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Introduction Hereditary diffuse leukoencephalopathy with neuroaxonal spheroids (HDLS) is a paediatric autosomal dominant dysmyelinating disease. 1 Rare adult onset cases manifest with personality change, cognitive decline and gait impairment. 1-3 Diagnosis is often made following brain biopsy with the presence of giant neuroaxonal swellings known as spheroids. 4 Characteristic brain MRI abnormalities of HDLS include decreased T1-weighted signal intensity of the frontoparietal white matter and corpus callosum. 2 T2-weighted images reveal patchy increased signal intensity in the subcortical white matter with corticospinal tract involvement. 1-4 To our knowledge, this is the first report of an abnormal apparent diffusion coefficient (ADC) map in HDLS. The brain biopsy specimen was significant for areas of demyelination, axonal dropout and unpigmented activated macrophages, and the presence of large neuroaxonal spheroids ( figure 1F , arrows, haematoxylin-eosin stain) diagnostic of HDLS.

No treatment has consistently shown efficacy in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS). We assessed the effect of siponimod, a selective sphingosine 1-phosphate (S1P) receptor1,5 modulator, on disability progression in patients with SPMS. This event-driven and exposure-driven, double-blind, phase 3 trial was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries. Using interactive response technology to assign numbers linked to treatment arms, patients (age 18–60 years) with SPMS and an Expanded Disability Status Scale score of 3·0–6·5 were randomly assigned (2:1) to once daily oral siponimod 2 mg or placebo for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression (CDP) events. The primary endpoint was time to 3-month CDP. Efficacy was assessed for the full analysis set (ie, all randomly assigned and treated patients); safety was assessed for the safety set. This trial is registered with ClinicalTrials.gov, number NCT01665144. 1651 patients were randomly assigned between Feb 5, 2013, and June 2, 2015 (1105 to the siponimod group, and 546 to the placebo group). One patient did not sign the consent form, and five patients did not receive study drug, all of whom were in the siponimod group. 1645 patients were included in the analyses (1099 in the siponimod group and 546 in the placebo). At baseline, the mean time since first multiple sclerosis symptoms was 16·8 years (SD 8·3), and the mean time since conversion to SPMS was 3·8 years (SD 3·5); 1055 (64%) patients had not relapsed in the previous 2 years, and 918 (56%) of 1651 needed walking assistance. 903 (82%) patients receiving siponimod and 424 (78%) patients receiving placebo completed the study. 288 (26%) of 1096 patients receiving siponimod and 173 (32%) of 545 patients receiving placebo had 3-month CDP (hazard ratio 0·79, 95% CI 0·65–0·95; relative risk reduction 21%; p=0·013). Adverse events occurred in 975 (89%) of 1099 patients receiving siponimod versus 445 (82%) of 546 patients receiving placebo; serious adverse events were reported for 197 (18%) patients in the siponimod group versus 83 (15%) patients in the placebo group. Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular oedema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo. Initial dose titration mitigated cardiac first-dose effects. Frequencies of infections, malignancies, and fatalities did not differ between groups. Siponimod reduced the risk of disability progression with a safety profile similar to that of other S1P modulators and is likely to be a useful treatment for SPMS. Novartis Pharma AG.

Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses. ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18–58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0–6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0–5·5 vs 6·0–6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181. Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66–1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74–1·53; nominal p=0·753) or the T25FW (0·98, 0·74–1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40–0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108–221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred. Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components. Biogen.

To describe the relative effects of graded central nervous system (CNS) depression, using increasing propofol infusion rates, on neurovegetative brainstem-mediated circulatory control mechanisms and higher cortical activity in healthy humans. Propofol was administered using an infusion scheme designed to achieve three target blood concentrations in ten healthy volunteers. Blood propofol concentrations and sedation scores were determined at baseline, during the three propofol infusion levels, and 30 min into the recovery period. Electroencephalographic (EEG) power was measured in three frequency bands to quantify cortical activity, and autonomic heart rate control was quantified using spontaneous baroreflex assessment and power spectral analysis of pulse interval. Sedation scores closely paralleled propofol blood concentrations (0, 0.53 +/- 0.34, 1.24 +/- 0.21, 3.11 +/- 0.80, and 0.96 +/- 0.42 microg x mL(-1) at baseline, three infusion levels and recovery respectively), and all subjects were unconscious at the deepest level. Indices of autonomic heart rate control were decreased only at the deepest levels of CNS depression, while EEG effects were apparent at all propofol infusion rates. These EEG effects were frequency specific, with power in the beta band being affected at light levels of sedation, and alpha and delta power altered at deeper levels. The results of this study support a relative preservation of neurovegetative circulatory control mechanisms during the early stages of CNS depression using gradually increasing rates of infusion of propofol. Indices of circulatory control did not reliably reflect depth of sedation.

