Elisabeth Jouve

Effect of ascorbic acid in patients with Charcot–Marie–Tooth disease type 1A: a multicentre, randomised, double-blind, placebo-controlled trial

BACKGROUND Charcot-Marie-Tooth disease type 1A (CMT1A) is a hereditary peripheral neuropathy that affects roughly one in 5000 births. No specific therapy currently exists for this degenerative disorder, which is characterised by distal progressive muscle atrophy and sensory loss, although ascorbic acid has been shown to reduce demyelination and improve muscle function in a transgenic mouse model of CMT1A. We tested the safety and efficacy of ascorbic acid in adults with CMT1A. METHODS This 12-month, randomised, double-blind, placebo-controlled study was undertaken between September, 2005, and October, 2008. Patients diagnosed with CMT1A according to clinical examination and confirmation by genotyping were randomly assigned in a 1:1:1 ratio to receive 1 g ascorbic acid per day, 3 g ascorbic acid per day, or placebo. Treatment allocation was based on a computer-generated list of random numbers in blocks of 12, with stratification according to study site and sex; all investigators and participants were unaware of treatment allocation. The primary outcome was the Charcot-Marie-Tooth disease neuropathy score (CMTNS) at 12 months. Analysis was by intention to treat. This study is registered with the Orphanet Database, number ORPHA60779. FINDINGS The median change in CMTNS from baseline to 12 months was 0.5 points (95% CI -0.3 to 1.4) for the placebo group (n=62), 0.7 points (0.0 to 1.4) for the 1 g ascorbic acid group (n=56), and -0.4 points (-1.2 to 0.4) for the 3 g ascorbic acid group (n=61). We did not find any significant difference in these changes between the groups (p=0.14). The occurrence of adverse events did not differ between the groups (p=0.74). INTERPRETATION Ascorbic acid at both doses was safe and well tolerated in adults with CMT1A over 12 months. However, there were no significant differences between the groups and the efficacy of ascorbic acid was not shown.

Liver Transplantation for Neuroendocrine Tumors in Europe—Results and Trends in Patient Selection A 213-Case European Liver Transplant Registry Study

Objective:The purpose of this study was to assess outcomes and indications in a large cohort of patients who underwent liver transplantation (LT) for liver metastases (LM) from neuroendocrine tumors (NET) over a 27-year period. Background:LT for NET remains controversial due to the absence of clear selection criteria and the scarcity and heterogeneity of reported cases. Methods:This retrospective multicentric study included 213 patients who underwent LT for NET performed in 35 centers in 11 European countries between 1982 and 2009. One hundred seven patients underwent transplantation before 2000 and 106 after 2000. Mean age at the time of LT was 46 years. Half of the patients presented hormone secretion and 55% had hepatomegaly. Before LT, 83% of patients had undergone surgical treatment of the primary tumor and/or LM and 76% had received chemotherapy. The median interval between diagnosis of LM and LT was 25 months (range, 1–149 months). In addition to LT, 24 patients underwent major resection procedures and 30 patients underwent minor resection procedures. Results:Three-month postoperative mortality was 10%. At 5 years after LT, overall survival (OS) was 52% and disease-free survival was 30%. At 5 years from diagnosis of LM, OS was 73%. Multivariate analysis identified 3 predictors of poor outcome, that is, major resection in addition to LT, poor tumor differentiation, and hepatomegaly. Since 2000, 5-year OS has increased to 59% in relation with fewer patients presenting poor prognostic factors. Multivariate analysis of the 106 cases treated since 2000 identified the following predictors of poor outcome: hepatomegaly, age more than 45 years, and any amount of resection concurrent with LT. Conclusions:LT is an effective treatment of unresectable LM from NET. Patient selection based on the aforementioned predictors can achieve a 5-year OS between 60% and 80%. However, use of overly restrictive criteria may deny LT to some patients who could benefit. Optimal timing for LT in patients with stable versus progressive disease remains unclear.

