Impact of methodological choices in comparative effectiveness studies: application in natalizumab versus fingolimod comparison among patients with multiple sclerosis.

BACKGROUND: Natalizumab and fingolimod are used as high-efficacy treatments in relapsing-remitting multiple sclerosis. Several observational studies comparing these two drugs have shown variable results, using different methods to control treatment indication bias and manage censoring. The objective of this empirical study was to elucidate the impact of methods of causal inference on the results of comparative effectiveness studies. METHODS: Data from three observational multiple sclerosis registries (MSBase, the Danish MS Registry and French OFSEP registry) were combined. Four clinical outcomes were studied. Propensity scores were used to match or weigh the compared groups, allowing for estimating average treatment effect for treated or average treatment effect for the entire population. Analyses were conducted both in intention-to-treat and per-protocol frameworks. The impact of the positivity assumption was also assessed. RESULTS: Overall, 5,148 relapsing-remitting multiple sclerosis patients were included. In this well-powered sample, the 95% confidence intervals of the estimates overlapped widely. Propensity scores weighting and propensity scores matching procedures led to consistent results. Some differences were observed between average treatment effect for the entire population and average treatment effect for treated estimates. Intention-to-treat analyses were more conservative than per-protocol analyses. The most pronounced irregularities in outcomes and propensity scores were introduced by violation of the positivity assumption. CONCLUSIONS: This applied study elucidates the influence of methodological decisions on the results of comparative effectiveness studies of treatments for multiple sclerosis. According to our results, there are no material differences between conclusions obtained with propensity scores matching or propensity scores weighting given that a study is sufficiently powered, models are correctly specified and positivity assumption is fulfilled.

Ten-year follow-up after mitoxantrone induction for early highly active relapsing-remitting multiple sclerosis: An observational study of 100 consecutive patients.

BACKGROUND: Six monthly courses of mitoxantrone were approved in France in 2003 for patients with highly active multiple sclerosis (MS). OBJECTIVE: To report the 10-year clinical follow-up and safety of mitoxantrone as an induction drug followed by maintenance therapy in patients with early highly active relapsing-remitting MS (RRMS) and an Expanded Disability Status Scale (EDSS) score<4, 12months prior to mitoxantrone initiation. METHODS: In total, 100 consecutive patients with highly active RRMS from the Rennes EDMUS database received monthly mitoxantrone 20mg combined with methylprednisolone 1g for 3 (n=75) or 6months (n=25) followed by first-line disease-modifying drug (DMD). The 10-year clinical impact was studied through clinical activity, DMD exposure, and adverse events. RESULTS: Twenty-four percent were relapse-free over 10years and the mean annual number of relapses was 0.2 at 10years. The mean EDSS score remained significantly improved for up to 10years, changing from 3.5 at mitoxantrone initiation to 2.7 at 10years. The probability of disability worsening and improvement from mitoxantrone initiation to 10years were respectively 27% and 58%, and 13% converted to secondary progressive MS. Patients only remained untreated or treated with a first-line maintenance DMD for 6.5years in average. In our cohort, mitoxantrone was generally safe. No leukemia was observed and six patients developed neoplasms, including 4 solid cancers. CONCLUSION: Monthly mitoxantrone for 3 or 6months, followed by maintenance first-line treatment, may be an attractive therapeutic option for patients with early highly active RRMS, particularly in low-income countries.

[External sphincterotomy in neurological patients with detrusor sphincter dyssynergia: Short and mid-term results]. / Résultat à court et moyen terme du traitement de la dyssynergie vésico-sphinctérienne par sphinctérotomie endoscopique.

