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Background: SMA1 is a neurodegenerative disease caused by bi-allelic survival motor neuron 1 gene (SMN1) deletion/mutation. In the phase 1 study, SMN GRT onasemnogene abeparvovec (AVXS-101) improved outcomes of symptomatic SMA1 patients. We report preliminary data of STR1VE, a pivotal study (NCT03306277) evaluating efficacy and safety of a one-time intravenous AVXS-101 infusion. Methods: STR1VE is a phase 3, multicenter, open-label, single-arm study in SMA1 patients aged <6 months (bi-allelic SMN1 loss, 2xSMN2). Primary outcomes: independent sitting for ≥30 seconds (18 months) and survival (14 months). Secondary outcomes: ability to thrive and ventilatory support (18 months). Exploratory outcomes: CHOP-INTEND and Bayley Scales of Infant and Toddler Development scores. Results: Enrollment is complete with 22 patients dosed. Mean age at symptom onset, genetic diagnosis, and enrollment was 1.9 (0–4.0), 2.1 (0.5–4.0), and 3.7 (0.5–5.9) months. At baseline, no patient required ventilatory/nutritional support, and all exclusively fed by mouth. Mean baseline CHOP-INTEND score was 32.6 (17.0–52.0), which increased 6.9 (-4.0–16.0, n=20), 10.4 (2.0–18.0, n=12), and 11.6 (-3.0–23.0, n=9) points at 1, 2, and 3 months; updates provided at congress. Conclusions: Preliminary data from STR1VE show rapid motor function improvements in SMA1 patients, paralleling phase 1 findings.
Background: Status epilepticus (SE) is the most common pediatric neurological emergency. Timely treatment is crucial, yet administration of rescue medications is often delayed and under-dosed. We aim to improve SE management by ensuring that every child at risk of SE in our province has an individualized seizure action plan (SAP) outlining the steps that should be taken during SE. Methods: A survey was distributed to parents of epilepsy patients aged 1 month to 19 years. Primary outcome was percentage of patients with SAPs. Secondary outcome was parental interest in a SAP mobile application. Following chart review, univariate and multivariate analysis was performed to identify variables that predict whether patients have SAPs. Results: Of 192 participants, 61.5% have SAPs. On univariate analysis, history of prior SE and male gender increased likelihood of having a SAP. On logistic regression, Nagelkerke R2 was 0.204 and our model correctly predicted 82.2% of patients with SAPs. 83.3% of parents were interested in a SAP mobile application. Conclusions: This is one of the first studies to examine SAP prevalence in a pediatric epilepsy population. There is a need to increase the percentage of epilepsy patients with SAPs. Most parents would find a SAP mobile application valuable in their child’s management.
Childhood maltreatment (CM) plays an important role in the development of major depressive disorder (MDD). The aim of this study was to examine whether CM severity and type are associated with MDD-related brain alterations, and how they interact with sex and age.
Within the ENIGMA-MDD network, severity and subtypes of CM using the Childhood Trauma Questionnaire were assessed and structural magnetic resonance imaging data from patients with MDD and healthy controls were analyzed in a mega-analysis comprising a total of 3872 participants aged between 13 and 89 years. Cortical thickness and surface area were extracted at each site using FreeSurfer.
CM severity was associated with reduced cortical thickness in the banks of the superior temporal sulcus and supramarginal gyrus as well as with reduced surface area of the middle temporal lobe. Participants reporting both childhood neglect and abuse had a lower cortical thickness in the inferior parietal lobe, middle temporal lobe, and precuneus compared to participants not exposed to CM. In males only, regardless of diagnosis, CM severity was associated with higher cortical thickness of the rostral anterior cingulate cortex. Finally, a significant interaction between CM and age in predicting thickness was seen across several prefrontal, temporal, and temporo-parietal regions.
Severity and type of CM may impact cortical thickness and surface area. Importantly, CM may influence age-dependent brain maturation, particularly in regions related to the default mode network, perception, and theory of mind.
Cougar Mountain Cave is located in Oregon's Fort Rock Basin. In 1958, avocationalist John Cowles excavated most of the cave's deposits and recovered abundant fiber, lithic, wood, and osseous artifacts. A crew from the University of California, Davis returned to the site in 1966 to evaluate the potential for further research, collecting additional lithic and fiber artifacts from disturbed deposits and in situ charcoal from apparently undisturbed deposits. Because Cowles took few notes or photographs, the Cougar Mountain Cave collection—most of which is housed at the Favell Museum in Klamath Falls, Oregon—has largely gone unstudied even though it contains diagnostic artifacts spanning the Holocene and, potentially, the terminal Pleistocene. We recently submitted charcoal and basketry from the site for radiocarbon dating, providing the first reliable sense of when Cougar Mountain Cave was first occupied. Our results indicate at least a Younger Dryas age for initial occupation. The directly dated basketry has provided new information about the age ranges and spatial distributions of diagnostic textile types in the northwestern Great Basin.
