Background: Phase 3 COMET trial (NCT02782741) compares avalglucosidase alfa (n=51) with alglucosidase alfa (n=49) in treatment-naïve LOPD. Methods: Primary objective: determine avalglucosidase alfa effect on respiratory muscle function. Secondary/other objectives include: avalglucosidase alfa effect on functional endurance, inspiratory/expiratory muscle strength, lower/upper extremity muscle strength, motor function, health-related quality of life, safety. Results: At Week 49, change (LSmean±SE) from baseline in upright forced vital capacity %predicted was greater with avalglucosidase alfa (2.89%±0.88%) versus alglucosidase alfa (0.46%±0.93%)(absolute difference+2.43%). The primary objective, achieving statistical non-inferiority (p=0.0074), was met. Superiority testing was borderline significant (p=0.0626). Week 49 change from baseline in 6-minute walk test was 30.01-meters greater for avalglucosidase alfa (32.21±9.93m) versus alglucosidase alfa (2.19±10.40m). Positive results for avalglucosidase alfa were seen for all secondary/other efficacy endpoints. Treatment-emergent adverse events (AEs) occurred in 86.3% of avalglucosidase alfa-treated and 91.8% of alglucosidase alfa-treated participants. Five participants withdrew, 4 for AEs, all on alglucosidase alfa. Serious AEs occurred in 8 avalglucosidase alfa-treated and 12 alglucosidase alfa-treated participants. IgG antidrug antibody responses were similar in both. High titers and neutralizing antibodies were more common for alglucosidase alfa. Conclusions: Results demonstrate improvements in clinically meaningful outcome measures and a more favorable safety profile with avalglucosidase alfa versus alglucosidase alfa. Funding: Sanofi Genzyme

Background: Cerebellar atrophy is characterized by loss of cerebellar tissue, with evidence on brain imaging of enlarged interfolial spaces compared to the foliae. Genetic ataxias associated with cerebellar atrophy are a heterogeneous group of disorders. We investigated the prevalence in Canada and the diagnostic yield of whole exome sequencing (WES) for this group of conditions. Methods: Between 2011 and 2017, WES was performed in 91 participants with cerebellar atrophy as part of one of two national research programs, Finding of Rare Genetic Disease Genes (FORGE) or Enhanced Care for Rare Genetic Diseases in Canada (Care4Rare). Results: A genetic diagnosis was established in 58% of cases (53/91). Pathogenic variants were found in 24 known genes, providing a diagnosis for 46/53 participants (87%), and in four novel genes, accounting for 7/53 cases (13%). 38/91 cases (42%) remained unsolved. The most common diagnoses were channelopathies in 12/53 patients (23%) and mitochondrial disorders in 9/53 (17%). Inheritance was autosomal recessive in the majority of cases. Additional clinical findings provided useful clues to some of the diagnoses. Conclusions: This is the first report on the prevalence of genetic ataxias associated with cerebellar atrophy in Canada, and the utility of WES for this group of conditions.

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.

Feeding stimulates robust increases in muscle protein synthesis (MPS); however, ageing may alter the anabolic response to protein ingestion and the subsequent aminoacidaemia. With this as background, we aimed to determine in the present study the dose–response of MPS with the ingestion of isolated whey protein, with and without prior resistance exercise, in the elderly. For the purpose of this study, thirty-seven elderly men (age 71 (sd 4) years) completed a bout of unilateral leg-based resistance exercise before ingesting 0, 10, 20 or 40 g of whey protein isolate (W0–W40, respectively). Infusion of l-[1-13C]leucine and l-[ring-13C6]phenylalanine with bilateral vastus lateralis muscle biopsies were used to ascertain whole-body leucine oxidation and 4 h post-protein consumption of MPS in the fed-state of non-exercised and exercised leg muscles. It was determined that whole-body leucine oxidation increased in a stepwise, dose-dependent manner. MPS increased above basal, fasting values by approximately 65 and 90 % for W20 and W40, respectively (P < 0·05), but not with lower doses of whey. While resistance exercise was generally effective at stimulating MPS, W20 and W40 ingestion post-exercise increased MPS above W0 and W10 exercised values (P < 0·05) and W40 was greater than W20 (P < 0·05). Based on the study, the following conclusions were drawn. At rest, the optimal whey protein dose for non-frail older adults to consume, to increase myofibrillar MPS above fasting rates, was 20 g. Resistance exercise increases MPS in the elderly at all protein doses, but to a greater extent with 40 g of whey ingestion. These data suggest that, in contrast to younger adults, in whom post-exercise rates of MPS are saturated with 20 g of protein, exercised muscles of older adults respond to higher protein doses.

