A decade of fingolimod in multiple sclerosis: Insights from a large real-world cohort study.

BACKGROUND AND OBJECTIVES: Ten years after its authorization, data about fingolimod use in real-world setting is still scarce. Here we describe the long-term evolution of fingolimod-treated relapsing-remitting MS (RRMS) patients and determine baseline characteristics associated with risk of relapses or disability. METHODS: We analyzed baseline characteristics and clinical evolution of 1227 patients with RRMS treated with fingolimod from 2010 to 2019 in 4 French MS referral centers. We used Cox models to determine risks factors of relapses and sustained EDSS worsening. RESULTS: Median follow-up duration was 50 months, and 63% of patients remained fingolimod-treated at the end of follow-up. Mean 5-years annualized relapse rate (ARR) decreased from 0.63 (0.60-0.67) to 0.26 (0.24-0.29, P<0.001), while the mean EDSS rose from 2.5 (2.4-2.6) to 3.0 (2.8-3.1, P<0.001). Female sex, lower age, higher EDSS and use of natalizumab were associated with relapse risk. Female sex was associated with sustained EDSS increase risk. CONCLUSIONS: Based on a large real-world cohort, our results confirm the durable reduction of the ARR described in pivot studies. Switching from moderate-efficacy DMT to fingolimod decreased the relapse risk. Switching patients from high-efficacy DMT increased risk of relapse, but the overall five-years ARR remained stable.

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.

[The fighting for history of medicine].

The article considers issues of actual discussion about "death of history of medicine". For a long time, history of medicine was set out the task to substantiate triumph of one national model and tradition over another one and "to place the past at the service of the future". For example, Richard Horton, the editor-in-chief of The Lancet, believes that historians of medicine in no way respond to such problems of today as commercialization of medicine, drug abuse, paralysis in public health, catastrophic failures in patient care. He assumes this fact being true sign of that the history of medicine "is creeping towards scientific cemetery". Another reason for appearance of "obituaries" of history of medicine is the regular fact that classical courses almost exclusively consisted of narratives about great physicians and progress of medical science and practice. Moreover, the "medical" history of medicine if is not killed then is severely wounded by arrows flying from all sides - accusations in mistakes, indications on blind spots, myths and deliberate distortion of facts. The analysis of above-listed problems the proposals were developed concerning possible ways of revising academic course according modern requirements: training in the field of critical thinking, communication skills, oral speech and written language, academic writing. These tasks can be achieved by involving materials from museums of history of medicine, museums of universities and medical institutions, by collaboration with historical sources, databases of scientific publications and by engaging invited lecturers of various specialties working with historical and medical topics within the framework of other methodologies.

Slowly fading super-luminous supernovae that are not pair-instability explosions.

Super-luminous supernovae that radiate more than 10(44) ergs per second at their peak luminosity have recently been discovered in faint galaxies at redshifts of 0.1-4. Some evolve slowly, resembling models of 'pair-instability' supernovae. Such models involve stars with original masses 140-260 times that of the Sun that now have carbon-oxygen cores of 65-130 solar masses. In these stars, the photons that prevent gravitational collapse are converted to electron-positron pairs, causing rapid contraction and thermonuclear explosions. Many solar masses of (56)Ni are synthesized; this isotope decays to (56)Fe via (56)Co, powering bright light curves. Such massive progenitors are expected to have formed from metal-poor gas in the early Universe. Recently, supernova 2007bi in a galaxy at redshift 0.127 (about 12 billion years after the Big Bang) with a metallicity one-third that of the Sun was observed to look like a fading pair-instability supernova. Here we report observations of two slow-to-fade super-luminous supernovae that show relatively fast rise times and blue colours, which are incompatible with pair-instability models. Their late-time light-curve and spectral similarities to supernova 2007bi call the nature of that event into question. Our early spectra closely resemble typical fast-declining super-luminous supernovae, which are not powered by radioactivity. Modelling our observations with 10-16 solar masses of magnetar-energized ejecta demonstrates the possibility of a common explosion mechanism. The lack of unambiguous nearby pair-instability events suggests that their local rate of occurrence is less than 6 × 10(-6) times that of the core-collapse rate.

[Modifications in therapy for patients with severe mental illness and intellectual disability: a qualitative study]. / Aanpassingen in behandeling van patiënten met ernstige psychiatrische aandoeningen en een lichte verstande-lijke beperking; een kwalitatief onderzoek.

