist circumference, T2D, obesity, hypertension, and dyslipidemia, but the only independent correlate found in multivariate analysis was BMI (p=0.01; R²=0.20). MTGC was correlated to LV diastolic dysfunction, notably with the global peak early diastolic circumferential strain rate (r=-0.17, p=0.003), the global peak late diastolic circumferential strain rate (r=0.40, p<0.0001) and global peak late diastolic longitudinal strain rate (r=0.24, p<0.0001). MTGC was also correlated to systolic dysfunction via end-systolic volume index (r=-0.34, p<0.0001) and stroke volume index (r=-0.31, p<0.0001), but not with longitudinal strain (r=0.009, p=0.88). Interestingly, the associations between MTGC and strain measures did not persist in multivariate analysis. Furthermore, MTGC was independently associated with LV end-systolic volume index (p=0.01, R²=0.29), LV end-diastolic volume index (p=0.04, R²=0.46), and LV mass (p=0.002, R²=0.58). Conclusions: Predicting MTGC remains a challenge in routine clinical practice, as only BMI independently correlates with increased MTGC. MTGC may play a role in LV dysfunction but does not appear to be involved in the development of subclinical strain abnormalities.

Tocilizumab versus anakinra in COVID-19: results from propensity score matching.

Background: Tocilizumab and anakinra are anti-interleukin drugs to treat severe coronavirus disease 2019 (COVID-19) refractory to corticosteroids. However, no studies compared the efficacy of tocilizumab versus anakinra to guide the choice of the therapy in clinical practice. We aimed to compare the outcomes of COVID-19 patients treated with tocilizumab or anakinra. Methods: Our retrospective study was conducted in three French university hospitals between February 2021 and February 2022 and included all the consecutive hospitalized patients with a laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection assessed by RT-PCR who were treated with tocilizumab or anakinra. A propensity score matching was performed to minimize confounding effects due to the non-random allocation. Results: Among 235 patients (mean age, 72 years; 60.9% of male patients), the 28-day mortality (29.4% vs. 31.2%, p = 0.76), the in-hospital mortality (31.7% vs. 33.0%, p = 0.83), the high-flow oxygen requirement (17.5% vs. 18.3%, p = 0.86), the intensive care unit admission rate (30.8% vs. 22.2%, p = 0.30), and the mechanical ventilation rate (15.4% vs. 11.1%, p = 0.50) were similar in patients receiving tocilizumab and those receiving anakinra. After propensity score matching, the 28-day mortality (29.1% vs. 30.4%, p = 1) and the rate of high-flow oxygen requirement (10.1% vs. 21.5%, p = 0.081) did not differ between patients receiving tocilizumab or anakinra. Secondary infection rates were similar between the tocilizumab and anakinra groups (6.3% vs. 9.2%, p = 0.44). Conclusion: Our study showed comparable efficacy and safety profiles of tocilizumab and anakinra to treat severe COVID-19.

Primary Non-Aortic Lesions Are Not Rare in Marfan Syndrome and Are Associated with Aortic Dissection Independently of Age.

PURPOSE: The study sought to estimate the prevalence of primary non-aortic lesions (PNAL) unrelated to extension of aortic dissection (AD) in a cohort of patients with Marfan syndrome (MFS). METHODS: Adult patients presenting with pathogenic FBN1 mutations and an available pan-aortic contrast-enhanced CTA in eight French MFS clinics from April to October 2018 were included. Clinical and radiological data, particularly the presence of aortic lesions and PNAL (including aneurysm and ectasia), were retrospectively analyzed. RESULTS: Out of 138 patients, 28 (20.3%) had PNAL. In total, 27 aneurysms in 13 patients and 41 ectasias in 19 patients were reported mainly in the subclavian, iliac, and vertebral segments. Four patients (31%) with aneurysms and none with ectasia required prophylactic intervention during follow-up (median: 46 months). In multivariate analysis, factors associated with PNAL were history of AD (OR = 3.9, 95%CI: 1.3-12.1, p = 0.018), history of previous descending aortic surgery (OR = 10.3, 95%CI: 2.2-48.3, p = 0.003) and age (per 10 years OR = 1.6, 95%CI: 1.1-2.4, p = 0.008). CONCLUSION: PNAL is not rare in MFS patients with evolutive aortic disease. Natural history may differ between aneurysms and ectasia, emphasizing the need for standardized definitions and systematic screening for PNAL.