Results from studies of twin concordance in multiple sclerosis have not conclusively differentiated between environmental and genetic factors that determine susceptibility to the disease. Published studies that have been based on case finding by public appeal have been characterized by difficulties in ascertainment. The data reported here are from a large population-based study of multiple sclerosis in twins, in which ascertainment has been relatively unbiased and the cooperation of patients nearly complete. A total of 5463 patients attending 10 multiple sclerosis clinics across Canada were surveyed. Twenty-seven monozygotic and 43 dizygotic twin pairs were identified, and the diagnosis of multiple sclerosis was verified by examination and laboratory investigation. Seven of 27 monozygotic pairs (25.9 percent) and 1 of 43 dizygotic pairs (2.3 percent) were concordant for multiple sclerosis. The concordance rate for 4582 nontwin siblings of patients at two multiple sclerosis clinics was 1.9 percent, closely paralleling the concordance rate in dizygotic twins. To the extent that the difference in concordance rates between monozygotic and dizygotic twins indicates genetic susceptibility, the results of this study show a major genetic component in susceptibility to multiple sclerosis. (N Engl J Med 1986; 315:1638–42.) STUDIES of twins have been a classic way of distinguishing between environmental and genetic determinants of susceptibility to disease. 1 Such studies are of special value in disorders in which either the mode of inheritance or the nature of the environmental effect is obscure. Multiple sclerosis is a chronic neurologic disorder in which both environmental 2 , 3 and genetic factors 3 , 4 appear to have a causal role. Evidence in support of genetic susceptibility to the disease has been inconclusive. 3 , 4 The results of several previous studies of twins have been ambiguous. 5 6 7 8 9 The largest of these studies 5 showed little difference in concordance rates between dizygotic and . . .

Four published genome screens have identified a number of markers with increased sharing in multiple sclerosis (MS) families, although none has reached statistical significance. One hundred and five markers previously identified as showing increased sharing in Canadian, British, Finnish, and American genome screens were genotyped in 219 sibling pairs ascertained from the database of the Canadian Collaborative Project on Genetic Susceptibility to MS (CCPGSMS). No markers examined met criteria for significant linkage. Markers located at 5p14 and 17q22 were analyzed in a total of 333 sibling pairs and attained mlod scores of 2.27 and 1.14, respectively. The known HLA Class II DRB1 association with MS was confirmed (P<0.0001). Significant transmission disequilibrium was also observed for D17S789 at 17q22 (P=0.0015). This study highlights the difficulty of searching for genes with only mild-to-moderate effects on susceptibility, although large effects of specific loci may still be present in individual families. Future progress in the genetics of this complex trait may be helped by (1) focussing on more ethnically homogeneous samples, (2) using an increased number of MS families, and (3) using transmission disequilibrium analysis in candidate regions rather than the affected relative pair linkage analysis.

More and more ecologists have started to resurvey communities sampled in earlier decades to determine long-term shifts in community composition and infer the likely drivers of the ecological changes observed. However, to assess the relative importance of and interactions among multiple drivers, joint analyses of resurvey data from many regions spanning large environmental gradients are needed. In this article, we illustrate how combining resurvey data from multiple regions can increase the likelihood of driver orthogonality within the design and show that repeatedly surveying across multiple regions provides higher representativeness and comprehensiveness, allowing us to answer more completely a broader range of questions. We provide general guidelines to aid the implementation of multiregion resurvey databases. In so doing, we aim to encourage resurvey database development across other community types and biomes to advance global environmental change research.

The current study aimed to determine the association between timing and completion of adjuvant chemotherapy and outcomes in real-world patients with early-stage pancreatic cancer. In this multi-center cohort study patients with early-stage pancreatic cancer who were diagnosed from 2007-2017 and underwent complete resection in the province of Saskatchewan were examined. Cox proportional multivariate analyses were performed for correlation with recurrence and survival. Of 168 patients, 71 eligible patients with median age of 69 years and M:F of 37:34 were identified. Median time to the start of adjuvant therapy from surgery was 73 days. Of all patients, 49 (69%) patients completed adjuvant chemotherapy and 22 (31%) required early treatment discontinuation. Median recurrence-free survival of patients who completed treatment was 22 months (95%CI:15.8-28.2) vs. 9 months (3.3-14.7) if treatment was discontinued early (P<0.001). Median overall survival of those who completed treatment was 33 (17.5-48.5) vs. 16 months (17.5-48.5) with early treatment discontinuation (P<0.001). In the multivariate analysis, treatment discontinuation was significantly correlated with recurrent disease, hazard ratio (HR), 2.57 (1.41-4.68), P = 0.002 and inferior survival, HR, 2.55 (1.39-4.68), P = 0.003. No correlation between treatment timing and survival was noted. Early discontinuation but not the timing of adjuvant chemotherapy correlates with inferior outcomes.

A World Meteorological Organization weather and climate extremes committee has judged that the world’s longest reported distance for a single lightning flash occurred with a horizontal distance of 321 km (199.5 mi) over Oklahoma in 2007, while the world’s longest reported duration for a single lightning flash is an event that lasted continuously for 7.74 s over southern France in 2012. In addition, the committee has unanimously recommended amendment of the AMS Glossary of Meteorology definition of lightning discharge as a “series of electrical processes taking place within 1 s” by removing the phrase “within 1 s” and replacing it with “continuously.” Validation of these new world extremes 1) demonstrates the recent and ongoing dramatic augmentations and improvements to regional lightning detection and measurement networks, 2) provides reinforcement regarding the dangers of lightning, and 3) provides new information for lightning engineering concerns.