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Background: Spinal Muscular Atrophy (SMA) is an autosomal recessive neurodegenerative disease. In June 2017, Health Canada approved Nusinersen, currently the only available drug for SMA. Since 2016, patients in Ontario have been treated clinically with Nusinersen through different access programs. Methods: Retrospective case series of patients with SMA treated clinically with Nusinersen in Ontario, describing clinical characteristics and logistics of intrathecal Nusinersen administration. Results: Twenty patients have been treated across four centres. To date, we have reviewed 8 cases at one centre (seven SMA Type I, one SMA Type II). Age at first dose ranged from 3-156 months and disease duration 9-166 months. Patients had received 4-7 doses at last evaluation. Three patients with scoliosis (2 with spinal rods) required fluoroscopy-guided radiologist administration, and 4 required general anesthesia. No complications/adverse events were reported. At last follow up, 5/8 families reported improved daily activities. Of 5 patients with baseline and follow up motor function testing, 3 demonstrated improved scores. One patient died due to respiratory decline at age 9 months, despite improved motor outcome scores. Conclusions: We describe the first Canadian post-marketing experience with Nusinersen. Timely dissemination of this information is needed to guide clinicians, hospital administrators, and policy-makers.
Introduction: Diagnosing pulmonary embolism (PE) can be challenging because the signs and symptoms are often non-specific. Studies have shown that evidence-based algorithms are not always adhered to in the Emergency Department (ED) and are often not used correctly, which leads to unnecessary CT scanning. The YEARS diagnostic algorithm, consisting of three items (clinical signs of deep vein thrombosis, hemoptysis, and whether pulmonary embolism is the most likely diagnosis) and D-dimer, is a novel and simplified way to approach suspected acute PE. The purpose of this study was to 1) evaluate the use of the YEARS algorithm in the ED and 2) to compare the rates of testing for PE if the YEARS algorithm was used. Methods: This was a health records review of ED patients investigated for PE at two emergency departments over a two-year period (April 2013-March 2015). Inclusion criteria were ED physician ordered CT pulmonary angiogram, ventilation-perfusion scan, or D-dimer for investigation of PE. Patients under the age of 18 and those without a D-dimer test were excluded. PE was considered to be present during the emergency department visit if PE was diagnosed on CT or VQ (subsegmental level or above), or if the patient was subsequently found to have PE or deep vein thrombosis during the next 30 days. Trained researchers extracted anonymized data. The rate of CT/VQ imaging and the false negative rate was calculated. Results: There were 1,163 patients that were tested for PE and 1,083 patients were eligible for our analysis. Of the total, 317/1,083 (29.3%; 95%CI 26.6-32.1%) had CT/VQ imaging for PE, and 41/1,083 (3.8%; 95%CI 2.8-5.1%) patients were diagnosed with PE at baseline. Three patients had a missed PE, resulting in a false negative rate of 0.4% (95%CI 0.1-1.2%). If the YEARS algorithm was used, 211/1,083 (19.5%; 95%CI 17.2-22.0%) would have required imaging for PE. Of the patients who would not have required imaging according to the YEARS algorithm, 8/872 (0.9%; 95%CI 0.5-1.8%) would have had a missed PE. Conclusion: If the YEARS algorithm was used in all patients with suspected PE, fewer patients would have required imaging with a small increase in the false negative rate.