BACKGROUND: In ambulant psychiatric care, intellectual disability (id) is often not recognised. Therefore, a Screener for Intelligence and Learning disabilities (scil) was recently introduced to assist recognition. However, because, current therapy is not adjusted for id-related problems, its effectiveness remains unknown.
AIM: To gain insight into adequate adaptation of interventions by professionals for patients with severe mental illness (smi) and id, to improve the quality of care without the need to develop a completely new program of therapy.
METHOD: A qualitative design (n=15) including 8 interviews and one focus group, among psychiatric practitioners and id experts.
RESULTS: Five main themes were identified to adjust therapy: treatment, communication, inclusion of the network, estimation of support needs and self-management. CONCLUSIONS To align therapy with the requirements of patients with smi and id, a patient-oriented approach to care is necessary. Simple but effective modifications, summarised in a toolkit, appear to contribute to this. To offer appropriate care to patients with smi and id, attention is needed for both a support-oriented and a recovery-oriented approach.

An ultraviolet-optical flare from the tidal disruption of a helium-rich stellar core.

The flare of radiation from the tidal disruption and accretion of a star can be used as a marker for supermassive black holes that otherwise lie dormant and undetected in the centres of distant galaxies. Previous candidate flares have had declining light curves in good agreement with expectations, but with poor constraints on the time of disruption and the type of star disrupted, because the rising emission was not observed. Recently, two 'relativistic' candidate tidal disruption events were discovered, each of whose extreme X-ray luminosity and synchrotron radio emission were interpreted as the onset of emission from a relativistic jet. Here we report a luminous ultraviolet-optical flare from the nuclear region of an inactive galaxy at a redshift of 0.1696. The observed continuum is cooler than expected for a simple accreting debris disk, but the well-sampled rise and decay of the light curve follow the predicted mass accretion rate and can be modelled to determine the time of disruption to an accuracy of two days. The black hole has a mass of about two million solar masses, modulo a factor dependent on the mass and radius of the star disrupted. On the basis of the spectroscopic signature of ionized helium from the unbound debris, we determine that the disrupted star was a helium-rich stellar core.

The RAPID-II Neuropsychological Test battery for subjects aged 20 to 49 years: Norms and cognitive profile.

INTRODUCTION: Cognitive evaluation of young subjects is now widely carried out for non-traumatic diseases such as multiple sclerosis, HIV, or sleep disorders. This evaluation requires normative data based on healthy adult samples. However, most clinicians use a set of tests that were normed in an isolated manner from different samples using different cutoff criteria. Thus, the score of an individual may be considered either normal or impaired according to the norms used. It is well established that healthy adults obtained low-test scores when a battery of tests is administered. Thus, the knowledge of low base rates is required so as to minimize false diagnosis of cognitive impairment. The aim of this study was twofold (1) to provide normative data for RAPID-II battery in healthy adults, and (2) estimate the proportion of healthy adults having low scores across this battery. METHODS: Norms for the 44 test scores of the RAPID-II test battery were developed using the overall sample of 335 individuals based on three categories of age (20 to 29, 30 to 39, and 40 to 49 years) and two educational levels: Baccalaureate or higher educational degree (high educational level), lower than baccalaureate (low educational level). The 5th, 25th, 50th, and 75th percentiles were calculated from the six age and education subsamples and used to define norms. The frequency of low scores on the RAPID-II battery was calculated by simultaneously examining the performance of 33 primary scores. A low score was defined as less than or equal to the 5th percentile drawn from the six age and education normative subsamples. In addition, the percentages of low scores were also determined when all possible combinations of two-test scores across the RAPID-II were considered in the overall normative sample. RESULTS: Our data showed that 59.4% subjects of the normative sample obtained at least one or more low score. With more than 9 test scores, this percentage was equal to 0% in the normative sample. Among all combinations of two-test scores, 96% had a false positive rate<2%. CONCLUSION: Low scores are very common in young healthy subjects and are more obvious when simultaneously analyzing test scores across a battery of tests and are thus not necessarily indicative of cognitive impairment. The combinations of two-test scores can be a useful tool to improve the interpretation of low scores.

Evaluation of the reliability of the Cutaneous Dermatomyositis Disease Area and Severity Index and the Cutaneous Assessment Tool-Binary Method in juvenile dermatomyositis among paediatric dermatologists, rheumatologists and neurologists.

