Background and objectives
Diagnosis of multiple sclerosis (MS) requires exclusion of diseases that could better explain the clinical and paraclinical findings. A systematic process for exclusion of ...alternative diagnoses has not been defined. An International Panel of MS experts developed consensus perspectives on MS differential diagnosis.
Methods
Using available literature and consensus, we developed guidelines for MS differential diagnosis, focusing on exclusion of potential MS mimics, diagnosis of common initial isolated clinical syndromes, and differentiating between MS and non-MS idiopathic inflammatory demyelinating diseases.
Results
We present recommendations for 1) clinical and paraclinical red flags suggesting alternative diagnoses to MS; 2) more precise definition of “clinically isolated syndromes” (CIS), often the first presentations of MS or its alternatives; 3) algorithms for diagnosis of three common CISs related to MS in the optic nerves, brainstem, and spinal cord; and 4) a classification scheme and diagnosis criteria for idiopathic inflammatory demyelinating disorders of the central nervous system.
Conclusions
Differential diagnosis leading to MS or alternatives is complex and a strong evidence base is lacking. Consensus-determined guidelines provide a practical path for diagnosis and will be useful for the non-MS specialist neurologist. Recommendations are made for future research to validate and support these guidelines. Guidance on the differential diagnosis process when MS is under consideration will enhance diagnostic accuracy and precision.
We hypothesized that chemoprophylaxis with the echinocandin micafungin would be an effective agent for antifungal prophylaxis during neutropenia in patients undergoing hematopoietic stem cell ...transplantation (HSCT). We therefore conducted a randomized, double-blind, multi-institutional, comparative phase III trial, involving 882 adult and pediatric patients, of 50 mg of micafungin (1 mg/kg for patients weighing <50 kg) and 400 mg of fluconazole (8 mg/kg for patients weighing <50 kg) administered once per day. Success was defined as the absence of suspected, proven, or probable invasive fungal infection (IFI) through the end of therapy and as the absence of proven or probable IFI through the end of the 4-week period after treatment. The overall efficacy of micafungin was superior to that of fluconazole as antifungal prophylaxis during the neutropenic phase after HSCT (80.0% in the micafungin arm vs. 73.5% in the fluconazole arm difference, 6.5%; 95% confidence interval, 0.9%-12%; P = .03). This randomized trial demonstrates the efficacy of an echinocandin for antifungal prophylaxis in neutropenic patients.
Background:
Understanding long-term disability in multiple sclerosis (MS) is a key goal of research; it is relevant to how we monitor and treat the disease.
Objectives:
The Magnetic Imaging in MS ...(MAGNIMS) collaborative group sought to determine the relationship of brain lesion load, and brain and spinal cord atrophy, with physical disability in patients with long-established MS.
Methods:
Patients had a magnetic resonance imaging (MRI) scan of their brain and spinal cord, from which we determined brain grey (GMF) and white matter (WMF) fractional volumes, upper cervical spinal cord cross-sectional area (UCCA) and brain T2-lesion volume (T2LV). We assessed patient disability using the Expanded Disability Status Scale (EDSS). We analysed associations between EDSS and MRI measures, using two regression models (dividing cohort by EDSS into two and four sub-groups).
Results:
In the binary model, UCCA (p < 0.01) and T2LV (p = 0.02) were independently associated with the requirement of a walking aid. In the four-category model UCCA (p < 0.01), T2LV (p = 0.02) and GMF (p = 0.04) were independently associated with disability.
Conclusions:
Long-term physical disability was independently linked with atrophy of the spinal cord and brain T2 lesion load, and less consistently, with brain grey matter atrophy. Combinations of spinal cord and brain MRI measures may be required to capture clinically-relevant information in people with MS of long disease duration.
Background and purpose
Multiple sclerosis (MS) is a complex disease with new drugs becoming available in the past years. There is therefore a need for a reference tool compiling current data to aid ...professionals in treatment decisions. The objective was to develop an evidence‐based clinical practice guideline for the pharmacological treatment of people with MS.
