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.

Life-threatening lactic acidosis occurring in adults with mitochondrial disorders.

Although relatively common in children, severe acute lactic acidosis is rare in adults with mitochondrial myopathies. We report here three cases, aged 27, 32 and 32 years, who developed life-threatening metabolic crisis with severe lactic acidosis, requiring hospitalisation in intensive care unit. Plasma lactates were elevated 10 to 15 fold normal values, necessitating extra-renal dialysis. By contrast CK levels were moderately increased (3 to 5N). No triggering factor was identified, but retrospectively all patients reported long-lasting mild muscle fatigability and weakness before their acute metabolic crisis. All of them recovered after prolonged intensive care but resting lactate levels remained elevated. Muscle biopsy showed ragged-red and COX-negative fibers in two patients and mild lipidosis in the third one. Heteroplasmic pathogenic point mutations were detected in MT-TL1 (m.3280G>A;m.3258C>T) and MT-TK (m.8363A>G). Life-threatening lactic acidosis may thus be a major inaugural clinical manifestation in adults with mitochondrial myopathies. Prolonged intensive care may lead to a dramatic and sustained improvement and is mandatory in such cases.

Alzheimer disease: modeling an Aß-centered biological network.

In genetically complex diseases, the search for missing heritability is focusing on rare variants with large effect. Thanks to next generation sequencing technologies, genome-wide characterization of these variants is now feasible in every individual. However, a lesson from current studies is that collapsing rare variants at the gene level is often insufficient to obtain a statistically significant signal in case-control studies, and that network-based analyses are an attractive complement to classical approaches. In Alzheimer disease (AD), according to the prevalent amyloid cascade hypothesis, the pathology is driven by the amyloid beta (Aß) peptide. In past years, based on experimental studies, several hundreds of proteins have been shown to interfere with Aß production, clearance, aggregation or toxicity. Thanks to a manual curation of the literature, we identified 335 genes/proteins involved in this biological network and classified them according to their cellular function. The complete list of genes, or its subcomponents, will be of interest in ongoing AD genetic studies.

De novo deleterious genetic variations target a biological network centered on Aß peptide in early-onset Alzheimer disease.

We hypothesized that de novo variants (DNV) might participate in the genetic determinism of sporadic early-onset Alzheimer disease (EOAD, onset before 65 years). We investigated 14 sporadic EOAD trios first by array-comparative genomic hybridization. Two patients carried a de novo copy number variation (CNV). We then performed whole-exome sequencing in the 12 remaining trios and identified 12 non-synonymous DNVs in six patients. The two de novo CNVs (an amyloid precursor protein (APP) duplication and a BACE2 intronic deletion) and 3/12 non-synonymous DNVs (in PSEN1, VPS35 and MARK4) targeted genes from a biological network centered on the Amyloid beta (Aß) peptide. We showed that this a priori-defined genetic network was significantly enriched in amino acid-altering DNV, compared with the rest of the exome. The causality of the APP de novo duplication (which is the first reported one) was obvious. In addition, we provided evidence of the functional impact of the following three non-synonymous DNVs targeting this network: the novel PSEN1 variant resulted in exon 9 skipping in patient's RNA, leading to a pathogenic missense at exons 8-10 junction; the VPS35 missense variant led to partial loss of retromer function, which may impact neuronal APP trafficking and Aß secretion; and the MARK4 multiple nucleotide variant resulted into increased Tau phosphorylation, which may trigger enhanced Aß-induced toxicity. Despite the difficulty to recruit Alzheimer disease (AD) trios owing to age structures of the pedigrees and the genetic heterogeneity of the disease, this strategy allowed us to highlight the role of de novo pathogenic events, the putative involvement of new genes in AD genetics and the key role of Aß network alteration in AD.

High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease.

Performing exome sequencing in 14 autosomal dominant early-onset Alzheimer disease (ADEOAD) index cases without mutation on known genes (amyloid precursor protein (APP), presenilin1 (PSEN1) and presenilin2 (PSEN2)), we found that in five patients, the SORL1 gene harbored unknown nonsense (n=1) or missense (n=4) mutations. These mutations were not retrieved in 1500 controls of same ethnic origin. In a replication sample, including 15 ADEOAD cases, 2 unknown non-synonymous mutations (1 missense, 1 nonsense) were retrieved, thus yielding to a total of 7/29 unknown mutations in the combined sample. Using in silico predictions, we conclude that these seven private mutations are likely to have a pathogenic effect. SORL1 encodes the Sortilin-related receptor LR11/SorLA, a protein involved in the control of amyloid beta peptide production. Our results suggest that besides the involvement of the APP and PSEN genes, further genetic heterogeneity, involving another gene of the same pathway is present in ADEOAD.

