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Background: ALS is a progressive neurodegenerative disease without a cure and limited treatment options. Edaravone, a free radical scavenger, was shown to slow disease progression in a select group of patients with ALS over 6 months; however, the effect on survival was not investigated in randomized trials. The objective of this study is to describe real-world survival effectiveness over a longer timeframe. Methods: This retrospective cohort study included patients with ALS across Canada with symptom onset up to three years. Those with a minimum 6-month edaravone exposure between 2017 and 2022 were enrolled in the interventional arm, and those without formed the control arm. The primary outcome of tracheostomy-free survival was compared between the two groups, accounting for age, sex, ALS-disease progression rate, disease duration, pulmonary vital capacity, bulbar ALS-onset, and presence of frontotemporal dementia or C9ORF72 mutation using inverse propensity treatment weights. Results: 182 patients with mean ± SD age 60±11 years were enrolled in the edaravone arm and 860 in the control arm (mean ± SD age 63±12 years). Mean ± SD time from onset to edaravone initiation was 18±10 months. Tracheostomy-free survival will be calculated. Conclusions: This study will provide evidence for edaravone effectiveness on tracheostomy-free survival in patients with ALS.
Background: The Canadian Registry for Amyloidosis Research (CRAR) is a nationwide disease registry of transthyretin (ATTR) and light-chain (AL) amyloidosis. Recent advances in disease-modifying therapy have improved prognosis, however there is a critical need for real-world evidence to address knowledge gaps, particularly longer-term therapeutic outcomes and surveillance strategies. Methods: A multi-stakeholder process was undertaken to develop a consensus dataset for ATTR- and AL-amyloidosis. This process included surveys to rank the importance of potential data items, and a consensus meeting of the CRAR steering committee, (comprised of multidisciplinary clinical experts, and patient organization representatives). Patients and patient organizations supported the development and implementation of a patient-reported dataset. Results: Consensus data items include disease onset, progression, severity, treatments, and outcomes, as well as patient-reported outcomes. Both prospective and retrospective (including deceased) patient cohorts are included. Further baseline data will be presented on an initial cohort of patients. Conclusions: CRAR has been established to collect a longitudinal, multidisciplinary dataset that will evaluate amyloidosis care and outcomes. CRAR has launched at multiple specialty amyloidosis centers nationally and is continually expanding. The growth of this program will promote opportunities to assess real-world safety and efficacy and inform the cost-effectiveness of therapies while supporting patient recruitment for research.
Background: The late-onset cerebellar ataxias (LOCAs) have until recently resisted molecular diagnosis. Contributing to this diagnostic gap is that non-coding structural variations, such as repeat expansions, are not fully accessible to standard short-read sequencing analysis. Methods: We combined bioinformatics analysis of whole-genome sequencing and long-read sequencing to search for repeat expansions in patients with LOCA. We enrolled 66 French-Canadian, 228 German, 20 Australian and 31 Indian patients. Pathogenic mechanisms were studied in post-mortem cerebellum and induced pluripotent stem cell (iPSC)-derived motor neurons from 2 patients. Results: We identified 128 patients who carried an autosomal dominant GAA repeat expansion in the first intron of the FGF14 gene. The expansion was present in 61%, 18%, 15% and 10% of patients in the French-Canadian, German, Australian and Indian cohorts, respectively. The pathogenic threshold was determined to be (GAA)≥250, although incomplete penetrance was observed in the (GAA)250-300 range. Patients developed a slowly progressive cerebellar syndrome at an average age of 59 years. Patient-derived post-mortem cerebellum and induced motor neurons both showed reduction in FGF14 RNA and protein expression compared to controls. Conclusions: This intronic, dominantly inherited GAA repeat expansion in FGF14 represents one of the most common genetic causes of LOCA uncovered to date.
Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive disease caused by mutations in the TTR gene leading to multisystem organ dysfunction. Pathogenic TTR aggregation, misfolding, and fibrillization lead to deposition of amyloid in multiple body organs and frequently involve the peripheral nerve system and the heart. Common neurologic manifestations include: sensorimotor polyneuropathy (PN), autonomic neuropathy, small-fiber PN, and carpal tunnel syndrome. Many patients have significant progression due to diagnostic delays as hATTR PN is not considered within the differential diagnosis. Recently, two effective novel disease-modifying therapies, inotersen and patisiran, were approved by Health Canada for the treatment of hATTR PN. Early diagnosis is crucial for the timely introduction of these disease-modifying treatments that reduce impairments, improve quality of life, and extend survival. In this guideline, we aim to improve awareness and outcomes of hATTR PN by making recommendations directed to the diagnosis, monitoring, and treatment in Canada.