Categorization of patients with systemic lupus erythematosus using disease activity, patient-reported outcomes, and transcriptomic signatures.

OBJECTIVE: Patients with systemic lupus erythematosus (SLE) display symptoms that are not always related to disease activity and may distort clinical trial results. Recently, a clinical categorization based on the presence of type 1 (inflammatory manifestations) and/or type 2 (widespread pain, fatigue, depression) symptoms has been proposed in SLE. Our aim was to develop a type 2 score derived from the Short-Form health survey (SF-36) to categorize SLE patients and to compare immunological and transcriptomic profiles between groups. METHOD: Seventeen items from the SF-36 were selected to build a type 2 score for 50 SLE patients (100 visits; LUPUCE cohort), and the SLEDAI was used to define type 1 symptoms. Patients were categorized into four groups: minimal (no symptoms), type 1, type 2, and mixed (both type 1 and type 2 symptoms). Clinical, immunological, and transcriptomic profiles were compared between the groups. RESULTS: Type 2 scores ranged from 0 to 31, with a cutoff value of 14 (75th percentile). The sample categorization was minimal in 39%, type 1 in 37%, and type 2 in 9%, and mixed in 15%. Type 2 patients were older than minimal patients and had a longer disease duration than type 1 and mixed patients. Immunological data and modular interferon signatures did not differ between the groups. CONCLUSION: Patients with SLE can be categorized into four clinical groups using the SLEDAI score and our SF-36-derived type 2 score. This categorization is non-redundant with immunological or transcriptomic profiles and could prove useful to stratify patients in clinical trials. Key Points • A score derived from selected items of the SF-36 can be used to identify SLE patients with type 2 symptoms according to the Duke University categorization. • Using the SLEDAI and this type 2 score, SLE patients can be categorized into four clinical groups. • This categorization is not related to immunological activity or blood transcriptome profiles (and not to the interferon signature in particular). • This categorization could be useful in the daily care of patients as well as in clinical trials, for upstream patient stratification or for the interpretation of results.

Riluzole for treating spasticity in patients with chronic traumatic spinal cord injury: Study protocol in the phase ib/iib adaptive multicenter randomized controlled RILUSCI trial.

BACKGROUND: Satisfactory treatment is often lacking for spasticity, a highly prevalent motor disorder in patients with spinal cord injury (SCI). Low concentrations of riluzole potently reduce the persistent sodium current, the post-SCI increase in which contributes to spasticity. The repurposing of this drug may therefore constitute a useful potential therapeutic option for relieving SCI patients suffering from chronic traumatic spasticity. OBJECTIVE: RILUSCI is a phase 1b-2b trial designed to assess whether riluzole is a safe and biologically effective means of managing spasticity in adult patients with traumatic chronic SCI. METHODS: In this multicenter double-blind trial, adults (aged 18-65 years) suffering from spasticity after SCI (target enrollment: 90 participants) will be randomly assigned to be given either a placebo or a recommended daily oral dose of riluzole for two weeks. The latter dose will be previously determined in phase 1b of the study by performing double-blind dose-finding tests using a Bayesian continuous reassessment method. The primary endpoint of the trial will be an improvement in the Modified Ashworth Score (MAS) or the Numerical Rating Score (NRS) quantifying spasticity. The secondary outcomes will be based on the safety and pharmacokinetics of riluzole as well as its impact on muscle spasms, pain, bladder dysfunction and quality of life. Analyses will be performed before, during and after the treatment and the placebo-controlled period. CONCLUSION: To the best of our knowledge, this clinical trial will be the first to document the safety and efficacy of riluzole as a means of reducing spasticity in patients with chronic SCI. TRIAL REGISTRATION: The clinical trial, which is already in progress, was registered on the ClinicalTrials.gov website on August 9, 2016 under the registration number NCT02859792. TRIAL SPONSOR: Assistance Publique-Hôpitaux de Marseille.

Developing and Validating an Individual-Level Deprivation Index for Children's Health in France.