BACKGROUND: The Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) and Cutaneous Assessment Tool-Binary Method (CAT-BM) have been shown to be reliable and valid outcome measures to assess cutaneous disease in adult dermatomyositis (DM) and juvenile DM (JDM), respectively. OBJECTIVES: This study compared the CDASI and CAT-BM for use by paediatric dermatologists, paediatric rheumatologists and paediatric neurologists in patients with JDM. METHODS: Five paediatric dermatologists, five paediatric rheumatologists and five paediatric neurologists each evaluated 14 patients with JDM using the CDASI, CAT-BM, and skin Physician Global Assessment (PGA) scales. Inter-rater reliability, intra-rater reliability, construct validity and completion time were compared. RESULTS: Inter-rater reliability for CDASI activity and damage scores was good to moderate for paediatric dermatologists and rheumatologists, but poor for paediatric neurologists. The inter-rater reliability for CAT-BM activity scores was moderate for paediatric dermatologists and rheumatologists, but poor for paediatric neurologists and poor across all specialties for damage scores. Intra-rater reliability for the CDASI and CAT-BM activity and damage scores was moderate to excellent for paediatric dermatologists, rheumatologists and neurologists. Strong associations were found between skin PGA activity and damage scores and CDASI or CAT-BM activity and damage scores, respectively (P < 0·002). The CDASI had a mean completion time of 5·4 min compared with that for the CAT-BM of 3·1 min. CONCLUSIONS: Our data confirm the reliability of the CDASI activity and damage scores and the CAT-BM activity scores when used by paediatric dermatologists and rheumatologists in assessing JDM. Significant variation existed in the paediatric neurologists' scores.

Birth of a relativistic outflow in the unusual γ-ray transient Swift J164449.3+573451.

Active galactic nuclei, which are powered by long-term accretion onto central supermassive black holes, produce relativistic jets with lifetimes of at least one million years, and the observation of the birth of such a jet is therefore unlikely. Transient accretion onto a supermassive black hole, for example through the tidal disruption of a stray star, thus offers a rare opportunity to study the birth of a relativistic jet. On 25 March 2011, an unusual transient source (Swift J164449.3+573451) was found, potentially representing such an accretion event. Here we report observations spanning centimetre to millimetre wavelengths and covering the first month of evolution of a luminous radio transient associated with Swift J164449.3+573451. The radio transient coincides with the nucleus of an inactive galaxy. We conclude that we are seeing a newly formed relativistic outflow, launched by transient accretion onto a million-solar-mass black hole. A relativistic outflow is not predicted in this situation, but we show that the tidal disruption of a star naturally explains the observed high-energy properties and radio luminosity and the inferred rate of such events. The weaker beaming in the radio-frequency spectrum relative to γ-rays or X-rays suggests that radio searches may uncover similar events out to redshifts of z ≈ 6.

Immunohistochemical c-kit expression in uterine serous carcinoma tissue.

AIM: Uterine serous carcinoma (USC) is an aggressive tumor that represents only 10% of endometrial cancer cases but accounts for a disproportionate number of deaths due to uterine cancer. Advances in the development of specific c-kit receptor-targeted drugs have promoted its potential therapeutic application as a target in tumor-related diseases. The aim of the present study was to evaluate imunohistochemical expression of c-kit in USC tissue in order to assess whether positive cases can be candidates for targeted therapy. MATERIALS AND METHODS: C-kit expression assessment by immunohistochemistry was performed on deparaffinized sections of paraffin-embedded tissue blocks of confirmed consecutive available USC uterine specimens of patients diagnosed from 2000 to 2014. Sections of gastrointestinal stromal tumor (GIST) tissue known to contain c-kit served as positive controls. RESULTS: Immunohisto- chemical c-kit staining was not observed in any of 31 USC tissue samples examined. Intense staining was observed in the sections of GIST tissue. CONCLUSION: The present results may indicate that primary USC is not a candidate for c-kit targeted therapy.

A gamma-ray burst at a redshift of z approximately 8.2.

Long-duration gamma-ray bursts (GRBs) are thought to result from the explosions of certain massive stars, and some are bright enough that they should be observable out to redshifts of z > 20 using current technology. Hitherto, the highest redshift measured for any object was z = 6.96, for a Lyman-alpha emitting galaxy. Here we report that GRB 090423 lies at a redshift of z approximately 8.2, implying that massive stars were being produced and dying as GRBs approximately 630 Myr after the Big Bang. The burst also pinpoints the location of its host galaxy.

[Assessment of 10 years of memory consultations in the Franche-Comté: Description and analysis of the RAPID regional database]. / Bilan de 10ans de consultations mémoire en Franche-Comté: description et analyse de la base de données RAPID.