Spinal muscular atrophy (SMA) is a devastating rare disease that affects individuals regardless of ethnicity, gender, and age. The first-approved disease-modifying therapy for SMA, nusinursen, was approved by Health Canada, as well as by American and European regulatory agencies following positive clinical trial outcomes. The trials were conducted in a narrow pediatric population defined by age, severity, and genotype. Broad approval of therapy necessitates close follow-up of potential rare adverse events and effectiveness in the larger real-world population.
Methods:
The Canadian Neuromuscular Disease Registry (CNDR) undertook an iterative multi-stakeholder process to expand the existing SMA dataset to capture items relevant to patient outcomes in a post-marketing environment. The CNDR SMA expanded registry is a longitudinal, prospective, observational study of patients with SMA in Canada designed to evaluate the safety and effectiveness of novel therapies and provide practical information unattainable in trials.
Results:
The consensus expanded dataset includes items that address therapy effectiveness and safety and is collected in a multicenter, prospective, observational study, including SMA patients regardless of therapeutic status. The expanded dataset is aligned with global datasets to facilitate collaboration. Additionally, consensus dataset development aimed to standardize appropriate outcome measures across the network and broader Canadian community. Prospective outcome studies, data use, and analyses are independent of the funding partner.
Conclusion:
Prospective outcome data collected will provide results on safety and effectiveness in a post-therapy approval era. These data are essential to inform improvements in care and access to therapy for all SMA patients.
Background: Calcium (Ca) and magnesium (Mg) are crucial in metabolism, excitability and neuroglial plasticity. Our aim was to evaluate whether Mg (20 mg/kg) or Ca (100 mg/kg) could improve the memory prognosis in the kainic model of mesial temporal epilepsy. Methods: Seizures were induced by systemic injection of kainate (8mg/kg) and mice were then treated by ions every 48 hours. A placebo (physiological solution) replaced kainate or ions in specific groups. Six cohorts were studied for seven weeks: control group (G0: no kainate and no ion, only placebo); untreated reference group (GR: kainate and then placebo); G1 groups were treated from the third day (G1m, G1c: kainate and then Mg/Ca); G2 groups were treated from the third week (G2m, G2c: kainate and then Mg/Ca). Radial maze and a classic maze were used for cognition evaluation. Results: The memory (short/long term) was differently affected by kainate or improved by Mg/Ca. The treated groups performed better than GR mice, but Mg was more effective. In addition, Mg demonstrated an increasing therapeutic effect over time while Ca showed an acute and apparently decreasing action in the G1c group. Conclusions: Mg should be considered for a clinical evaluation of its effect on epileptic disorders.
The importance of chronic low-grade inflammation in the pathology of numerous age-related chronic conditions is now clear. An unresolved inflammatory response is likely to be involved from the early stages of disease development. The present position paper is the most recent in a series produced by the International Life Sciences Institute's European Branch (ILSI Europe). It is co-authored by the speakers from a 2013 workshop led by the Obesity and Diabetes Task Force entitled ‘Low-grade inflammation, a high-grade challenge: biomarkers and modulation by dietary strategies’. The latest research in the areas of acute and chronic inflammation and cardiometabolic, gut and cognitive health is presented along with the cellular and molecular mechanisms underlying inflammation–health/disease associations. The evidence relating diet composition and early-life nutrition to inflammatory status is reviewed. Human epidemiological and intervention data are thus far heavily reliant on the measurement of inflammatory markers in the circulation, and in particular cytokines in the fasting state, which are recognised as an insensitive and highly variable index of tissue inflammation. Potential novel kinetic and integrated approaches to capture inflammatory status in humans are discussed. Such approaches are likely to provide a more discriminating means of quantifying inflammation–health/disease associations, and the ability of diet to positively modulate inflammation and provide the much needed evidence to develop research portfolios that will inform new product development and associated health claims.
To describe a relatively unknown clinical entity – inflammatory cast of the tympanic membrane after acute otitis media – and its simple out-patient treatment.
Study design:
Retrospective review of case series.
Setting:
Subspecialty practice at a tertiary hospital.
Patients:
Seven patients diagnosed previously with acute otitis media with perforation or otitis externa, and with persistent ear discomfort.
Methods:
Retrospective chart review.
