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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.
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.
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.
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.
This article examines the conflict between traditional Marxist attitudes toward war and the problem of the nuclear revolution. It shows how the advent of the nuclear revolution in the 1950s undermined traditional Marxist-Leninist concepts of war, and then goes on to argue that this development must be placed at the centre of contemporary Marxian IR if it is to have explanatory power in the twenty-first century. To make this case directly, it engages with Justin Rosenberg’s revival of Trotsky’s idea of uneven and combined development and its subsidiary law of ‘the whip of external necessity’, and argues that the whip can remain salient today only if one accepts the political utility of nuclear war. The impasse created by the nuclear revolution, it concludes, points Marxist IR in the direction of classic Marxist visions of supranationalism and human unity.
Energy intake (EI) and energy expenditure (EE) should not be considered independent entities, but more an inter-connected system. With increased physical activity and reduced snacking initiatives as prevalent Public Health measures, any changes to subsequent EI from these recommendations should be monitored. The aim of this study was to investigate changes in acute EI and appetite over four conditions: (1) a control condition with no snack and no exercise (CON); (2) a snack condition (+1 MJ; SK); (3) a moderate-intensity cycling exercise condition (−1 MJ; EX); and finally (4) both snack and exercise condition (+1 MJ, −1 MJ; EXSK). Acute changes in appetite (visual analogue scale) and lunchtime EI (ad libitum pizza meal) were recorded in twenty boys and eighteen girls (12–13 years). Lunch EI was not significantly different between conditions or sexes (P>0·05). Relative EI was calculated, where the energy manipulation (+1 MJ from the snack or −1 MJ from the exercise) was added to lunchtime EI. Relative EI indicated no significant differences between the sexes (P>0·05); however, in the EX condition, relative EI was significantly lower (P<0·001) compared with all other conditions. Appetite increased significantly over time (P<0·001) and was significantly higher in the CON and EX conditions compared with the SK and EXSK conditions. No significant sex differences were found between conditions. When aiming to evoke an acute energy deficit, increasing EE created a significantly larger relative energy deficit than the removal of the mid-morning snack. Sex was not a confounder to influence EI or appetite between any of the conditions.
Multiple sulfatase deficiency (MSD) is a rare autosomal recessive inborn error of lysosomal metabolism. The clinical phenotypic spectrum encompasses overlapping features of variable severity and is suggestive of individual single sulfatase deficiencies (i.e., metachromatic leukodystrophy, mucopolysaccharidosis, and X-linked ichthyosis).
We describe a 3-year-old male with severe hypotonia, developmental regression and progressive neurodegeneration, coarse facial features, nystagmus (from ocular albinism), and dysmyelinating motor sensory neuropathy. Ethics approval was obtained from the Western University Ontario.
Extensive investigative work-up identified deficiencies of multiple sulfatases: heparan sulfate sulfamidase: 6.5 nmoles/mg/protein/17 hour (reference 25.0-75.0), iduronate-2-sulfate sulfatase: 9 nmol/mg/protein/4 hour (reference 31-110), and arylsulfatase A: 3.8 nmoles/hr/mg protein (reference 22-50). The identification of compound heterozygous pathogenic mutations in the SUMF1 gene c.836 C>T (p.A279V) and c.1045C>T (p.R349W) confirmed the diagnosis of MSD.
The complex clinical manifestations of MSD and the unrelated coexistence of ocular albinism as in our case can delay diagnosis. Genetic counselling should be provided to all affected families.
For more than four decades the twin goals of nuclear nonproliferation and disarmament have been an almost unchallenged objective of the “international community.” Like drought prevention, or bans on the use of child soldiers, nonproliferation remains a mostly uncontroversial, largely universalistic initiative to which few object. The proponents of nonproliferation are fond of stressing that the Treaty on the Nonproliferation of Nuclear Weapons (NPT) has more signatories than any other arms control treaty. Who would not want to prevent more states from obtaining nuclear weapons? And who, for that matter, would oppose the ideal of a world free of such weapons?
Patient registries represent an important method of organizing “real world” patient information for clinical and research purposes. Registries can facilitate clinical trial planning and recruitment and are particularly useful in this regard for uncommon and rare diseases. Neuromuscular diseases (NMDs) are individually rare but in aggregate have a significant prevalence. In Canada, information on NMDs is lacking. Barriers to performing Canadian multicentre NMD research exist which can be overcome by a comprehensive and collaborative NMD registry.
We describe the objectives, design, feasibility and initial recruitment results for the Canadian Neuromuscular Disease Registry (CNDR).
The CNDR is a clinic-based registry which launched nationally in June 2011, incorporates paediatric and adult neuromuscular clinics in British Columbia, Alberta, Ontario, Quebec, New Brunswick and Nova Scotia and, as of December 2012, has recruited 1161 patients from 12 provinces and territories. Complete medical datasets have been captured on 460 “index disease” patients. Another 618 “non-index” patients have been recruited with capture of physician-confirmed diagnosis and contact information. We have demonstrated the feasibility of blended clinic and central office-based recruitment. “Index disease” patients recruited at the time of writing include 253 with Duchenne and Becker muscular dystrophy, 161 with myotonic dystrophy, and 71 with ALS.
The CNDR is a new nationwide registry of patients with NMDs that represents an important advance in Canadian neuromuscular disease research capacity. It provides an innovative platform for organizing patient information to facilitate clinical research and to expedite translation of recent laboratory findings into human studies.