BACKGROUND: To evaluate in the short and mid-term the success of external sphincterotomy (ES) in neurological patients with detrusor sphincter dyssynergia (DSD). METHODS: Retrospective, monocentric study, conducted in 51 patients who had a first ES between January 2003 and June 2018, with at least two years of follow-up. The success of ES was defined by maintenance of reflex voiding mode at the end of follow-up. Secondary outcomes were early postoperative complications, rate of revision, functional impact, urodynamic follow-up and upper urinary tract impact. RESULTS: The median age was 50.6 years and the median follow-up was 4.6 years. The success rate was 80% (n=41). Ten patients had to change their voiding mode. For 5 patients, it was related to secondary detrusor low contractility. A second ES was required for 39% of patients. At the end of follow-up, there was a significant improvement in Autonomic Dysreflexia (AD) (26 vs 7 patients, P<0.001), urinary tract infections (UTI) (31 vs 15 patients, P<0.001) and a significant decrease in post-voiding residuals (200 vs 50mL, P<0.001). CONCLUSION: ES allowed to maintain reflex voiding in 80% of our patients. It significantly improves AD and UTI despite a high rate of re-operation (39%). A long-term follow-up is mandatory in order not to ignore a recurrence of bladder outlet obstruction and/or decrease in detrusor contractility, which may justify a re-operation or an alternative bladder management. LEVEL OF EVIDENCE: III.

[Safety and efficacy of percutaneous nephrolithotomy in patients with neurogenic bladder]. / Néphrolithotomie percutanée chez les patients neurologiques : efficacité et morbidité à long terme.

INTRODUCTION: To assess the efficacy and morbidity of percutaneous nephrolithotomy (PNLT) in the treatment of renal stones in patients with neurogenic lower urinary tract dysfunction (NLUTD). METHODS: Retrospective, monocentric study including all patients with NLUTD who had undergone PNLT between 2005 and 2017. Pre-operative clinical data (neurological condition, voiding mode, preoperative urine culture…), peri-operative and post-operative data (success and morbidity) were collected from the patients' charts. Success was defined by the absence of residual fragment (RF), on imaging or intraoperative endoscopy. Partial efficacy was defined by the presence of RF lower than 4mm. Early complications were reported according to the Clavien-Dindo classification. RESULTS: In all, 53 PNLTs were performed, in 35 patients, mostly with spinal cord injury. The success and partial efficacy rates were 66.0% and 71.7% respectively. The failure rate was correlated with increased stone burden (P=0.03), increased size of the largest stone (P=0.02), and the presence of complex stones (P<0.02). The rate of early complications was 41.5%, with 27.3% major, mostly septic, and bleeding. The retreatment rate within 3 years was 41.5%. CONCLUSION: In patients with NLUTD, PNLT allows a high success rate, but with a significant rate of retreatment and infectious complications. However, NLPC remains the gold standard in this population, especially for renal stones larger 20mm, allowing a higher success rate than ureteroscopy and a lower retreatment rate.

Quantitative brainstem and spinal MRI in amyotrophic lateral sclerosis: implications for predicting noninvasive ventilation needs.

BACKGROUND: Respiratory complications resulting from motor neurons degeneration are the primary cause of death in amyotrophic lateral sclerosis (ALS). Predicting the need for non-invasive ventilation (NIV) in ALS is important for advance care planning and clinical trial design. The aim of this study was to assess the potential of quantitative MRI at the brainstem and spinal cord levels to predict the need for NIV during the first six months after diagnosis. METHODS: Forty-one ALS patients underwent MRI and spirometry shortly after diagnosis. The need for NIV was monitored according to French health guidelines for 6 months. The performance of four regression models based on: clinical variables, brainstem structures volumes, cervical spinal measurements, and combined variables were compared to predict the need for NIV within this period. RESULTS: Both the clinical model (R2 = 0.28, AUC = 0.85, AICc = 42.67, BIC = 49.8) and the brainstem structures' volumes model (R2 = 0.30, AUC = 0.85, AICc = 40.13, BIC = 46.99) demonstrated good predictive performance. In addition, cervical spinal cord measurements model similar performance (R2 = 0.338, AUC = 0.87, AICc = 37.99, BIC = 44.49). Notably, the combined model incorporating predictors from all three models yielded the best performance (R2 = 0.60, AUC = 0.959, AICc = 36.38, BIC = 44.8). These findings are supported by observed positive correlations between brainstem volumes, cervical (C4/C7) cross-sectional area, and spirometry-measured lung volumes. CONCLUSIONS: Our study shows that brainstem volumes and spinal cord area are promising measures to predict respiratory intervention needs in ALS.

[Post-traumatic syringomyelia: What should know the urologist?]. / Syringomyélie post-traumatique : ce que doit savoir l'urologue ?