The aim of this study was to evaluate the impact, on a regional scale (Franche-Comté), of 3 National Alzheimer care plans, particularly concerning the development of the offer of care management by clinicians as well as the panel of diagnoses concerned. Data on sociodemographic, neuropsychological and diagnostic characteristics were retrieved from the RAPID regional database between 1st January 2003 and 31st December 2012. These analyses focused exclusively on patients who had an initial consultation (n=12,017) during the same period. The existence of a previously established health network capable of carrying out governmental health plans has produced an effective interface between regional administrative structures responsible for the implementation of these plans and health professionals responsible for carrying out them out. This network study, the use of a battery of tests and a common software database have enabled the development of patient care management throughout the Franche-Comté region. It also showed the diversification of diagnoses mentioned over the past years as well as changes in clinical practices on how to address the issue of cognitive impairment.

A prospective observational post-marketing study of natalizumab-treated multiple sclerosis patients: clinical, radiological and biological features and adverse events. The BIONAT cohort.

BACKGROUND AND PURPOSE: BIONAT is a French multicentric phase IV study of natalizumab (NTZ)-treated relapsing-remitting multiple sclerosis (MS) patients. The purpose of this study was to collect clinical, radiological and biological data on 1204 patients starting NTZ, and to evaluate the clinical/radiological response to NTZ after 2 years of treatment. METHODS: Patients starting NTZ at 18 French MS centres since June 2007 were included. Good response to NTZ was defined by the absence of clinical and radiological activity. Data analysed in this first report on the BIONAT study focus on patients who started NTZ at least 2 years ago (n = 793; BIONAT2Y ). RESULTS: NTZ was discontinued in 17.78% of BIONAT2Y. The proportion of patients without combined disease activity was 45.59% during the first two successive years of treatment. Systematic dosage of anti-NTZantibodies (Abs) detected only two supplementary patients with anti-NTZ Abs compared with strict application of recommendations. A significant decrease of IgG,M concentrations at 2 years of treatment was found. CONCLUSIONS: The efficacy of NTZ therapy on relapsing-remitting MS in a real life setting is confirmed in the BIONAT cohort. The next step will be the identification of biomarkers predicting response to NTZ therapy and adverse events.

An extremely luminous X-ray outburst at the birth of a supernova.

Massive stars end their short lives in spectacular explosions--supernovae--that synthesize new elements and drive galaxy evolution. Historically, supernovae were discovered mainly through their 'delayed' optical light (some days after the burst of neutrinos that marks the actual event), preventing observations in the first moments following the explosion. As a result, the progenitors of some supernovae and the events leading up to their violent demise remain intensely debated. Here we report the serendipitous discovery of a supernova at the time of the explosion, marked by an extremely luminous X-ray outburst. We attribute the outburst to the 'break-out' of the supernova shock wave from the progenitor star, and show that the inferred rate of such events agrees with that of all core-collapse supernovae. We predict that future wide-field X-ray surveys will catch each year hundreds of supernovae in the act of exploding.

Sipuleucel-T immunotherapy for castration-resistant prostate cancer.

BACKGROUND: Sipuleucel-T, an autologous active cellular immunotherapy, has shown evidence of efficacy in reducing the risk of death among men with metastatic castration-resistant prostate cancer. METHODS: In this double-blind, placebo-controlled, multicenter phase 3 trial, we randomly assigned 512 patients in a 2:1 ratio to receive either sipuleucel-T (341 patients) or placebo (171 patients) administered intravenously every 2 weeks, for a total of three infusions. The primary end point was overall survival, analyzed by means of a stratified Cox regression model adjusted for baseline levels of serum prostate-specific antigen (PSA) and lactate dehydrogenase. RESULTS: In the sipuleucel-T group, there was a relative reduction of 22% in the risk of death as compared with the placebo group (hazard ratio, 0.78; 95% confidence interval [CI], 0.61 to 0.98; P=0.03). This reduction represented a 4.1-month improvement in median survival (25.8 months in the sipuleucel-T group vs. 21.7 months in the placebo group). The 36-month survival probability was 31.7% in the sipuleucel-T group versus 23.0% in the placebo group. The treatment effect was also observed with the use of an unadjusted Cox model and a log-rank test (hazard ratio, 0.77; 95% CI, 0.61 to 0.97; P=0.02) and after adjustment for use of docetaxel after the study therapy (hazard ratio, 0.78; 95% CI, 0.62 to 0.98; P=0.03). The time to objective disease progression was similar in the two study groups. Immune responses to the immunizing antigen were observed in patients who received sipuleucel-T. Adverse events that were more frequently reported in the sipuleucel-T group than in the placebo group included chills, fever, and headache. CONCLUSIONS: The use of sipuleucel-T prolonged overall survival among men with metastatic castration-resistant prostate cancer. No effect on the time to disease progression was observed. (Funded by Dendreon; ClinicalTrials.gov number, NCT00065442.)