While the summit of the Antarctic Plateau has long been expected to harbor the best ground-based sites for terahertz (THz) frequency astronomical investigations, it is only recently that direct observations of exceptional THz atmospheric transmission and stability have been obtained. These observations, in combination with recent technological advancements in astronomical instrumentation and autonomous field platforms, make the recognition and realization of terahertz observatories on the high plateau feasible and timely. Here, we will explore the context of terahertz astronomy in the era of Herschel, and the crucial role that observatories on the Antarctic Plateau can play. We explore the important scientific questions to which observations from this unique environment may be most productively applied. We examine the importance and complementarity of Antarctic THz astronomy in the light of contemporary facilities such as ALMA, CCAT, SOFIA and (U)LDB ballooning. Finally, building from the roots of THz facilities in Antarctica to present efforts, we broadly highlight future facilities that will exploit the unique advantages of the Polar Plateau and provide a meaningful, lasting astrophysical legacy.
We carried out a population-based study of dystrophin mutations in patients followed by members of the Canadian Paediatric Neuromuscular Group (CPNG) over a ten-year period.
We aimed to describe the changes in diagnostic testing for dystrophinopathy and to determine the frequency of dystrophin mutations from 2000 to 2009.
De-identified data containing the clinical phenotypes, diagnostic methods, and mutational reports from dystrophinopathy patients followed by CPNG centres from January 2000 to December 2009 were analyzed using descriptive statistics.
773 patients had a confirmed diagnosis of dystrophinopathy based on genetic testing (97%), muscle biopsy (2%), or family history (1%). 573 (74%) had complete deletion/duplication analysis of all 79 exons or whole gene sequencing, resulting in 366 (64%) deletions, 64 (11%) duplications, and 143 (25%) point mutations. The percentage of patients who were diagnosed using currently accepted genetic testing methods varied across Canada, with a mean of 63% (SD 23). 246 (43%) mutations involved exons 45 to 53. The top ten deletions (n=147, 26%) were exons 45-47, 45-48, 45, 45-50, 45-55, 51, 45-49, 45-52, 49-50, and 46-47. 169 (29%) mutations involved exons 2 to 20. The most common duplications (n=29, 5.1%) were exons 2, 2-7, 2-17, 3-7, 8-11, 10, 10-11, and 12.
This is the most comprehensive report of dystrophin mutations in Canada. Consensus guidelines regarding the diagnostic approach to dystrophinopathy will hopefully reduce the geographical variation in mutation detection rates in the coming decade.
The Abecedarian study was designed to learn the extent to which an early childhood intervention program might prevent progressive developmental retardation among children born into poverty. Forty years ago, cross-sectional examinations of the cognitive development of children from poor families indicated that their cognitive test scores tended to be within the average range in infancy, but that disproportionate declines occurred after that period (Ramey, 1971). A particularly striking cross-sectional graph charted this kind of progressive decline in intellectual test performance among children born to mothers who themselves had low IQs (Heber, Dever, & Conry, 1968). Because at that time no biologically based etiology for most cases of mild retardation had been identified, many scientists believed that early “social deprivation or environmental deprivation” was implicated in the development of this condition. It followed that intervening to improve the intellectual stimulus value of the environment might prevent or ameliorate the disorder.
Largely based on animal research, evidence mounted that early experience supported development in ways that were critical for later functioning (e.g., Hunt, 1961). More to the point, this line of reasoning was supported by human-subject research conducted by Skeels and his colleagues (1938) in which one group of infants reared within institutions showed dramatic gains in developmental abilities when they were given the kinds of affectionate attention and handling not experienced by others from the same orphanage.
Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy in childhood.
To assess the current care of paediatric DMD patients in Canada, a questionnaire was mailed to 17 physicians who were members of the Canadian paediatric neuromuscular group. Areas of enquiry included; 1) multidisciplinary team composition; 2) means of DMD diagnosis; 3) corticosteroid use; surveillance and management for: 4) orthopaedic, 5) respiratory and 6) cardiac complications and 7) health maintenance (nutrition & immunizations).
Completed surveys were returned by 14/17 (82%) of physicians. Twelve respondents followed DMD patients. All centres had multidisciplinary teams, including respirology (11/12), child neurology or physiatry (11), physiotherapy (9), occupational therapy (9) and orthopaedic surgery (7). Deflazacort 0.9mg/kg/d was used at all centres, which was continued after loss of independent ambulation (11), along with routine calcium and vitamin D supplementation (10). Night splints were prescribed at all centres. Routine surveillance studies included pulmonary function testing (11), sleep studies (10), EKG/echocardiogram (10), bone density (DEXA) scans (10), spine radiography (9), and dietician referral (4).
Paediatric DMD patients are receiving relatively consistent care in multidisciplinary clinics across Canada, in accordance with recommended guidelines for DMD.
The theory of Power Preponderance put forward by Stephen Brooks and William Wohlforth is poised to replace structural balance-of-power theory as the leading American Realist interpretation of international politics. Power Preponderance argues that would-be rivals to the US are not balancing against it because they are dissuaded from doing so by geopolitical and structural factors, rather than because they love the US or are cowed by it. This article shows why the central analytical claim of Power Preponderance would be substantially enhanced by incorporating the logic of the nuclear revolution, but that its main policy recommendation – indefinite and magnanimous American preponderance – is undermined by the spectre of nuclear war. In the nuclear age, normative solutions to the problem of anarchy invariably gravitate toward the logic of a world state.