Introduction: Diagnosing pulmonary embolism (PE) can be challenging because the signs and symptoms are often non-specific. Studies have shown that evidence-based algorithms are not always adhered to in the Emergency Department (ED), which leads to unnecessary CT scanning. The pulmonary embolism rule-out criteria (PERC) can identify patients who can be safely discharged from the ED without further investigation for PE. The purpose of this study is to evaluate the use of the PERC rule in the ED and to compare the rates of testing for PE if the PERC rule was used. Methods: This was a health records review of ED patients investigated for PE at two emergency departments over a two-year period (April 2013-March 2015). Inclusion criteria were ED physician ordered CT pulmonary angiogram, ventilation-perfusion scan, or D-dimer for investigation of PE. Patients under the age of 18 were excluded. PE was considered to be present during the emergency department visit if PE was diagnosed on CT or VQ (subsegmental level or above), or if the patient was subsequently found to have PE or deep vein thrombosis during the next 30 days. Trained researchers extracted anonymized data. The rate of CT/VQ imaging and the negative predictive value was calculated. Results: There were 1,163 patients that were tested for PE and 1,097 patients were eligible for our analysis. Of the total, 330/1,097 (30.1%; 95%CI 27.4-32.3%) had CT/VQ imaging for PE, and 48/1,097 (4.4%; 95%CI 3.3-5.8%) patients were diagnosed with PE. 806/1,097 (73.5%; 95%CI 70.8-76.0%) were PERC positive, and of these, 44 patients had a PE (5.5%; 95%CI 4.1-7.3%). Conversely, 291/1,097 (26.5%; 95%CI 24.0-29.2%) patients were PERC negative, and of these, 4 patients had a PE (1.4%; 95%CI 0.5-3.5%). Of the PERC negative patients, 291/291 (100.0%; 95%CI 98.7-100.0%) had a D-dimer test done, and 33/291 (11.3%; 95%CI 8.2-15.5%) had a CT angiogram. If PERC was used, CT/VQ imaging would have been avoided in 33/1,097 (3%; 95%CI 2.2-4.2%) patients and the D-dimer would have been avoided in 291/1,097 (26.5%; 95%CI 24.0-29.2%) patients. Conclusion: If the PERC rule was used in all patients with suspected PE, fewer patients would have further testing. The false negative rate for the PERC rule was low.
The correlation between objective and subjective nasal obstruction is poor, and dissatisfaction rates after surgery for nasal obstruction are high. Accordingly, novel assessment techniques may be required. This survey aimed to determine patient experience and preferences for the measurement of nasal obstruction.
Prospective survey of rhinology patients.
Of 72 questionnaires distributed, 60 were completed (response rate of 83 per cent). Obstruction duration (more than one year) (χ2 = 13.5, p = 0.00024), but not obstruction severity, affected willingness to spend more time being assessed. Questionnaires (48 per cent) and nasal inspiratory peak flow measurement (53 per cent) are the most commonly used assessment techniques. Forty-nine per cent of participants found their assessment unhelpful in understanding their obstruction. Eighty-two per cent agreed or strongly agreed that a visual and numerical aid would help them understand their blockage.
Many patients are dissatisfied with current assessment techniques; a novel device with visual or numerical results may help. Obstruction duration determines willingness to undergo longer assessment.
Background: Absence epilepsy (AE) is believed to be generated by a thalamocortical network. Our laboratory showed that hippocampal neuronal firings were synchronous with the SWDs in the gamma butyrolactone (GBL) model of AE in rats. Here, we hypothesize that high frequency oscillations (HFOs) in the hippocampus and other parts of the limbic system were phase modulated by SWDs Methods: GBL (200 mg/kg i.p) was injected to induce SWDs in 6 male Long-Evans rats. Spontaneous local field potentials (LFPs) were recorded from electrodes implanted in the hippocampus and ventrolateral thalamus bilaterally and the right frontal cortex. For each LFP, modulation index (MI) gives the cross-frequency amplitude modulation of the HFOs (;90-250 Hz) by the phase of the SWD frequency at 2-8 Hz Results: Phase modulation of the HFOs by 2-8 Hz frequency increased for >45 min after GBL injection. MI increase was higher for hippocampal than thalamic LFPs, and not significant for frontal cortical LFP. MI for the nucleus accumbens LFP (N= 1 rat) also increased after GBL Conclusions: The modulation of HFOs (presumed local neural activity) by SWD frequency provides further support that the hippocampus and connected limbic system may become synchronous with the SWDs in AE
Introduction: Sepsis protocols call for the acquisition of blood cultures in septic emergency department (ED) patients.However, the criteria for blood cultures are vague, they are costly, only positive 8-12% of the time, with up to half of these being false positives. The objective of this study was to establish if positive blood cultures could be excluded in low-risk sepsis patients with levels of CRP below 20 ml/L. Methods: This was a multicenter prospective cohort study of 765 ED patients at St Paul’s and Mount St Joseph’s hospitals in Vancouver with sepsis (2 or more SIRS criteria and infection) and none of: immuncompromised, injection drug use, indwelling vascular device or septic shock (SBP<90 mmhg). Consecutive patients with sepsis had CRP and blood cultures obtained at the same time.OUTCOMES. True positive blood cultures, false positive blood cultures, positive blood cultures that changed patient management. True and false positive blood cultures were based on Infectious Disease Society of America Guidelines, and change in management was defined as change in type or length of antibiotic therapy and was blindly adjudicated by a medical microbiologist. Results: 765 ED patients with sepsis met inclusion criteria. Mean age was 48.3 years and 57% were male. Blood cultures were positive in 99/765 (12.9%) subjects, of which 19 were false positive (19.2%). CRP was >20 mg/L in 595/765 (77.8%) of patients. Of 170 subjects with a CRP<20 mg/L, 3 had a positive blood culture (1.8%; 95% CI 0.1%- 5%). Management was not changed in any patient with a positive blood culture and CRP level<20 mg/L. Of 19 subjects with a false positive blood culture, CRP was <20 mg/L for 6 (31.6%). Conclusion: In this cohort of low-risk sepsis patients, based on a CRP of <20 mg/L, acquisition of blood cultures could be safely avoided in 22.2% of patients, at significant savings to the health care system.