Iatrogenic events in admitted neonates: a prospective cohort study

BACKGROUND Iatrogenic events are increasingly recognised as an important problem in all people admitted to hospital. However, few epidemiological data are available for iatrogenic events in neonatal high-risk units. We aimed to assess the incidence, nature, preventability, and severity of iatrogenic events in a neonatal centre and to establish the association of patient characteristics with the occurrence of iatrogenic events in neonates. METHODS We undertook an observational, prospective study from Jan 1, 2005, to Sept 1, 2005, including all neonates admitted in the Division of Neonatology of an academic, tertiary neonatal centre in southern France. Iatrogenic events were defined as any event that compromised the safety margin for the patient, in the presence or absence of harm. The report of an iatrogenic event was voluntary, anonymous, and non-punitive. The primary outcome was the rate of iatrogenic events per 1000 patient days. FINDINGS A total of 388 patients were studied during 10 436 patient days. We recorded 267 iatrogenic events in 116 patients. The incidence of iatrogenic events was 25.6 per 1000 patient days. 92 (34%) were preventable and 78 (29%) were severe. Two iatrogenic events (1%) were fatal, but neither was preventable. The most severe iatrogenic events were nosocomial infections (49/62 [79%]) and respiratory events (nine of 26 [35%]). Cutaneous injuries were frequent (n=94) but generally minor (89 [95%]), as were medication errors (15/19 [76%]). Most medication errors occurred during administration stage (12/19 [63%]) and were ten-fold errors (nine of 19 [47%]). The major risk factors were low birthweight and gestational age (both p<0.0001), length of stay (p<0.0001), a central venous line (p<0.0001), mechanical ventilation (p=0.0021), and support with continuous positive airwary pressure (p=0.0076). INTERPRETATION Iatrogenic events occur frequently and are often serious in neonates, especially in infants of low birthweight. Improved knowledge of the incidence and characteristics of iatrogenic events, and continuous monitoring could help to improve quality of health care for this vulnerable population.

Safety, tolerability and potential efficacy of injection of autologous adipose-derived stromal vascular fraction in the fingers of patients with systemic sclerosis: an open-label phase I trial

Background In patients with systemic sclerosis (scleroderma, SSc), impaired hand function greatly contributes to disability and reduced quality of life, and is insufficiently relieved by currently available therapies. Adipose tissue-derived stromal vascular fraction (SVF) is increasingly recognised as an easily accessible source of regenerative cells with therapeutic potential in ischaemic or autoimmune diseases. We aimed to measure for the first time the safety, tolerability and potential efficacy of autologous SVF cells local injections in patients with SSc with hand disability. Methods We did an open-label, single arm, at one study site with 6-month follow-up among 12 female SSc patients with Cochin Hand Function Scale score >20/90. Autologous SVF was obtained from lipoaspirates, using an automated processing system, and subsequently injected into the subcutaneous tissue of each finger in contact with neurovascular pedicles. Primary outcome was the number and the severity of adverse events related to SVF-based therapy. Secondary endpoints were changes in hand disability and fibrosis, vascular manifestations, pain and quality of life from baseline to 2 and 6 months after cell therapy. Findings All enrolled patients had surgery, and there were no dropouts or patients lost to follow-up. No severe adverse events occurred during the procedure and follow-up. Four minor adverse events were reported and resolved spontaneously. A significant improvement in hand disability and pain, Raynauds phenomenon, finger oedema and quality of life was observed. Interpretation This study outlines the safety of the autologous SVF cells injection in the hands of patients with SSc. Preliminary assessments at 6 months suggest potential efficacy needing confirmation in a randomised placebo-controlled trial on a larger population. Funding GFRS (Groupe Francophone de Recherche sur la Sclérodermie). Clinical Trials number NCT01813279.

Pharmacokinetic and pharmacodynamic analysis of sedative and amnesic effects of lorazepam in healthy volunteers.