BACKGROUND: Deprivation generates many health inequalities. This has to be taken in account to enhance appropriate access to care. This study aimed to develop and validate a pediatric individual-level index measuring deprivation, usable in clinical practice and in public health. METHODS: The French Individual Child Deprivation Index (FrenChILD-Index) was designed in four phases: item generation then reduction using the literature review and expert opinions, and index derivation then validation using a cross-sectional study in two emergency departments. During these last two phases, concordance with a blinded evaluation by an expert enabled us to determine thresholds for two levels of moderate and severe deprivation. RESULTS: The generation and reduction phases retained 13 items. These were administered to 986 children for the derivation and validation phases. In the validation phase, the final 12 items of the FrenChILD-Index showed for moderate deprivation (requiring single specific care for deprived children) a sensitivity of 96.0% [92.6; 98.7] and specificity of 68.3% [65.2; 71.4]. For severe deprivation (requiring a multidisciplinary level of care), the sensitivity was 96.3% [92.7; 100] and specificity was 91.1% [89.2; 92.9]. CONCLUSIONS: The FrenChILD-Index is the first pediatric individual-level index of deprivation validated in Europe. It enables clinical practice to address the social determinants of health and meet public health goals.

Intra Articular Injection of Autologous Microfat and Platelets-Rich Plasma in the Treatment of Wrist Osteoarthritis: A Pilot Study.

No injection treatment has been proven to be effective in wrist osteoarthritis. When conservative measures fail, its management involves invasive surgery. Emergence of biotherapies based on adipose derived stem cells (ADSC) offers promising treatments for chondral degenerative diseases. Microfat (MF) and platelets-rich plasma (PRP) mixture, rich in growth factors and ADSC could be a minimally invasive injectable option in the treatment of wrist osteoarthritis. The aim of this uncontrolled prospective study was to evaluate the safety of a 4 mL autologous MF-PRP intra-articular injection, performed under local anesthesia. The secondary purpose was to describe the clinical and MRI results at 12 months of follow-up. Patients' data collected were: occurrence of adverse effects, Visual analog scale (VAS), Disabilities of the Arm, Shoulder and Hand score (DASH) and Patient-Rated Wrist Evaluation (PRWE) scores, wrist strength, wrist range of motion and 5-level satisfaction scale. No serious adverse event was recorded. A statistically significant decrease in pain, DASH, PRWE and force was observed at each follow-up. Our preliminary results suggest that intra-articular autologous MF and PRP injection may be a new therapeutic strategy for wrist osteoarthritis resistant to medical symptomatic treatment prior to surgical interventions.

Tap Water Consumption Is Associated with Schoolchildren's Cognitive Deficits in Afghanistan.

Environmental influence on intelligence quotient (IQ) is poorly understood in developing countries. We conducted the first cross-sectional investigation to assess the role of socio-economic and environmental factors on schoolchildren's IQ in Jalalabad, Afghanistan. A representative sample of 245 schoolchildren aged 7-15 was randomly selected in five schools. Children's records included: non-verbal IQ TONI-1 scale, body mass index, socio-economic status, and further environmental indicators (water supply, proximity to a heavy-traffic road, use of surma traditional cosmetics). The mean age of the children was 11.7 years old (±2.0 years), and 70.2% and 29.8% were male and female, respectively. The children's mean IQ was 83.8 (±12.6). In total, 37 (14.9%) of the children were overweight, 78 (31.5%) were living below the USD 1.25 poverty line, 133 (53.6%) used tap water supply, 76 (30.6%) used surma, and 166 (66.9%) were exposed to heavy road traffic. The children's IQ was significantly and independently lowered by tap water use (-3.9; 95% CI [-7.1; -0.6]) and by aging (-1.4; 95% CI [-2.2; -0.6]), as revealed in multivariate analysis, independently of gender, socio-economic status, exposure to heavy road traffic, overweight status, and surma use. Lower IQ among older children is possibly attributed to chronic stress experienced by adolescents due to living conditions in Afghanistan. While using tap water prevents fecal peril, it may expose children to toxic elements such as lead which is known to lower their intellectual development.

What Do We Know About Medical Cannabis in Neurological Disorders and What Are the Next Steps?