Biomechanical findings in rats undergoing fascial reconstruction with graft materials suggested as an alternative to polypropylene.

AIMS: Graft materials used for pelvic floor reinforcement should still be considered as investigational and, therefore, evaluated experimentally and within clinical trials. The present report describes our biomechanical findings in rats implanted with selected novel implant materials, which in recent years have been suggested as alternatives to plain polypropylene (PP) meshes. METHODS: Full thickness abdominal wall defects were primarily repaired by the implant of interest. Experiments involved eight different implant materials: two partly degradable synthetic implants, that is, a hybrid of polyglactin 910 with PP (Vypro II) and collagen coated PP (Pelvitex); two non-cross linked (Surgisis, InteXen LP) and two cross-linked materials (Pelvicol, Pelvisoft) and two porous modifications of InteXen LP and Pelvicol implants. At different time points (7, 14, 30, and 90 days), the implants and surrounding host tissue (explant) were harvested and tensiometry was performed. Tensile strength and location of breakage were recorded. RESULTS: In general resorbable non-cross linked collagen matrices and porous materials were weaker after 90 days; similar behavior was seen for implant materials alone and their construction with the surrounding native tissue. Both non-porous and porous modification of InteXen LP appeared at 90 days as a very thin layer of collagen that was two-thirds, respectively one-third of the initial thickness. CONCLUSIONS: In experimental conditions, sufficient strength was obtained only after 3 months, and PP containing constructs appeared as the strongest though reconstruction with Pelvicol showed comparable outcomes. Lower values for strength of non-cross linked and porous collagen materials are questioning their efficacy for pelvic floor reconstruction.

[Fragile X premutation presenting as postural tremor and ataxia (FXTAS syndrome)]. / Tremblement postural et ataxie révélant une prémutation X fragile ou syndrome FXTAS.

We report a case of FXTAS in a 58-year-old man who presented with postural tremor, mild ataxia and dysexecutive cognitive signs. The syndrome had a slow progressive course. Brain imaging by MRI showed characteristic abnormalities with mild cerebellar atrophy, symmetric high signals in the middle cerebellar peduncles and in the subcortical white matter of cerebral hemispheres. The diagnosis was confirmed by molecular genetics showing by southern blot a 100-120 expansion repeat of the CGG trinucleotide. FXTAS is a recently described syndrome, still unknown by most neurologists and probably rather frequent in men older than 60. We emphasize the value of clinical evaluation and brain imaging by MRI in some patients presenting with non specific motor or cognitive symptoms. A diagnosis of FXTAS may have implications for genetic counselling of female relatives.

Case report of pallido-pyramidal disease with supplementary motor area involvement.

An C-flumazenil positron emission tomography (PET) study in a patient with pallido-pyramidal disease revealed a marked decrease in benzodiazepine-receptor density in the precentral gyrus cortex and the mesial frontal cortex. We suggest that, in addition to dysfunction of basal ganglia-dependent systems, degeneration of the supplementary motor area could also be involved in the patient's bradykinesia.

[Diagnostic criteria of borderline forms of multiple sclerosis]. / Critères diagnostiques des formes frontières de sclérose en plaques.

Border forms of multiple sclerosis (MS) can be separated in two groups: either they are variants of MS or they are distinct from MS but they share several characteristics with MS thus representing for some of them a continuum with MS. All these entities are central nervous system demyelinating diseases. Here we describe, for the first group, MS in childhood, MS in elderly subjects, Balò's concentric sclerosis, Schilder's myelinoclastic diffuse sclerosis and MS simulating a mass lesion, and for the second group, acute disseminated encephalomyelitis and Devic's neuromyelitis optica.

[Diagnostic criteria of multiple sclerosis in neuroimaging]. / Critères diagnostiques de la sclérose en plaques en neuroimagerie.