The incidence of post-traumatic syringomyelia (PTS) is estimated according to recent studies at 25 to 30% of patients with traumatic spinal cord injuries in magnetic resonance imaging (MRI), which remains the gold standard exam for syringomyelia diagnosis and monitoring. Syringomyelia is translated by an increased cord signal (similar to CSF) with low-density T1-weighted image and high-density T2-weighted image, which extends beyond site of initial lesion at least to two vertebral segments. Two conditions are required for development of PTS: traumatic spinal cord injury and blocked the flow of CSF epidural. The mean interval from spinal cord injury to diagnosis SPT was 2.8years (range, 3months to 34years). The commonest symptoms are pain and sensory loss. PTS should be suspected if the patient has new neurological symptoms above level of injury, such as dissociated sensory injuries, reflexes abolition, and motor deficit, after the neural function becomes stable for certain time. In urologic practice, new neurological symptoms could be bladder and/or erectile dysfunction. The medical management based on prevention efforts with closed-glottis pushing, which could aggravate the syrinx cavity. In urology, extracorporeal shockwave lithotripsy, and laparoscopic or robotic surgery could extend the syrinx cavity for the same reason (increase abdominal pressure). The indications for surgical intervention and optimal surgical treatment technique for patients with PTS are not consensual. The literature demonstrated that surgery PTS is effective at arresting or improving motor deterioration, but not sensory dysfunction or pain syndromes.

Comparison of spinal magnetic resonance imaging and classical clinical factors in predicting motor capacity in amyotrophic lateral sclerosis.

BACKGROUND: Motor capacity is crucial in amyotrophic lateral sclerosis (ALS) clinical trial design and patient care. However, few studies have explored the potential of multimodal MRI to predict motor capacity in ALS. This study aims to evaluate the predictive value of cervical spinal cord MRI parameters for motor capacity in ALS compared to clinical prognostic factors. METHODS: Spinal multimodal MRI was performed shortly after diagnosis in 41 ALS patients and 12 healthy participants as part of a prospective multicenter cohort study, the PULSE study (NCT00002013-A00969-36). Motor capacity was assessed using ALSFRS-R scores. Multiple stepwise linear regression models were constructed to predict motor capacity at 3 and 6 months from diagnosis, based on clinical variables, structural MRI measurements, including spinal cord cross-sectional area (CSA), anterior-posterior, and left-to-right cross-section diameters at vertebral levels from C1 to T4, and diffusion parameters in the lateral corticospinal tracts (LCSTs) and dorsal columns. RESULTS: Structural MRI measurements were significantly correlated with the ALSFRS-R score and its sub-scores. And as early as 3 months from diagnosis, structural MRI measurements fit the best multiple linear regression model to predict the total ALSFRS-R (R2 = 0.70, p value = 0.0001) and arm sub-score (R2 = 0.69, p value = 0.0002), and combined with DTI metric in the LCST and clinical factors fit the best multiple linear regression model to predict leg sub-score (R2 = 0.73, p value = 0.0002). CONCLUSIONS: Spinal multimodal MRI could be promising as a tool to enhance prognostic accuracy and serve as a motor function proxy in ALS.

Polysaccharide films built by simultaneous or alternate spray: a rapid way to engineer biomaterial surfaces.

We investigated polysaccharide films obtained by simultaneous and alternate spraying of a chitosan (CHI) solution as polycation and hyaluronic acid (HA), alginate (ALG), and chondroitin sulfate (CS) solutions as polyanions. For simultaneous spraying, the film thickness increases linearly with the cumulative spraying time and passes through a maximum for polyanion/CHI molar charge ratios lying between 0.6 and 1.2. The size of polyanion/CHI complexes formed in solution was compared with the simultaneously sprayed film growth rate as a function of the polyanion/CHI molar charge ratio. A good correlation was found. This suggests the importance of polyanion/polycation complexation in the simultaneous spraying process. Depending on the system, the film topography is either liquid-like or granular. Film biocompatibility was evaluated using human gingival fibroblasts. A small or no difference is observed in cell viability and adhesion between the two deposition processes. The CHI/HA system appears to be the best for cell adhesion inducing the clustering of CD44, a cell surface HA receptor, at the membrane of cells. Simultaneous or alternate spraying of CHI/HA appears thus to be a convenient and fast procedure for biomaterial surface modifications.