Introduction: Diagnosing pulmonary embolism (PE) can be challenging because the signs and symptoms are often non-specific. Studies have shown that evidence-based diagnostic algorithms are not always adhered to in the Emergency Department (ED), which leads to unnecessary CT scanning. In 2013, the American College of Chest Physicians identified CT pulmonary angiography as one of the top five avoidable tests. One solution is to use a clinical prediction rule combined with the D-dimer, which safely reduces the use of CT scanning. The objective of this study was to compare the proportion of patients tested for PE in two emergency departments, who 1) had a CT-PE and 2) whose diagnosis of PE was missed. We compared these rates to those if the Wells rule and D-dimer had been applied as standard. Methods: This was a retrospective chart review of ED patients investigated for PE at two hospitals from April 2013 to March 2015 (24 months). Inclusion criteria were the ED physician ordered CT-PE, Ventilation-Perfusion (VQ) scan or D-dimer for investigation of PE. Patients under the age of 18 were excluded. PE was defined as CT/VQ diagnosis of acute PE or acute PE/DVT in 30-day follow-up. Trained researchers extracted anonymized data. The rate of CT/VQ imaging and the false-negative rates were calculated. The false-negative rate was calculated as the number of patients diagnosed with PE within 30 days as a proportion of those patients who did not have a CT/VQ scan at initial presentation. Results: There were 1,189 patients included in this study. 55/1,189 patients (4.6%; 95%CI 3.6-6.0%) were ultimately diagnosed with PE within 30 days. 397/1,189 patients (33.4%; 95%CI 30.8-36.1%) had CT/VQ scans for PE. 3 out of 792 who were not scanned had a missed PE resulting in a false-negative rate of 0.4% (95% CI 0.1-1.1%). 80 patients had an elevated D-dimer or high Wells score but were not imaged. Furthermore, 75 patients who did not have an elevated D-dimer nor a high Wells score were imaged. Had Wells rule/D-dimer been adhered to, 402/1,189 patients (33.8%; 95%CI 31.9-36.6%) would have undergone imaging and the false negative rate would be 0/727, 0% (95%CI 0.0-0.5%). Conclusion: If the Wells rule and D-dimer was used in all patients tested for PE, a similar proportion would have a CT scan but fewer PEs would be missed.
Introduction: Diagnosing pulmonary embolism (PE) in the emergency department can be challenging due to non-specific signs and symptoms; this often results in the over-utilization of CT pulmonary angiography (CT-PA). In 2013, the American College of Chest Physicians identified CT-PA as one of the top five avoidable tests. Age-adjusted D-dimer has been shown to decrease CT utilization rates. Recently, clinical-probability adjusted D-dimer has been promoted as an alternative strategy to reduce CT scanning. The aim of this study is to compare the safety and efficacy of the age-adjusted D-dimer rule and the clinical probability-adjusted D-dimer rule in Canadian ED patients tested for PE. Methods: This was a retrospective chart review of ED patients investigated for PE at two hospitals from April 2013 to March 2015 (24 months). Inclusion criteria were the ED physician ordered CT-PA, Ventilation-Perfusion (VQ) scan or D-dimer for investigation of PE. Patients under the age of 18 were excluded. PE was defined as CT/VQ diagnosis of acute PE or acute PE/DVT in 30-day follow-up. Trained researchers extracted anonymized data. The age-adjusted D-dimer and the clinical probability-adjusted D-dimer rules were applied retrospectively. The rate of CT/VQ imaging and the false negative rates were calculated. Results: In total, 1,189 patients were tested for PE. 1,129 patients had a D-dimer test and a Wells score less than 4.0. 364/1,129 (32.3%, 95%CI 29.6-35.0%) would have undergone imaging for PE if the age-adjusted D-dimer rule was used. 1,120 patients had a D-dimer test and a Wells score less than 6.0. 217/1,120 patients (19.4%, 95%CI 17.2-21.2%) would have undergone imaging for PE if the clinical probability-adjusted D-dimer rule was used. The false-negative rate for the age-adjusted D-dimer rule was 0.3% (95%CI 0.1-0.9%). The false-negative rate of the clinical probability-adjusted D-dimer was 1.0% (95%CI 0.5-1.9%). Conclusion: The false-negative rates for both the age-adjusted D-dimer and clinical probability-adjusted D-dimer are low. The clinical probability-adjusted D-dimer results in a 13% absolute reduction in CT scanning compared to age-adjusted D-dimer.