Methods
This guideline has been developed using the GRADE methodology and following the updated EAN recommendations for guideline development. Clinical questions were formulated in PICO format (patient, intervention, comparator, outcome) and outcomes were prioritized according to their relevance to clinical practice. Literature searches up to December 2016 were performed and the evidence is presented narratively and, when possible, combined in a meta‐analysis. The quality of evidence was rated into four categories – very high, high, low and very low − according to the risk of bias. The recommendations with assigned strength (strong, weak) were formulated based on the quality of evidence and the risk−benefit balance. Consensus between the panelists was reached by use of the modified nominal group technique.
Results
A total of 10 questions have been agreed, encompassing treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and treatment strategies in MS and pregnancy. The guideline takes into account all disease‐modifying drugs approved by the European Medicine Agency at the time of publication. A total of 21 recommendations were agreed by the guideline working group members after three rounds of consensus.
Conclusion
The present guideline, which includes descriptions of the evidence together with recommendations, will enable homogeneity of treatment decisions across Europe.
It is known that temperature estimates of macroscopic systems in equilibrium are most precise when their energy fluctuations are large. However, for nanoscale systems deviations from standard ...thermodynamics arise due to their interactions with the environment. Here we include such interactions and, using quantum estimation theory, derive a generalised thermodynamic uncertainty relation valid for classical and quantum systems at all coupling strengths. We show that the non-commutativity between the system's state and its effective energy operator gives rise to quantum fluctuations that increase the temperature uncertainty. Surprisingly, these additional fluctuations are described by the average Wigner-Yanase-Dyson skew information. We demonstrate that the temperature's signal-to-noise ratio is constrained by the heat capacity plus a dissipative term arising from the non-negligible interactions. These findings shed light on the interplay between classical and non-classical fluctuations in quantum thermodynamics and will inform the design of optimal nanoscale thermometers.
Recent research has concluded that forest wildfires in the western United States are becoming larger and more frequent. A more significant question may be whether the ecosystem impacts of wildfire ...are also increasing. We show that a large area (approximately 120000 km²) of California and western Nevada experienced a notable increase in the extent of forest stand-replacing (“high severity”) fire between 1984 and 2006. High severity forest fire is closely linked to forest fragmentation, wildlife habitat availability, erosion rates and sedimentation, post-fire seedling recruitment, carbon sequestration, and various other ecosystem properties and processes. Mean and maximum fire size, and the area burned annually have also all risen substantially since the beginning of the 1980s, and are now at or above values from the decades preceding the 1940s, when fire suppression became national policy. These trends are occurring in concert with a regional rise in temperature and a long-term increase in annual precipitation. A close examination of the climate-fire relationship and other evidence suggests that forest fuels are no longer limiting fire occurrence and behavior across much of the study region. We conclude that current trends in forest fire severity necessitate a re-examination of the implications of all-out fire suppression and its ecological impacts.
ABSTRACT Luminous quasars at can be studied in detail with the current generation of telescopes and provide us with unique information on the first gigayear of the universe. Thus far, these studies ...have been statistically limited by the number of quasars known at these redshifts. Such quasars are rare, and therefore, wide-field surveys are required to identify them, and multiwavelength data are required to separate them efficiently from their main contaminants, the far more numerous cool dwarfs. In this paper, we update and extend the selection for the quasars presented in Bañados et al. (2014) using the Pan-STARRS1 (PS1) survey. We present the PS1 distant quasar sample, which currently consists of 124 quasars in the redshift range that satisfy our selection criteria. Of these quasars, 77 have been discovered with PS1, and 63 of them are newly identified in this paper. We present the composite spectra of the PS1 distant quasar sample. This sample spans a factor of ∼20 in luminosity and shows a variety of emission line properties. The number of quasars at presented in this work almost doubles the previously known quasars at these redshifts, marking a transition phase from studies of individual sources to statistical studies of the high-redshift quasar population, which was impossible with earlier, smaller samples.
Due to a heightened risk of progressive multifocal leukoencephalopathy (PML) with increased natalizumab exposure, some physicians interrupt treatment of patients with multiple sclerosis (MS) despite ...a lack of data regarding the safety of treatment interruption, the rate and severity of MS disease activity return after treatment interruption, or alternative treatment strategies.
To determine the effects of natalizumab treatment interruption on clinical and MRI measures of disease activity in relapsing patients with MS.