Simultaneous spray coating of interacting species: general rules governing the poly(styrene sulfonate)/poly(allylamine) system.

Simultaneous spraying of two solutions of interacting species onto a substrate held vertically leads to the formation of nanometer-sized coatings. Here we investigate the simultaneous spraying of poly(styrene sulfonate) (PSS) and poly(allylamine hydrochloride) (PAH) solutions leading to the formation of a film composed of PSS/PAH complexes. The thickness of this film increases linearly with the cumulative spraying time. For a given spraying rate of PAH (respectively PSS), the growth rate of the film depends strongly upon the PSS/PAH ratio and passes through a maximum for a PSS/PAH ratio lying between 0.55 and 0.8. For a PSS/PAH ratio that is maintained constant, the growth speed of the film increases linearly with the spraying rate of polyelectrolyte of both solutions. Using X-ray photoelectron spectroscopy, we find that the film composition is almost independent of the PSS/PAH (spayed) ratio, with composition very close to 1:1 in PSS:PAH film. The 1:1 PSS:PAH composition is explained by the fact that the simultaneous spraying experiments are carried out with salt-free solutions; thus, electroneutrality in the film requires exact matching of the charges carried by the polyanions and the polycations. Zeta potential measurements reveal that, depending on whether the PSS/PAH spraying rate ratio lies below or above the optimal spraying rate ratio, the film acquires a positive or a negative excess charge. We also find that the overall film morphology, investigated by AFM, is independent of the spraying rate ratio and appears to be composed of nanometer-sized grains which are typically in the 100 nm range.

Use of healthcare services by patients with multiple sclerosis in France over 2010-2015: a nationwide population-based study using health administrative data.

BACKGROUND: Most of the knowledge about people with multiple sclerosis (PwMS) in France comes from cohorts, which may suffer from recruitment bias or from the unique registry located in Lorraine, East France. OBJECTIVE: To describe use of care in the French population of PwMS, over 2010-2015. METHODS: All PwMS in the French national health data system (97% of the general population covered) were included. Demographics, and use of care were described (visits with general practitioners (GPs), neurologists, nurses, physiotherapists and hospitalisations). A focus on the neurological follow-up was also conducted. RESULTS: A total of 112,415 PwMS were identified (sex ratio F:M = 2.4, median age 46), of whom 5005 died during follow-up. The median numbers of visits with GPs and neurologists were 6.6 and 1.3 respectively per patient-year. Moreover, 53,457 (47.6%) received multiple sclerosis (MS) treatments; about 13% of patients had no neurological follow-up, and 81.8% had at least one hospitalisation. CONCLUSIONS: For the first time in France, this exhaustive dataset offered the opportunity to provide objective figures regarding care practices for MS at the national level, without any selection bias. It also allowed description of patients with MS according to their neurological follow-up, especially those who were absent from cohorts led by neurologists.

Effect of risedronate on bone mass, remodelling and biomechanical strength in orchidectomized rats.

BACKGROUND: The ability of risedronate to prevent and/or treat orchidectomy-induced osteoporosis in male rats was studied. METHODS: Ninety-five 10-week-old male Wistar rats were sham-operated or orchidectomized. Prevention study: Sham: sham-operated rats; ORX: orchidectomized rats; ORX + RSD: orchidectomized rats, treated for 6 weeks with risedronate. Animals were sacrificed 6 weeks after surgery. Treatment study: Sham(1) and ORX(1): sham and orchidectomized rats sacrificed 3 months after orchidectomy; Sham(2), ORX(2) and ORX(2) + RSD: sham-operated, and orchidectomized rats treated with placebo or risedronate for 6 weeks starting 3 months after orchidectomy, and then sacrificed. Risedronate (0.5 mg/kg/day) and placebo (saline) were administered via oral gavage. After sacrifice, bone mineral density by DEXA, bone volume (BV/TV), osteocalcin (BGP), and serum carboxyterminal telopeptide of collagen type I (CTX) were measured. Femur low-rate torsion testing was performed. RESULTS: Orchidectomy produced an increase in bone remodelling with loss of BV/TV, without effects on torsional strength. Risedronate treatment partially prevented these effects. In the treatment study, risedronate reduced bone remodelling and restored BV/TV to levels higher than those of the sham group, improving biomechanical parameters. CONCLUSIONS: These results suggest that risedronate could be used as a prevention or treatment of male osteoporosis due to hypogonadism.