Results:
The patients presented with weeks to months of persistent hearing loss after acute otitis media with perforation or acute otitis externa. Visits to their primary care physicians had been uninformative. After comparison of the affected and unaffected tympanic membranes, a thin, hard cast was identified and removed from the affected tympanic membrane. Improvement in hearing was documented in the three patients who underwent audiometric testing; the remainder had subjective improvement without audiometric evaluation.
Conclusion:
Otolaryngologists should be aware of the possibility of an inflammatory cast of the tympanic membrane following acute otitis media with perforation or otitis externa, and should carefully compare the unaffected and affected ears in such cases. Treatment – removal of the rigid cast – is both simple and effective.
This book documents how a complex branch of science was started and encouraged to grow both nationally and internationally, as seen through the eyes of two authors who together played a major role in many of the events that they describe. It traces the beginning and subsequent development of a space science programme for British scientists from the early 1950s to the early 1980s, and gives the scientific, technological and administrative background whilst highlighting some of the outstanding successes of the programme. Cooperation with NASA in the United States is described in some detail, and the part played by Britain in establishing European cooperation in space science is outlined, as is the more modest cooperative programme with Commonwealth countries. This historical account will be of interest to all space scientists, geophysicists and astronomers, as well as to those concerned with the administration and organisation of large, co-operative scientific programmes.
The influence of negative substrate bias on the chemical, electrical and mechanical properties of silicon carbide (SiC) thin films deposited onto (100) silicon substrate by dc magnetron cosputtering without external substrate heating is reported. These studies were performed by using the following techniques: Rutherford backscattering spectroscopy (RBS), profilometry, Raman spectroscopy, four-point probe method and nanoindentation. The results indicate that there is a good correlation between the substrate bias voltage and the argon incorporation into SiC film, namely, the SiC films deposited under substrate bias of –200 V and –300 V have higher argon content and higher elastic modulus and hardness than those deposited at 0 V. An opposite behavior was found for electrical resistivity: the SiC deposited at –300 V has resistivity of 0.45 Ω.cm whereas the deposited at 0 V has 7.0 Ω.cm.
This paper reports the deposition of titanium dioxide thin films on p-type Si(100) substrates using two techniques called conventional magnetron sputtering (CMS) and hollow cathode magnetron sputtering (HCMS). The influence of the plasma parameters on the film characteristics (topography, morphology and crystallinity) was investigated. Films were deposited at different oxygen concentrations (in the Ar + O2 gas mixture) and axial distances for fixed values of working pressure (5.0 mTorr) and DC power (55 W). They were analyzed by profilometry, AFM and XRD. The gas discharge was diagnosed by single Langmuir probe and OES. Under experimental conditions used in this work, results show that HCMS favors the growing of rutile phase due to the increase of the energy on the film surface caused by the hollow cathode effect. On the other hand, films deposited by CMS present preferentially anatase phase due to the low energy transferred to the growing film. Further studies regarding the influence of plasma properties on the films formation were done in order to understand the plasma-surface correlation.
Cylindrical hollow cathode magnetron sputtering (HCMS) system was used to deposit crystalline titanium dioxide thin films on p-Si (100) substrates. For a fixed pressure of 0.6 Pa total gas flow rate of 20 sccm and power of 55 W, the influence of the oxygen percentage in the Ar+O2 gas mixture on the structural and surface properties of the films was studied by profilometry, XRD and AFM. The substrates were placed inside the hollow cathode at different positions along its symmetrical axis. Numerical simulations of cathode ion collection probability (CICP) were done in order to compare calculated data with the deposition process characteristics. The results indicate that the deposition rate and the surface roughness gradually decrease with the distance from the bottom of the cathode, due to the decrease of the CICP. The increase of the oxygen percentage in the gas discharge influences directly the deposition rate and decrease the surface roughness. The XRD analyses show that all the films are crystalline with predominant anatase (101) and rutile (110) orientations.
Semiconductor nanowires are attractive nano- building blocks for microelectronics. However, the requirements for their manufacturing and application in the microelectronics industry are very demanding. Beyond compatibility with Si technology, full control on the characteristics of the grown wires (diameter, location, crystallinity, etc..), homogeneity on wafer –scale and reproducibility are essential. In this study we review critically important challenges for a controlled process of In –mediated growth of Si nanowires. First, we stress the importance of surface type for both particle catalysts and growth substrates. Both selection and preparation of such surfaces have large impact on growth, as they influence the initiation and the driving forces for the VLS growth mechanism. Moreover, wire characteristics such as morphology, crystalline quality and growth orientation appear more difficult to control when growing from particles with sizes below 40-50nm. This limitation arises as a result of both fundamental mechanisms and more specific constrains linked to the In-Si system.