We aimed to determine the effect of consuming pure isolated micellar casein or pure whey protein isolate on rates of myofibrillar protein synthesis (MPS) at rest and after resistance exercise in elderly men. Healthy elderly men (72 (sem 1) years; BMI 26·4 (sem 0·7) kg/m2) were divided into two groups (n 7 each) who received a primed, constant infusion of l-[ring-13C6]phenylalanine to measure MPS at rest and during 4 h of exercise recovery. Participants performed unilateral leg resistance exercise followed by the consumption of isonitrogenous quantities (20 g) of casein or whey. Blood essential amino acids and leucine concentration peaked 60 min post-drink and were greater in amplitude after whey protein ingestion (both, P < 0·05). MPS in the rested leg was 65 % higher (P = 0·002) after ingestion of whey (0·040 (sem 0·003) %/h) when compared with micellar casein (0·024 (sem 0·002) %/h). Similarly, resistance exercise-stimulated rates of MPS were greater (P < 0·001) after whey ingestion (0·059 (sem 0·005) %/h) v. micellar casein (0·035 (sem 0·002) %/h). We conclude that ingestion of isolated whey protein supports greater rates of MPS than micellar casein both at rest and after resistance exercise in healthy elderly men. This result is probably related to a greater hyperaminoacidaemia or leucinaemia with whey ingestion.

Two earlier studies conducted in the vicinity of London (Heathrow) Airport compared the rate of admissions to a psychiatric hospital from areas exposed to different levels of aircraft noise. Their methods and results were not identical. A third study, reported here, examined standardized rates of admission to the same hospital for a longer period and for a larger area divided into 4 bands of aircraft noise. Statistically significant trends of decreasing admission with increasing noise levels were found. Comparisons between the investigations show how the contradictory results are related to the methods used and the accuracy of the data, and that caution should be exercised in formulating conclusions from exploratory research.

Results of the investigation of a sample of size N = 200, half of whom live in the vicinity of a main airport, are reported. Three health indicators were examined: (1) annoyance reactions measured with a scale which did not include symptoms; (2) a symptom score, obtained with a screening instrument which identifies possible psychiatric cases; and (3) confirmed psychiatric cases identified with a traditional diagnosis after an interview by a psychiatrist. Noise was undoubtedly associated with annoyance. An association between noise and psychiatric measures was only present in a subgroup of respondents of high education. There was a marked association between annoyance and psychiatric measures. An attempt was made to clarify the nature of this relationship. Hypersensitivity to noise was associated with a high frequency of psychiatric symptoms and should be considered among the high risk factors for psychiatric illness.

A sample of 77 women of high and low noise sensitivity, living in areas of high and low exposure to aircraft noise drawn from the 1977 West London Survey, were interviewed in the community in 1980. Women of high, intermediate and low noise sensitivity in 1980 were compared for measures of psychiatric disorder, personality and reactivity to the other sensory stimuli. In addition, the noise sensitivity measures defining the three groups in 1980 were compared with further measures of noise sensitivity. High noise sensitive women exhibited significantly more psychiatric symptoms, higher neuroticism scores, and greater reactivity to other sensory stimuli than intermediate and low noise sensitive women.