What is the place of electroneuromyographic studies in the diagnosis and management of pudendal neuralgia related to entrapment syndrome?

Entrapment of the pudendal nerve may be at the origin of chronic perineal pain. This syndrome must be diagnosed because this can result in the indication of surgical decompression of the entrapped nerve for pain relief. Electroneuromyographic (ENMG) investigation is often performed in this context, based on needle electromyography and the study of sacral reflex and pudendal nerve motor latencies. The limits of ENMG investigation, owing to various pathophysiological and technical considerations, should be known. The employed techniques do not assess directly the pathophysiological mechanisms of pain but rather correlate to structural alterations of the pudendal nerve (demyelination or axonal loss). In addition, only direct or reflex motor innervation is investigated, whereas sensory nerve conduction studies should be more sensitive to detect nerve compression. Finally, ENMG cannot differentiate entrapment from other causes of pudendal nerve lesion (stretch induced by surgical procedures, obstetrical damage, chronic constipation...). Thus, perineal ENMG has a limited sensitivity and specificity in the diagnosis of pudendal nerve entrapment syndrome and does not give direct information about pain mechanisms. Pudendal neuralgia related to nerve entrapment is mainly suspected on specific clinical features and perineal ENMG examination provides additional, but no definitive clues, for the diagnosis or the localization of the site of compression. In fact, the main value of ENMG is to assess objectively pudendal motor innervation when a surgical decompression is considered. Perineal ENMG might predict the outcome of surgery but is of no value for intraoperative monitoring.

[Efficacy of repeat injections of botulinum A toxin to the detrusor in neurogenic bladder overactivity]. / Efficacité des injections intradétrusoriennes répétées de toxine A dans l'hyperactivité vésicale d'origine neurologique.

PURPOSE: Toxin injections are an effective treatment for neurogenic detrusor overactivity. The efficacy of repeat injections is not well documented. The objective of this study was to evaluate the efficacy of repeat injections of toxin A to the detrusor in patients with neurogenic overactive bladders. MATERIALS AND METHODS: Patients who had received 300-UI injections of Botox(R) were retrospectively studied. The clinical data included continence, duration of the absence of incontinence, changes in anticholinergic dosage or pad use and patient satisfaction. Urodynamic data analyzed were maximal cystometric capacity, bladder contraction and detrusor pressure during contraction. Data were analyzed by Wilcoxon and Kruskal-Wallis tests. RESULTS-DISCUSSION: Data for 42 patients (30 men, 12 women) were analysed. Pathologic features were trauma to the spinal cord, multiple sclerosis or varied causes of myelopathy. Patients received 1 to 6 injections of Botox(R). The mean duration of efficacy was 6 months. Efficacy did not differ among successive injections. Anticholinergic drugs were discontinued in 43% of patients and pad use in 48%. A total of 80% of the patients were satisfied with the treatment. Bladder contraction disappeared in 70% of patients. The mean maximal cystometric capacity increase was 144 ml. CONCLUSION: Clinical and urodynamic data show that repeat injection of toxins to the detrusor remains an effective therapy for neurogenic bladder overactivity. Efficacy for continence is maintained during successive injections.

A multi-marker model for detecting chromosomal segments displaying QTL activity.

A statistical method is presented for detecting quantitative trait loci (QTLs), based on the linear model. Unlike methods able to detect a few well separated QTLs and to estimate their effects and positions, this method considers the genome as a whole and enables the detection of chromosomal segments involved in the differences between two homozygous lines, and their backcross, doubled haploid, or F2 progenies, for a quantitative trait. Genetic markers must be codominant, but missing markers are accepted, provided they are missing independently from the experiment. Asymptotic properties, which are of practical use, are developed. This method does not rely on strong genetic hypotheses, and thus does not permit any precise genetic analysis of the trait under study, but it does assess which regions of the genome are involved, whatever the complexity of the genetic determinism (number, effects and interactions among QTLs). Simultaneous use of several methods, including this one, should lead to better efficiency in QTL detection.