Medical use of cannabis has been receiving growing attention over the last few decades in modern medicine. As we know that the endocannabinoid system is largely involved in neurological disorders, we focused on the scientific rationale of medical cannabis in three neurological disorders: amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease through pharmacological plausibility, clinical studies, and patients' view. Clinical studies (randomized controlled trials, open-label studies, cohorts, and case reports) exploring medical cannabis in these disorders show different results depending on the methods and outcomes. Some show benefits on motor symptoms and others on non-motor symptoms and quality of life. Concerning patients' view, several web surveys were collected, highlighting the real use of cannabis to relieve symptoms of neurological disorders, mostly outside a medical pathway. This anarchic use keeps questioning particularly in terms of risks: consumption of street cannabis, drug-drug interactions with usual medical treatment, consideration of medical history, and adverse reactions (psychiatric, respiratory, cardiovascular disorders, etc.), underlining the importance of a medical supervision. To date, most scientific data support the therapeutic potential of cannabis in neurological disorders. As far as patients and patients' associations are calling for it, there is an urgent need to manage clinical studies to provide stronger evidence and secure medical cannabis use.

[Increasing methylphenidate abuse: Tracking and profiles during 13-years]. / Augmentation de l'abus de méthylphénidate : repérage et profils sur 13 années.

BACKGROUND: Methylphenidate is indicated for attention deficit hyperactivity disorder (ADHD). Several studies have evaluated its abuse in specific populations (students, drug users) and few in the general population. This work describes the extent of its abuse in a region of more than 5 million inhabitants. METHOD: Based on regional health insurance data from 2005 to 2017, the clustering method identifies different methylphenidate use profiles according to several characteristics (number of different prescribers and pharmacies, number of dispensations, number of defined daily dose dispensed). The groups characterised by high values of these variables will be qualified as "deviant". RESULTS: In 13 years, the number of patients with at least one dispensation in the first quarter has been multiplied by 5.8 times. The proportion of adults has increased (20% in 2017) and their number has been multiplied by 10. Five groups are identified, three of them are characterised by "deviant" behaviour. Group 5 (n=11, 0.04%) has higher values than 4 (n=112, 0.4%) and 3 (n=407, 1.6%). These patients are older and more frequently use benzodiazepines and opiate substitution drugs. Groups 1 (n=13,132, 51%) and 2 (n=11,941, 46.7%) are more likely to be taken up by young subjects. The number of subjects with "deviant" behaviour increased until 2011 and after a decrease, the highest number of subjects concerned has been observed since 2015. CONCLUSION: In view of the increase of subjects with "deviant" behaviour, it is necessary to make the medical community and patients aware on the risk of abuse of methylphenidate. The recent extension of the indication for ADHD in adults and the broadening of the conditions of prescription require increased vigilance.

Three-year outcome of local injection of autologous stromal vascular fraction cells and microfat in refractory perianal fistulas of Crohn's disease.

Perianal fistulas in Crohn's disease are frequent and disabling, with a major impact on patients' quality of life. Cell-based therapy using mesenchymal stem cells represents new hope for these patients, but long-term efficacy remains challenging. In a pilot study, including patients with refractory complex perianal fistulas, autologous adipose-derived stromal vascular fraction (ADSVF) combined with microfat achieved combined remission in 60% of cases, with a good safety profile at 1 year. The purpose of this study is to assess whether these results were maintained at longer term. The safety and efficacy data of the ten patients were evaluated retrospectively 3 years after injection on the basis of clinical and radiological data. MRI were analysed according to the MAGNIFI-CD score. No adverse event was attributed to the experimental stem-cell treatment. Combined remission was achieved in 7 patients (70%) and associated with a significant improvement in the MAGNIFI-CD MRI score. In conclusion, the safety and efficacy of ADSVF and microfat injection in Crohn's disease fistulas were maintained at 3 years, demonstrating that this innovative strategy is effective in producing a long-lasting healing effect. The ongoing multicentre randomized placebo-controlled trial (NCT04010526) will be helpful to define the place for this approach in the current therapeutic arsenal.

BDNF Val66Met gene polymorphism modulates brain activity following rTMS-induced memory impairment.

The BDNF Val66Met gene polymorphism is a relevant factor explaining inter-individual differences to TMS responses in studies of the motor system. However, whether this variant also contributes to TMS-induced memory effects, as well as their underlying brain mechanisms, remains unexplored. In this investigation, we applied rTMS during encoding of a visual memory task either over the left frontal cortex (LFC; experimental condition) or the cranial vertex (control condition). Subsequently, individuals underwent a recognition memory phase during a functional MRI acquisition. We included 43 young volunteers and classified them as 19 Met allele carriers and 24 as Val/Val individuals. The results revealed that rTMS delivered over LFC compared to vertex stimulation resulted in reduced memory performance only amongst Val/Val allele carriers. This genetic group also exhibited greater fMRI brain activity during memory recognition, mainly over frontal regions, which was positively associated with cognitive performance. We concluded that BDNF Val66Met gene polymorphism, known to exert a significant effect on neuroplasticity, modulates the impact of rTMS both at the cognitive as well as at the associated brain networks expression levels. This data provides new insights on the brain mechanisms explaining cognitive inter-individual differences to TMS, and may inform future, more individually-tailored rTMS interventions.