Clinical relapses and gadolinium-enhanced (Gd+) lesions were analyzed over an 8-month period in patients from the AFFIRM, SENTINEL, and GLANCE studies of natalizumab, and their respective safety extension studies, following the voluntary suspension of natalizumab dosing that occurred in February 2005.
Relapses were analyzed in 1,866 patients, and Gd+ lesions were analyzed in 341 patients. Annualized relapse rates and Gd+ lesions both increased shortly after natalizumab interruption and peaked between 4 and 7 months. A consistent return of disease activity was observed regardless of overall natalizumab exposure, whether or not patients received alternative MS therapies, and in patients with highly active MS disease. A rebound of relapse or Gd+ lesion activity, beyond placebo-treated levels from the clinical studies, was not observed in any of the analyses conducted.
Following interruption of natalizumab treatment, MS disease activity returned in a pattern that was consistent with known pharmacokinetic and pharmacodynamic properties of natalizumab, and did not show evidence of rebound.
In a 2-year, placebo-controlled trial (the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis AFFIRM study), involving 942 patients with relapsing multiple sclerosis (MS), ...natalizumab significantly reduced the relapse rate by 68% and progression of sustained disability by 42% vs placebo. We report the effect of natalizumab on MRI measures from the AFFIRM study.
The number and volume of gadolinium (Gd)-enhancing, new or enlarging T2-hyperintense, and new T1-hypointense lesions and brain parenchymal fraction were measured from annual scans obtained at baseline, 1 year, and 2 years.
Compared with placebo, natalizumab produced a 92% decrease in Gd-enhancing lesions (means 2.4 vs 0.2; p < 0.001), an 83% decrease in new or enlarging T2-hyperintense lesions (means 11.0 vs 1.9; p < 0.001), and a 76% decrease in new T1-hypointense lesions (means 4.6 vs 1.1; p < 0.001) over 2 years. Median T2-hyperintense lesion volume increased by 8.8% in the placebo group and decreased by 9.4% in the natalizumab group (p < 0.001); median T1-hypointense lesion volume decreased by 1.5% in the placebo group and decreased by 23.5% in the natalizumab group (p < 0.001). Brain atrophy was greater in year 1 and less in year 2 in natalizumab-treated patients.
Natalizumab has a sustained effect in preventing the formation of new lesions in patients with relapsing multiple sclerosis.
Natalizumab is the first alpha4 integrin antagonist in a new class of selective adhesion-molecule inhibitors. We report the results of a two-year phase 3 trial of natalizumab in patients with ...relapsing multiple sclerosis.
Of a total of 942 patients, 627 were randomly assigned to receive natalizumab (at a dose of 300 mg) and 315 to receive placebo by intravenous infusion every four weeks for more than two years. The primary end points were the rate of clinical relapse at one year and the rate of sustained progression of disability, as measured by the Expanded Disability Status Scale, at two years.
Natalizumab reduced the risk of sustained progression of disability by 42 percent over two years (hazard ratio, 0.58; 95 percent confidence interval, 0.43 to 0.77; P<0.001). The cumulative probability of progression (on the basis of Kaplan-Meier analysis) was 17 percent in the natalizumab group and 29 percent in the placebo group. Natalizumab reduced the rate of clinical relapse at one year by 68 percent (P<0.001) and led to an 83 percent reduction in the accumulation of new or enlarging hyperintense lesions, as detected by T2-weighted magnetic resonance imaging (MRI), over two years (mean numbers of lesions, 1.9 with natalizumab and 11.0 with placebo; P<0.001). There were 92 percent fewer lesions (as detected by gadolinium-enhanced MRI) in the natalizumab group than in the placebo group at both one and two years (P<0.001). The adverse events that were significantly more frequent in the natalizumab group than in the placebo group were fatigue (27 percent vs. 21 percent, P=0.048) and allergic reaction (9 percent vs. 4 percent, P=0.012). Hypersensitivity reactions of any kind occurred in 25 patients receiving natalizumab (4 percent), and serious hypersensitivity reactions occurred in 8 patients (1 percent).
Natalizumab reduced the risk of the sustained progression of disability and the rate of clinical relapse in patients with relapsing multiple sclerosis. Adhesion-molecule inhibitors hold promise as an effective treatment for relapsing multiple sclerosis. (ClinicalTrials.gov number, NCT00027300.).
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