The definitive stoma: complications and treatment in 50 patients.

Intestinal stomas remain required in many operations for inflammatory bowel disease, for colorectal tumours, trauma and diverticulitis. During one year, 50 patients (20 ileostomies and 30 colostomies) underwent an intestinal stoma and were followed by an enterostomal therapist. The morbidity, the local complications and the treatment are analyzed. An appropriate skin protection is mandatory in the early post-operative period after performing ileostomy or right colostomy. The mucocutaneous dehiscence can be treated by local protection. The quality of life of patients with a stoma is improved by information and careful medical attention given by the surgeon and the enterostomal therapist.

[Post-traumatic syringomyelia]. / Syringomyélie post-traumatique.

Clinical and neuroradiological data were recorded in a series of 73 spinal cord injured patients (33 in Nantes, 40 in Paris-Bicêtre) in whom a post traumatic syringomyelia (PTS) developed. These findings and a review of the literature allow to point out some of the main characteristics in such a pathology. Clinical symptoms are frequent, the commonest of them are pain and sensory loss but any alteration of the neurological status after spinal cord injury has to be considered. Magnetic resonance imaging (MRI), sagittal and axial T1 and T2 weighted images, confirms the diagnosis of syrinx (area with the same signal intensity as CSF extending beyond the site of the initial lesion at least on 2 vertebral segments). MRI allows the diagnosis when it is performed in the follow up of asymptomatic patients. So PTS is not infrequent in spinal cord injured patients, for some of them in the first year after the trauma. The highest incidence is found in patients with complete thoracic lesions. Pathophysiology and surgical management have to take into account post traumatic residual stenosis of the vertebral canal.

Noninvasive molecular methods to identify live scarab larvae: an example of sympatric pest and nonpest species in New Zealand.

Despite the negative impact that many scarab larvae have on agro-ecosystems, very little attention has been paid to their taxonomy. Their often extremely similar morphological characteristics have probably contributed to this impediment, which has also meant that they are very difficult to identify in the field. Molecular methods can overcome this challenge and are particularly useful for the identification of larvae to enable management of pest species occurring sympatrically with nonpest species. However, the invasive collection of DNA samples for such molecular methods is not compatible with subsequent behavioural, developmental or fitness studies. Two noninvasive DNA sampling and DNA analysis methods suitable for the identification of larvae from closely related scarab species were developed here. Using the frass and larval exuviae as sources of DNA, field-collected larvae of Costelytra zealandica (White) and Costelytra brunneum (Broun) (Scarabaeidae: Melolonthinae) were identified by multiplex PCR based on the difference in size of the resulting PCR products. This study also showed that small quantities of frass can be used reliably even 7 days after excretion. This stability of the DNA is of major importance in ecological studies where timeframes rarely allow daily monitoring. The approach developed here is readily transferable to the study of any holometabolous insect species for which morphological identification of larval stages is difficult.

Methodology for jointly assessing myocardial infarct extent and regional contraction in 3-D CMRI.

Automated extraction of quantitative parameters from cardiac magnetic resonance images is crucial for the management of patients with myocardial infarct. This paper proposes a postprocessing procedure to jointly analyze Cine and delayed-enhanced (DE) acquisitions, in order to provide an automatic quantification of myocardial contraction and enhancement parameters and a study of their relationship. For that purpose, the following processes are performed: 1) DE/Cine temporal synchronization and 3-D scan alignment, 2) 3-D DE/Cine rigid registration in a region about the heart, 3) myocardium segmentation on Cine-MRI and superimposition of the epicardial and endocardial contours on the DE images, 4) quantification of the myocardial infarct extent (MIE), 5) study of the regional contractile function using a new index, the amplitude to time ratio (ATR). The whole procedure was applied to ten patients with clinically proven myocardial infarction. The comparison between the MIE and the visually assessed regional function scores demonstrated that the MIE is highly related to the severity of the wall motion abnormality. In addition, it was shown that the newly developed regional myocardial contraction parameter (ATR) decreases significantly in delayed enhanced regions. This largely automated approach enables the combined study of regional MIE and left ventricular function.