A sample of 77 women of high and low noise sensitivity in 1977, living in areas of high and low exposure to aircraft noise, were interviewed in the community in 1980. High, intermediate and low noise sensitive women were compared, using measures of blood pressure, heart rate, skin conductance, hearing threshold, uncomfortable loudness level and magnitude estimation of six tones. These physiological measures did not clearly distinguish different noise sensitivity groups, except that highly noise sensitive women had a consistently slower heart rate. Noise sensitivity was not related to auditory threshold. In the high aircraft noise area there were significantly more skin conductance responses than in the low aircraft noise area, irrespective of noise sensitivity. This may be the result of chronic exposure to high aircraft noise.

A domiciliary survey (sample size circa 6000) was conducted in areas of different aircraft noise exposure affected by London (Heathrow) Airport. Respondents were urban dwellers aged 16+. Their use of medicines, general practitioner services, hospital facilities and community services were investigated in relation both to the level of aircraft noise and to the degree of annoyance it causes. None of the indicators showed higher uptake in the high noise areas. The relationships between health indicators, noise and annoyance were not uniform. In areas exposed to high noise the use of non-prescribed drugs was significantly higher among ‘very annoyed’ than among ‘less annoyed’ respondents. The uptake of psychotropic drugs, and the use of general practice and out-patient services, tended to increase with increasing annoyance both in high- and low-noise areas, but the differences were not in all cases statistically significant. Parallels were drawn between these results and those of earlier analyses of the same survey related to the prevalence of acute and chronic symptoms. Suggestions for the analysis and interpretation of health effects of noise are put forward.

Summary

Objective: To assess the ability of medical students to learn and retain skills of airway manipulation for insertion of the endotracheal tube, the laryngeal mask airway (Laryngeal Mask Company, Henley-on-Thames, UK) and the oesophageal–tracheal Combitube® (Kendall-Sheridan Catheter Corp., Argyle, NY, USA).

Methods: A 6-month prospective study was conducted among fifth-year medical students attending a 3-week clerkship in the Division of Anesthesiology and Critical Care Medicine in the Soroka Medical Center. All the students viewed a demonstration of insertion technique for the endotracheal tube, the laryngeal mask airway and the Combitube®, followed by formal teaching in a mannikin. At the end of the program, the insertion skills were demonstrated in the mannikin, the success rate on the first attempt was registered and the students were requested to assess (by questionnaire) their ability to execute airway manipulation (phase 1). Six months later, the students were requested to repeat the insertion technique, and a similar re-evaluation applied (phase 2).

Results: The success rate, during the first phase, at first attempts was 100% for the laryngeal mask airway and the Combitube®, compared to 57.4% for the endotracheal tube (P < 0.02), and 92.6%, 96.2% and 62.9% (P < 0.02) respectively for the second phase of the study.

Conclusion: Learning and retention skills of medical students, in a mannikin, are more accentuated with the laryngeal mask airway and the Combitube® than seen with an endotracheal tube.

Magnetic recording media used today are based on sputtered cobalt alloy films with thicknesses in the order of 50 nm. As recording density is increased, the microstructure of the film must be controlled with increasing level of sophistication to achieve the magnetic properties necessary for good recording performance. Recording density has been increasing at the compound annual rate of 30%, and in recent years at a higher rate. Already, 1 Gb/in2 has been achieved in the laboratory [1], and 10 Gb/in2 is being contemplated [2]. In order to achieve such densities, microstructural characteristics such as grain morphology, size distribution, crystallographic orientation, and grain separation must be controlled with great precision, and their relationship to magnetic properties must be understood. The paper will describe the effect of sputter process conditions and the selection of magnetic alloys on the film microstructure and describe what might be required to achieve high recording densities. Particular attention will be paid to grain size distribution and grain separation. Grain separation is important for low noise performance of the media. Alloy selection and sputtering conditions can be manipulated to achieve different levels of separation between the grains.