A few perspectives are given for the achievement of a controlled Si nanowire growth in a Si –technology compatible fashion.
The Arcetri/Bologna H2O maser group has been monitoring the 1.3-cm water maser emission from a sample of 43 star-forming regions (SFRs) and 22 late-type stars for about 20 years at a sampling rate of 4-5 observations each year, using the 32-m Medicina Radio Telescope (HPBW 1.′9 at 22 GHz). For the late-type stars we observe representative samples of OH/IR-stars, Mira's, semi-regular variables, and supergiants. The SFR-sample spans a large interval in FIR luminosity of the associated Young Stellar Object (YSO), from 20 L⊙ to 1.5 × 106 L⊙, and offers a unique data base for the study of the long-term (years) variability of the maser emission in regions of star formation.
This presentation concerns only the masers in SFRs. The information obtained from single-dish monitoring is complementary to what is extracted from higher-resolution (VLA and VLBI) observations, and can better explore the velocity domain and the long-term variability therein.
We characterize the variability of the sources in various ways and we study how it depends on the luminosity and other properties of the associated YSO and its environment.
We present the preliminary results of a statistical analysis carried out on a 1° × 1° CO(1-0) map of the intermediate mass star forming region Vela-D Cloud. Our goal is to determine statistical parameters suitable to quantify the structure of the observed cloud, in particular the power-law exponent of the map power spectrum. Furthermore, to help in removing the degeneracy implied in using a single parameter, we also resort to the multifractal approach.
Psychiatric consultation and supportive psychotherapy provide many benefits for women with breast cancer including an opportunity to address existential, physical, emotional, social, psychosexual and relationship (family and others) concerns. The psychiatrist is a source of meaningful information and helps the patient challenge pessimistic thoughts and consider life, health, family and career priorities. The management of psychiatric symptoms and the treatment of side effects helps promote adherence to cancer treatment.
A detailed transmission electron microscopy study is performed on the
pyramidal inversion domains that appear in highly Mg-doped GaN grown by
metalorganics vapor phase epitaxy or by the high-pressure, high-temperature
method. From a comparison between high resolution images of the inversion
domain boundaries and simulations using different atomic models, we conclude
that both basal and inclined domain boundaries are likely formed of a
monomolecular layer of the definite compound Mg3N2. We show that,
due to their high concentration, the formation of these defects may account
for auto-compensation in Mg-doped GaN. We also show that the local band
bending induced by the polarity inversion due to these defects can be at the
origin of the blue luminescence of highly Mg-doped GaN, always observed when
nanometric pyramidal inversion domains are also present.
We present here the results of a search for new microquasars at low galactic latitudes, based on a cross-identification between the ROSAT all sky Bright Source Catalog (RBSC) and the NRAO VLA Sky Survey (NVSS) and follow-up observations. The results obtained up to now suggest that persistent/silent microquasars such as LS 5039 are rare objects in our Galaxy, and indicate that future deeper surveys, and harder than the RBSC in X-rays, will play a fundamental role in order to discover them.
The high power RF device performance decreases as operation
temperature increases (e.g. fall of electron mobility impacting the cut-off frequencies
and degradation of device reliability). Therefore the determination of device
temperature is a key issue for device topology optimisation. This work presents the
comparison between pulsed I-V at different temperature and DC measurements of
AlGaN/GaN HEMTs grown on two different substrates: sapphire and silicon. This
technique allows the determination of mean channel temperature and the device
thermal resistance. The thermal resistance is a classical way to define the average
channel temperature as a function of the dissipated power. In this work the thermal
resistance ratio of the HEMT grown on sapphire compared to the one grown on silicon
is found to be 1.7 instead of 3 as expected from straightforward thermal conductivity
ratio. This lower difference is clearly attributed to the contribution of the GaN buffer
layer.
In a recent paper [Phys. Rev. B 68, 153313 (2003)], we reported the first experimental observation of the strong coupling regime in a GaN-based microcavity. The λ/2 GaN optical cavity was grown by molecular beam epitaxy on a Si(111) substrate. The upper mirror is a SiO2/Si3N4 dielectric mirror and the silicon substrate acts as the bottom mirror. With such a relatively simple and low-finesse microcavity, a Rabi splitting of 31 meV was measured at 5K. On the basis of this very encouraging result, approaches to fabricate high-finesse GaN-based cavities exhibiting strong coupling with stable polaritons at room temperature are discussed.