Recent observations on strength and deformation of small metals containing microstructures, including dislocation patterns, grain boundaries, and second-phase precipitates are reviewed. These microstructures impose an internal length scale that may interplay with the extrinsic length scale due to the specimen size to affect strength and deformation in an intricate manner. For micro-crystals containing pre-existing dislocations, Taylor work-hardening may dictate the dependence of strength on specimen size. The presence of grain boundaries in a small specimen may lead to effects far from the conventional Hall–Petch behavior. Precipitate–dislocation interactions in a small specimen may lead to an interesting weakest-size behavior.
Research on close binary systems has continued at a high level during the past triennium, although the rate of growth is noticeably slower – probably reflecting the cutbacks in funds to which many of us are subject. There have also been changes of emphasis within the field, which are commented on in the pages that follow. These reflect both changing opportunities for observation and the natural development of the subject. In many areas, the time is ripe for a more critical look at ideas that previously seemed adequate.
We discuss different methods to separate high- from low-redshift galaxies based on a combination of spectroscopic and photometric observations. Our baseline scenario is the Hobby-Eberly Telescope Dark Energy eXperiment (HETDEX) survey, which will observe several hundred thousand Lyman Alpha Emitting (LAE) galaxies at 1.9 < z < 3.5, and for which the main source of contamination is [OII]-emitting galaxies at z < 0.5. Additional information useful for the separation comes from empirical knowledge of LAE and [OII] luminosity functions and equivalent width distributions as a function of redshift. We consider three separation techniques: a simple cut in equivalent width, a Bayesian separation method, and machine learning algorithms, including support vector machines. These methods can be easily applied to other surveys and used on simulated data in the framework of survey planning.
We examined factors affecting the immunogenicity of trivalent inactivated influenza vaccination (TIV) in children using the antibody titres of children participating in a Hong Kong community-based study. Antibody titres of strains included in the 2009–2010 northern hemisphere TIV [seasonal A(H1N1), seasonal A(H3N2) and B (Victoria lineage)] and those not included in the TIV [2009 pandemic A(H1N1) and B (Yamagata lineage)] were measured by haemagglutination inhibition immediately before and 1 month after vaccination. Multivariate regression models were fitted in a Bayesian framework to characterize the distribution of changes in antibody titres following vaccination. Statistically significant rises in geometric mean antibody titres were observed against all strains, with a wide variety of standard deviations and correlations in rises observed, with the influenza type B antibodies showing more variability than the type A antibodies. The dynamics of antibody titres after vaccination can be used in more complex models of antibody dynamics in populations.
The epidemiology of varicella is believed to differ between temperate and tropical countries. We conducted a varicella seroprevalence study in elementary and college students in the US territory of American Samoa before introduction of a routine varicella vaccination programme. Sera from 515 elementary and 208 college students were tested for the presence of varicella-zoster virus (VZV) IgG antibodies. VZV seroprevalence increased with age from 76·0% in the 4–6 years group to 97·7% in those aged ⩾23 years. Reported history of varicella disease for elementary students was significantly associated with VZV seropositivity. The positive and negative predictive values of varicella disease history were 93·4% and 36·4%, respectively, in elementary students and 97·6% and 3·0%, respectively, in college students. VZV seroprevalence in this Pacific island appears to be similar to that in temperate countries and suggests endemic VZV circulation.