This study describes for the first time the pharmacokinetic and pharmacodynamic modeling of the psychomotor and amnesic effects of a single 2-mg oral dose of lorazepam in healthy volunteers. Twelve healthy volunteers were included in this randomized, double-blinded, placebo-controlled two-way crossover study. The effect of lorazepam was examined for a battery of tests that explored mood, vigilance, psychomotor performance, and memory. The pharmacokinetic and pharmacodynamic modeling of these tests was performed using the indirect response model. Vigilance and psychomotor performance were significantly impaired. Short-term memory was not affected, but a paradoxical tendency to improvement of the score was observed 0.4 hours after drug intake. Significant impairment was observed for immediate and delayed cued verbal recall, for immediate and delayed free recall, and for picture recognition as well as for visual-verbal recall, but not for cued visual-spatial recall or priming. Globally, the different effects were greatest between 0.4 to 3 hours after dosing. However, the time course profile of the recovery period suggests a possible dissociation between the kinetics of the effects of lorazepam on vigilance, psychomotor performance, and visual episodic memory, on the one hand, and on verbal episodic memory, on the other. The pharmacokinetic and pharmacodynamic model used two compartments with first-order absorption to describe the lorazepam concentrations and an indirect response model with inhibition or stimulation of Kin to describe the effects. The mean values for calculated median effective concentration (EC50) derived from the pharmacokinetic and pharmacodynamic modeling of the different tests ranged from 11.3 to 39.8 ng/mL. According to these EC50 values, lorazepam seemed to be more potent on the delayed-recall trials than on the immediate-recall trials; similar observations were made concerning the free-recall versus cued-recall trials. The previously stated results suggest that the tests performed in this study represent sensitive measurements of the effects of lorazepam on the central nervous system. Moreover, the parameter values derived from pharmacokinetic and pharmacodynamic modeling, especially, the EC50 values, may provide sensitive indices that can be used to compare the central nervous system effects of benzodiazepines.

Autologous adipose-derived stromal vascular fraction in patients with systemic sclerosis: 12-month follow-up

OBJECTIVE Impaired hand function greatly contributes to disability and reduced quality of life in SSc patients. Autologous adipose-derived stromal vascular fraction (ADSVF) is recognized as an easily accessible source of regenerative cells. We reported positive 6-month safety and efficacy results from an open-label clinical trial assessing s.c. injection of autologous ADSVF into the fingers in SSc patients. The objective of this report is to describe the effects at 12 months. METHODS Twelve females, mean age 54.5 years (s.d. 10.3), were assessed 1 year after ADSVF injection. Patients were eligible if they had a Cochin Hand Function Scale score >20/90. ADSVF was obtained from lipoaspirate using an automated processing system and subsequently injected into the s.c. tissue of each finger in contact with neurovascular pedicles in a one-time procedure. Endpoints were changes in hand disability and skin fibrosis, vascular manifestations, pain and quality of life at the 12 month follow-up. During the visit, patients estimated the benefit of the procedure with a specific self-completed questionnaire. RESULTS A significant decrease from baseline of 51.3% (P < 0.001) for Cochin Hand Function Scale score, 63.2% (P < 0.001) for RP severity and 46.8% (P = 0.001) for quality of life (Scleroderma Health Assessment Questionnaire) was observed. A significant improvement of finger oedema, skin sclerosis, motion and strength of the hands and of the vascular suppression score was also noted. The reduction in hand pain approached statistical significance (P = 0.052). The questionnaire revealed a benefit in daily activities, housework and social activities. CONCLUSION ADSVF injection is a promising therapy and appears to have benefits that extend for at least 1 year.

Iatrogenic Events in Neonates: Beneficial Effects of Prevention Strategies and Continuous Monitoring

OBJECTIVES: To assess the impact of continuous incident reporting and subsequent prevention strategies on the incidence of severe iatrogenic events and targeted priorities in admitted neonates. METHODS: We performed preintervention (January 1 to September 1, 2005) and postintervention (January 1, 2008, to January 1, 2009) prospective investigations based on continuous incident reporting. Patient-safety initiatives were implemented for a period of 2 years. The main outcome was a reduction in the incidence of severe iatrogenic events. Secondary outcomes were improvements in 5 targeted priorities: catheter-related infections; invasive procedures; unplanned extubations; 10-fold drug infusion-rate errors; and severe cutaneous injuries. RESULTS: The first and second study periods included totals of 388 and 645 patients (median gestational ages: 34 and 35 weeks, respectively; P = .015). In the second period the incidence of severe iatrogenic events was significantly reduced from 7.6 to 4.8 per 1000 patient-days (P = .005). Infections related to central catheters decreased significantly from 13.9 to 8.2 per 1000 catheter-days (P < .0001), as did exposure to central catheters, which decreased from 359 to 239 days per 1000 patient-days (P < .0001). Tenfold drug-dosing errors were reduced significantly (P = .022). However, the number of unplanned extubations increased significantly from 5.6 to 15.5 per 1000 ventilation-days (P = .03). CONCLUSIONS: Prospective, continuous incident reporting followed by the implementation of prevention strategies are complementary procedures that constitute an effective system to improve the quality of care and patient safety.