To date, there is no biological test available with enough confidence to make alone a diagnosis of Multiple Sclerosis (MS). MS diagnosis criteria are then an association of clinical and para clinical criteria that allow an objective demonstration of dissemination of lesions in both time and space. Adapted MRI criteria from Barkhof have a good sensitivity and the best specificity to evaluate MS. 3 of 4 criteria are necessary: 1 gadolinium enhancing lesion or 9 T2 hyper intense lesions; at least 1 infratentorial lesion; at least 1 juxtacortical lesion; at least four periventricular lesions; NB: 1 spinal cord lesion can substitute for 1 brain lesion. News methods as spectroscopy, magnetization transfer, diffusion MRI and functional MRI complete results of conventional MRI and give new informations about physiopathology of MS demyelinating lesions.

Gel-test: interpretation and value of a new technique for the detection of irregular antibodies.

Here we report on our experience with the use of a 'Gel-Test' (DiaMed-ID Micro Typing System) technique for the detection and identification of irregular antibodies in a general hospital. This easy-to-use, standardized technique poses the question of the impact of its sensitivity on the specificity of the results. Of the 10% of observed positive reactions, 3.7% were irregular antibodies, 3.8% papain auto-antibodies, 1% cold antibodies and 2% not elucidated. Two hundred and eighteen irregular antibodies identified and titred with the 'gel-test' system were tested in parallel by 'tube' method. Sixty-three of these antibodies (29%) were not detected by the 'tube' method. While anti-Kell was always detected by both methods, we found the following false natives with the tube method: 15% anti-D, 32% anti-E, 42% anti-Cw and 58% anti-Lea. 68% of these false negatives had a low titre. The immunoglobulin class of the anti-E was studied; the sensitivity of the 'gel-test' system was associated with IgM in the anti-E. The sensitivity and standardization of the 'gel-test' technique guarantee greater safety in blood transfusion and increase efficiency in the prevention of foeto-maternal stimulation of anti-D.

[Linoleic acid in nutritional balance: experimental studies]. / L'acide linoléique dans l'équilibre alimentaire: recherches expérimentales.

In the male rat a diet rich in beef fat facilitates the occurrence of hyperinsulinemia after a glucose load whereas fats rich in linoleic acid produce no such effect. The combination of saturated fat and saccharose facilitates the occurrence of hypertriglyceridemia in the male rat, no such effect is produced by the combination of fats rich in linoleic acid and saccharose. Linoleic acid prevents natrium chloride from provoking hypertriglyceridemia in male and in female rats subjected to a diet enriched in saccharose and fat. Estrogen-induced hypertriglyceridemia in castrated animals is strongly inhibited if the diet is rich in linoleic acid. Physical effort can prevent saccharose combined with saturated fats from inducing hypertriglyceridemia.

[Effect of progesterone on the hypertriglyceridemia due to the diet and the oestrogens (author's transl)]. / Action de la progestérone sur l'hypertriglycéridémie due à l'action combinée du régime et des oestrogènes

PIP: Observations conducted on male and female castrated rats fed with a heavy diet of beef fat and saccarose, and treated with estrogens, show that progesterone does not affect hypertriglyceridemia, and has practically no effect on cholesterol level.^ieng

[Influence of sucrose and many fats on carbohydrate metabolism and insulinemia by the rat (author's transl)]. / Influence réciproque du saccharose et de diverses graisses sur le métabolisme glucidique et l'insulinémie du rat

Rats are fed during one month with normal diet or diet enriched with 25% of many fats. It is no change of the hyperglycemia curve with the addition of 25% sucrose to these diets but 1 degree by male on the normal diet or on the diet enriched with corn oil the insulin discharge is higher; it is no change with the diet enriched with beef fat or with M.C.T. 2 degrees by the female the insulin discharge is higher with all the diets.

[Proceedings: Effect of oestrogens and diet on lipids in the plasma of castrated rats of both sexes (author's transl)]. / Influence des oestrogènes et du régime sur les lipides plasmatiques du rat castré des deux sexes

The hypertriglyceridemia after treatment with oestrogens by the castrated rats is of the same amplitude in both sexes with regimes enriched with saccharose or with beaf fat or with both. The gonosomes not influenced the hypertriglyceridemia after treatment with oestrogens.