Hemodynamics is a complex problem with several distinct characteristics; fluid is non-Newtonian, flow is pulsatile in nature, flow is three-dimensional due to cholesterol/plague built up, and blood vessel wall is elastic. In order to simulate this type of flows accurately, any proposed numerical scheme has to be able to replicate these characteristics correctly, efficiently, as well as individually and collectively. Since the equations of the finite difference lattice Boltzmann method (FDLBM) are hyperbolic, and can be solved using Cartesian grids locally, explicitly and efficiently on parallel computers, a program of study to develop a viable FDLBM numerical scheme that can mimic these characteristics individually in any model blood flow problem was initiated. The present objective is to first develop a steady FDLBM with an immersed boundary (IB) method to model blood flow in stenoic artery over a range of Reynolds numbers. The resulting equations in the FDLBM/IB numerical scheme can still be solved using Cartesian grids; thus, changing complex artery geometry can be treated without resorting to grid generation. The FDLBM/IB numerical scheme is validated against known data and is then used to study Newtonian and non-Newtonian fluid flow through constricted tubes. The investigation aims to gain insight into the constricted flow behavior and the non-Newtonian fluid effect on this behavior.
One viable approach to the study of haemodynamics is to numerically model this flow behavior in normal and stenosed arteries. The blood is either treated as Newtonian or non-Newtonian fluid and the flow is assumed to be pulsating, while the arteries can be modeled by constricted tubes with rigid or elastic wall. Such a task involves formulation and development of a numerical method that could at least handle pulsating flow of Newtonian and non-Newtonian fluid through tubes with and without constrictions where the boundary is assumed to be inelastic or elastic. As a first attempt, the present paper explores and develops a time-accurate finite difference lattice Boltzmann method (FDLBM) equipped with an immersed boundary (IB) scheme to simulate pulsating flow in constricted tube with rigid walls at different Reynolds numbers. The unsteady flow simulations using a time-accurate FDLBM/IB numerical scheme is validated against theoretical solutions and other known numerical data. In the process, the performance of the time-accurate FDLBM/IB for a model blood flow problem and the ease with which the no-slip boundary condition can be correctly implemented is successfully demonstrated.
Fluid flow through a two-dimensional fracture network has been simulated using a discrete fracture model. The computed field-scale permeabilities were then compared to those obtained using an equivalent continuum approach in which the permeability of each grid block is first obtained by performing fine-scale simulations of flow through the fracture network within that region. In the equivalent continuum simulations, different grid-sizes were used, corresponding to N by N grids with N = 10, 40, 100 and 400. The field-scale permeabilities found from the equivalent continuum simulations were generally within 10% of the values found from the discrete fracture simulations. The discrepancies between the two approaches seemed to be randomly related to the grid size, as no convergence was observed as N increased. An interesting finding was that the equivalent continuum approach gave accurate results in cases where the grid block size was clearly smaller than the 'representative elementary volume'.
Fullerene chemistry is booming, but how the chemical reactions affect fullerene's materials properties has seldom been studied. We have investigated optical limiting behavior of a series of fullerene derivatives, polymers, and glasses and have observed the following structure-property relationships for optical limiting in the fullerene materials: (i) The fullerene polymers with aromatic and chlorine moieties, i.e., C60-containing polycarbonate (C60-PC), polystyrene (C60- PS), and poly(vinyl chloride) (C60-PVC), limit the 8-ns pulses of 532-nm laser light more effectively than does the parent C60; (ii) the fullerene polymers with carbonyl groups, i.e., C60- containing CR-39 (C60-CR-39) and poly(methyl methacrylate), (C60-PMMA), do not enhance C60's limiting power; and (iii) the aminated fullerene derivatives, i.e., HxC60 (NHR)x [R = -(CH2CH2O)2H (1), x = 11; -(CH2)6OH (2), x = 7; -cyclo-C6H11 (3), x = 11; -(CH2)3Si(OC2H5)3 (4), x = 4], and their sol-gel glasses, i.e., 1–3/SiO2 (physical blending) and 4-SiO2 (chemical bonding), show complex limiting responses, with 4(-SiO2) performing consistently better than 1-3(/SiO2). The fullerene glasses are optically stable and their optical limiting properties remainunchanged after being subjected to continuous attack by the strong laser pulses for ca. 1 h.