RESPONSE TO TREATMENT IN PATIENTS WITH LEWIS-SUMNER SYNDROME

Our aim was to document the classification of Lewis–Sumner syndrome (L‐SS) based on the response to treatment and the pattern of progression over time.

Effects of subanesthetic doses of ketamine on sensorimotor information processing in healthy subjects.

Ketamine, an antagonist N-Methyl-D-Aspartate receptor, induces a broad range of anomalies in healthy subjects similar to those observed in psychosis. Previous studies have shown that information sensorimotor processing was impaired in patients with schizophrenia. The aim of the study was to assess the effects of subanesthetic doses of ketamine on behavior symptoms and information processing in healthy volunteers. A double-blind, crossover, placebo-controlled study was performed with eight subjects. Brief Psychiatric Rating Scale, Scale for the Assessment of Negative Symptoms, and Scale for the Assessment of Positive Symptoms assessed behavior changes. Information processing was assessed using a choice reaction time. Three experimental factors (stimulus intensity, stimulus response compatibility, and foreperiod duration) chosen to affect a different stage of information processing were manipulated. Our study has demonstrated that administration of ketamine produced significant effects on Brief Psychiatric Rating Scale, Scale for the Assessment of Negative Symptoms, and Scale for the Assessment of Positive Symptoms scores. Results on choice reaction time demonstrated a significant longer reaction time under ketamine. Effects of stimulus intensity and compatibility stimulus response were similar under ketamine and under placebo. Moreover, there was a specific interaction between ketamine and foreperiod. This interaction indicated that foreperiods effect was more prolonged under ketamine (29 ms) than under placebo (17 ms). These results showed that the clinical effects of ketamine were associated with schizophrenic-like impairments on choice reaction time in healthy subjects.

Analysis, evaluation and adaptation of the ReTransQoL: a specific quality of life questionnaire for renal transplant recipients

BackgroundEnd stage renal disease (ESRD) profoundly impacts the lives of patients. Kidney transplantation provides the greatest health-related quality of life (HRQOL) improvement. Its measurement has become an important outcome parameter and a very important criterion in the evaluation of any type of medical treatment, especially in the field of renal transplantation.In 2007, a specific self-administered questionnaire for renal transplant recipients was developed in the French language: the ReTransQol (RTQ).After 5 years of use, the properties of the RTQ needed to be re-evaluated in a larger sample.This paper describes the analysis of the ReTransQol and its adaptation to achieve an improved and revised version.MethodsThe study design included three analysis phases for two samples of adult renal transplant recipients which came from two cross-sectional multicenter studies carried out in France in 2007 and 2012. Psychometrics properties like construct validity, acceptability and feasibility, reliability and convergent validity were evaluated and every analysis resulted in a new version of the questionnaire: the RTQ V2. The construct validity of the new RTQ was assessed with a Confirmatory Factor Analysis on a large sample of patients.ResultsThe study samples included 1,059 patients and 1,591 patients, respectively.After a principal component analysis, item reduction was performed and a total of 13 items were deleted. A final version of the RTQ V2 was created and comprised of 32 items describing 5 domains: Physical Health, Social Functioning, Medical Care, Treatment and Fear of Losing Graft.The explained variance between the first and second RTQ versions improved from 46.3% to 53.1%. All psychometric properties of RTQ V2 were satisfactory: IIC >0.4, IDV (%) of 100% and Cronbach’s Alpha >0.7 in every dimension. The confirmatory analysis showed that the overall scalability of the RTQ V2 was satisfactory; all items showed a good fit to the Rasch model within each dimension, and showed INFIT statistics inside the acceptable range.ConclusionsPsychometric properties allow this new version of the questionnaire to be used to assess different specific dimensions for the renal transplant population, more effectively than previously possible.