Adipose tissue-derived stromal vascular fraction for treating hands of patients with systemic sclerosis: a multicentre randomized trial Autologous AD-SVF versus placebo in systemic sclerosis.

OBJECTIVE: To assess the superiority of adipose tissue-derived stromal vascular fraction (AD-SVF) injection into the fingers vs placebo in reducing hand disability in systemic sclerosis (SSc) patients. METHODS: We performed a double-blind, multicentre, phase II trial from October 2015 to January 2018 in France. SSc patients with a Cochin Hand Function Scale (CHFS) ≥20/90 were randomized 1:1 to receive injection of AD-SVF or placebo. AD-SVF was obtained using the automated processing Celution 800/CRS system. The placebo was lactated Ringer's solution. The primary efficacy end point was the change of the CHFS score from baseline to 3 months. Secondary efficacy endpoints included the CHFS score at 6 months, hand function, vasculopathy, hand pain, skin fibrosis, sensitivity of the finger pulps, Scleroderma Health Assessment Questionnaire, patients and physician satisfaction, and safety. RESULTS: Forty patients were randomized. The AD-SVF and placebo groups were comparable for age, sex ratio, disease duration, skin fibrosis of the hands and main cause of hand disability. After 3 months' follow-up, hand function significantly improved in both groups with no between-group difference of CHFS (mean change of -9.2 [12.2] in the AD-SVF group vs -7.6 [13.2] in the placebo group). At 6 months, hand function improved in both groups. CONCLUSION: This study showed an improvement of hand function in both groups over time, with no superiority of the AD-SVF. Considering the limits of this trial, studies on a larger population of patients with homogeneous phenotype and hand handicap should be encouraged to accurately assess the benefit of AD-SVF therapy. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT02558543. Registered on September 24, 2015.

Effect of physical therapy on 7- to 10-year-old children with autism spectrum disorder: A retrospective study in a university day hospital.

More than half of children who have autism spectrum disorder (ASD) suffer from motor impairment. In a retrospective study, the authors investigated the effect of a body-mediated workshop with dance movement therapy (DMT) on the motor skills and social skills of children with ASD by comparing 10 autistic children aged 7 to 10 years who benefited from DMT with 10 autistic children in a control group. Scores on the Movement Assessment Battery for Children and the Vineland Adaptive Behavior Scale were compared. The body-mediated workshop had significant benefits for motricity, especially manual dexterity, and for relational skills. A body-mediated workshop may have a multimodal effect and requires transmodal training. Regarding the mechanisms that explain the benefits and the cascading effect, the roles of imitation and multimodal connections are important.

Early combination therapy with hydroxychloroquine and azithromycin reduces mortality in 10,429 COVID-19 outpatients.

We evaluated the age-specific mortality of unselected adult outpatients infected with SARS-CoV-2 treated early in a dedicated COVID-19 day hospital and we assessed whether the use of hydroxychloroquine (HCQ) + azithromycin (AZ) was associated with improved survival in this cohort. A retrospective monocentric cohort study was conducted in the day hospital of our center from March to December 2020 in adults with PCR-proven infection who were treated as outpatients with a standardized protocol. The primary endpoint was 6-week mortality, and secondary endpoints were transfer to the intensive care unit and hospitalization rate. Among 10,429 patients (median age, 45 [IQR 32-57] years; 5597 [53.7%] women), 16 died (0.15%). The infection fatality rate was 0.06% among the 8315 patients treated with HCQ+AZ. No deaths occurred among the 8414 patients younger than 60 years. Older age and male sex were associated with a higher risk of death, ICU transfer, and hospitalization. Treatment with HCQ+AZ (0.17 [0.06-0.48]) was associated with a lower risk of death, independently of age, sex and epidemic period. Meta-analysis evidenced consistency with 4 previous outpatient studies (32,124 patients-Odds ratio 0.31 [0.20-0.47], I2 = 0%). Early ambulatory treatment of COVID-19 with HCQ+AZ as a standard of care is associated with very low mortality, and HCQ+AZ improve COVID-19 survival compared to other regimens.