Olfactory dysfunction in multiple sclerosis: evidence of a decrease in different aspects of olfactory function.

BACKGROUND/AIMS: Numerous authors have described olfactory dysfunction in multiple sclerosis (MS) in recent years. The aim of this study was to specify the aspects of olfactory perception that are most affected and to identify any correlations with clinical, anatomical and functional data. METHODS: 50 patients with remitting or secondary progressive MS were included. Personal data were collected (medical history, characteristics of their disease, depression and disability scores and number of lesions on cerebral imaging). An olfactory test (Sniffin Sticks®) was used to evaluate subjects' olfactory function. RESULTS: The odor detection threshold is the most sensitive marker, with 40% of patients presenting hyposmia. The ability to identify odors is affected later on, and is inversely correlated with the level of disability. CONCLUSION: Our results confirm that several aspects of olfactory function are altered in MS, particularly those aspects requiring greater cognitive involvement, such as discrimination and identification of odors.

[Cavitary lesions in multiple sclerosis: multicenter study on twenty patients]. / Formes cavitaires de sclérose en plaques: étude multicentrique sur vingt patients.

INTRODUCTION: Cavitary white matter changes are mainly described in leukodystrophies and especially in vanishing white matter disease. Large cavitary lesions are not typical for multiple sclerosis (MS). METHODS: We studied MS patients with large cavitary brain lesions. Patient characteristics, disease onset/duration/subtype, expanded disability status scale (EDSS), mini mental state (MMS), vanishing white matter disease genetic analysis, and MRI characteristics of the cavitary lesions were analyzed. RESULTS: Twenty patients were analyzed (6 men and 14 women). Mean age at disease onset was 37.6 (range 17-58). Mean disease duration was 10 years (range 2-20). Five patients had initial relapsing-remitting MS and nine patients had primary-progressive MS. Mean EDSS was 5.5 (range 2-8). Mean MMS was 20/30. Vanishing white matter disease genetic analysis was performed and negative in seven patients. Inferior corpus callosum lesions were seen in all patients with available sagittal FLAIR sequences. Cavitary lesions were strictly supratentorial, and located inside the diffuse leukoencephalopathy, with often a posterior predominance. CONCLUSION: MS patients with large cavitary lesions seem to represent a MS subgroup, predominantly women, with relatively late disease onset, predominantly primary-progressive type, relatively high EDSS scores, and severe cognitive dysfunction.

Patterns of metastatic progression and association with clinical outcomes in canine osteosarcoma: A necropsy study of 83 dogs.

Osteosarcoma is a highly metastatic primary bone tumour that occurs spontaneously in both pet dogs and humans. Patterns of metastasis to organs beyond the most common site (lung) are poorly characterised and it is unknown whether specific associations between patterns of metastatic progression and patient features exist. This retrospective study characterised the necropsy findings of 83 dogs receiving standardised therapy and clinical monitoring in a prospective clinical trial setting to document patterns of metastasis and correlate outcomes with these patterns and other patient and tumour-specific factors. A total of 20 different sites of metastasis were documented, with lung as the most common site, followed by bone, kidney, liver, and heart. Two distinct clusters of dogs were identified based on patterns of metastasis. There was no significant association between site of enrollment, trial arm, sex, serum alkaline phosphatase (ALP) activity, or tumour location and clinical outcomes. A second cancer type was identified at necropsy in 10 dogs (10/83; 12%). These data showcase the extensive nature of osteosarcoma metastasis beyond the lung and provide a benchmark for clinical monitoring of the disease. Further, this study provides insight into transcriptional features of primary tumours that may relate to a propensity for osteosarcoma metastasis to specific organs and tissues.

A novel explosive process is required for the gamma-ray burst GRB 060614.

Over the past decade, our physical understanding of gamma-ray bursts (GRBs) has progressed rapidly, thanks to the discovery and observation of their long-lived afterglow emission. Long-duration (> 2 s) GRBs are associated with the explosive deaths of massive stars ('collapsars', ref. 1), which produce accompanying supernovae; the short-duration (< or = 2 s) GRBs have a different origin, which has been argued to be the merger of two compact objects. Here we report optical observations of GRB 060614 (duration approximately 100 s, ref. 10) that rule out the presence of an associated supernova. This would seem to require a new explosive process: either a massive collapsar that powers a GRB without any associated supernova, or a new type of 'engine', as long-lived as the collapsar but without a massive star. We also show that the properties of the host galaxy (redshift z = 0.125) distinguish it from other long-duration GRB hosts and suggest that an entirely new type of GRB progenitor may be required.