Assessing the upper motor neuron in amyotrophic lateral sclerosis using the triple stimulation technique: A multicenter prospective study.

OBJECTIVE: To evaluate the relevance of transcranial magnetic stimulation (TMS) using triple stimulation technique (TST) to assess corticospinal function in amyotrophic lateral sclerosis (ALS) in a large-scale multicenter study. METHODS: Six ALS centers performed TST and conventional TMS in upper limbs in 98 ALS patients during their first visit to the center. Clinical evaluation of patients included the revised ALS Functional Rating Scale (ALSFRS-R) and upper motor neuron (UMN) score. RESULTS: TST amplitude ratio was decreased in 62% of patients whereas conventional TMS amplitude ratio was decreased in 25% of patients and central motor conduction time was increased in 16% of patients. TST amplitude ratio was correlated with ALSFRS-R and UMN score. TST amplitude ratio results were not different between the centers. CONCLUSIONS: TST is a TMS technique applicable in daily clinical practice in ALS centers for the detection of UMN dysfunction, more sensitive than conventional TMS and related to the clinical condition of the patients. SIGNIFICANCE: This multicenter study shows that TST can be a routine clinical tool to evaluate UMN dysfunction at the diagnostic assessment of ALS patients.

VITADIAL "Does correction of 25 OH-VITAmin D with cholecalciferol supplementation increase muscle strength in hemoDIALysis patients?": study protocol for a randomized controlled trial.

BACKGROUND: Muscle strength decreases as kidney failure progresses. Low muscle strength affects more than 50% of hemodialysis patients and leads to daily life activities impairment. In the general population, numerous studies have linked low 25OH-vitamin D (25OHD) concentrations to the loss of the muscle strength and low physical performances. Data on native vitamin D and muscle function are scarce in the chronic kidney disease (CKD) population, but low 25OHD levels have been associated with poor muscle strength. We present in this article the protocol of an ongoing study named VITADIAL testing if cholecalciferol supplementation in hemodialysis patients with low 25OHD improves their muscle strength. METHODS/DESIGN: VITADIAL is a prospective open randomized French multicenter study. All patients will have 25OHD levels ≤50nmol/L at randomization. One group will receive 100,000 UI cholecalciferol once a month during 6 months; the other group will receive no treatment during 6 months. In order to randomize patients with 25OHD ≤50nmol/L, supplemented patients will undergo a 3 months wash-out period renewable 3 times (maximum of 12 months wash-out) until 25OHD reaches a level ≤50nmol/L. The main objective of this study is to analyze if a 6-month period of oral cholecalciferol (i.e., native vitamin D) supplementation improves muscle strength of hemodialysis patients with low 25OHD vitamin D levels. Muscle strength will be assessed at 0, 3, and 6 months, by handgrip strength measured with a quantitative dynamometer. Secondary objectives are (1) to analyze 25OHD plasma levels after vitamin D wash-out and/or supplementation, as well as factors associated with 25OHD lowering speed during wash-out, and (2) to analyze if this supplementation improves patient's autonomy, reduces frailty risk, and improves quality of life. Fifty-four patients are needed in each group to meet our main objective. DISCUSSION: In the general population, around 30 randomized studies analyzed the effects of vitamin D supplementation on muscle strength. These studies had very different designs, sizes, and studied population. Globally, these studies and the meta-analysis of studies favor a beneficial effect of vitamin D supplementation on muscle strength, but this effect is mainly found in the subgroup of aged patients and those with the lowest 25OHD concentrations at inclusion. We reported a positive independent association between 25OHD and handgrip strength in a population of 130 hemodialysis patients in a dose-dependent manner. In our cohort, a plateau effect was observed above 75 nmol/L. Only two randomized studies analyzed the effect of native vitamin D supplementation on muscle strength in hemodialysis patients, but unfortunately, these two studies were underpowered. VITADIAL is a trial specifically designed to assess whether cholecalciferol might benefit to hemodialysis patient's muscle strength. TRIAL REGISTRATION: ClinicalTrials.gov NCT04262934 . Registered on 10 February 2020 - Retrospectively registered.