In the absence of partisan ownership of an issue, what factors shape public preferences for federal, state and local policy action? The Zika virus provides a unique context in which to examine this question, as it is a new threat to public health in the United States and lacks clear partisan ownership. We examine (1) which Zika policies do citizens support, (2) at which level(s) of government and (3) what factors explain citizen assignment of policy responsibility to different levels of government? Using nationally representative survey data, we find that the three most popular policy responses to Zika are travel warnings, research funding and public education, with the federal government being the preferred policy actor. In the absence of clear partisan issue ownership, we find that Republicans are significantly more likely to prefer state policy action, while partisanship has no impact on public preferences for federal or local policy action.
Background: Epileptic encephalopathy (EE) is a severe neurological disorder characterized by treatment-resistant seizures and poor neurodevelopmental outcomes. EE is associated with mutant genes, including those that encode for γ-aminobutyric acid type A (GABAA) receptor subunits. We identified a novel de novo GABRA1 mutation in a patient with EE, characterized its impact on GABAA receptor function, and sought potential therapeutic options. Methods: We described the clinical and electrophysiological features of a patient with a novel de novo GABRA1 (R214C) mutation; performed functional studies; and determined the effect of diazepam and insulin on wild type and mutant GABAA receptors. Results: The patient is a 10-year-old girl with EE, treatment-resistant seizures, intellectual disability and autism. Her GABRA1 (R214C) mutation dramatically decreased whole-cell GABA-evoked currents by reducing GABAA surface receptors, decreasing single channel open time, and altering channel kinetic properties. The combination of diazepam and insulin partially repaired these effects by enhancing channel activity and increasing the number of surface receptors, respectively. Conclusions: Diazepam and insulin partially mitigated a de novo GABRA1 (R214C) mutation’s effects on GABAA receptor number and function. Given the risks of insulin use, pharmacological agents with similar mechanisms of action but fewer side effects, such as IGF-1, should be studied and considered for clinical application.
In vitro techniques have been developed to facilitate the measurement of nutritional variability amongst food. Many kinetic studies have utilized the modified Tilley and Terry technique, with long-term incubations carried out in Erlenmeyer flasks. These are inefficient in utilizing incubator space for large scale studies. However substitution of Erlenmeyer flasks with tubes as fermentation units leaves the system prone to ‘bridging’, the formation of dense mats of forage particles by entrapped gas, above the level of the media in a fermentation unit. The objective of experiment 1 was to establish an effective incubation technique to eliminate the random variation caused by bridging.
Background: Perampanel (PER) is a new anti-seizure medication that inhibits the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) class of glutamate receptors. It is available in Canada for children since 2014. It is important for physicians to be aware of the efficacy and tolerability of drugs in the post-marketing phase. Methods: We did a retrospective review of our experience with PER at BC Children’s Hospital. Patients on PER were identified. Clinical data, including demographics, efficacy, tolerability, adverse effects (AE) and retention rates were obtained by review of clinical records. Results: Of 24 patients pediatric patients prescribed PER, 21 (87%) had focal and three had symptomatic generalized epilepsy. Ten (42%) had greater than 50% reduction in seizures. In fifteen patients, (63%) PER was discontinued due to AE or poor response. Twelve (50%) had behavioral AE and eight (33%) had non-behavioral AE. PER was effective, at lower doses than required for adults. One third experienced serious AE. One patient experienced oculogyric crisis, not previously reported with PER. AE were not associated with high doses and were reversible. Possible risk factors for behavioral AE include behavioral problems with other medications and pre-existing behavioral co-morbidities. Conclusions: It is important for clinicians to be aware of and counsel patients about serious AE, particularly behavioral, when prescribing PER.
Background: Hemimegalencephaly (HME) is a hamartomatous malformation of one cerebral hemisphere, resulting in refractory epilepsy, intellectual disability, and autistic features. Hemispherectomy is the definitive treatment, but there is risk of high morbidity and mortality, especially when done in early infancy. Various preclinical studies have shown that dysregulation of the mTOR pathway has an integral role in the development of various epilepsy syndromes, including tuberous sclerosis complex (TSC), focal cortical dysplasia and HME. Recently, mTOR inhibitors were proven to be effective in treating seizures in TSC. Methods: We present a case of a 6 day old female with refractory epilepsy despite the trial of 9 anti-seizure medications and the ketogenic diet. As the patient was awaiting epilepsy surgery, an mTOR inhibitor, rapamycin was initiated. Results: After 1 week of the initiation, she had over a 50% reduction in seizures. At two weeks, the parents felt that for the first time, she was making developmental gains. She also appeared brighter and more interactive. Due to her response to treatment, her hemispherectomy was deferred to when she is older, so there will be a decreased risk of complications from the surgery. Conclusions: This case exemplifies how mTOR inhibitors should be considered as a treatment option for patients with HME and refractory epilepsy.
Background: The KCNT1 gene encodes subunits of the Na+-activated K+ channel, widely expressed in the CNS. Mutations of this gene have been implicated in Malignant Migrating Partial Seizures of Infancy (MMPSI). This early-onset epileptic encephalopathy represents a challenge due to pharmacoresistance. The channel-specific mutation represents the potential for targeted pharmacotherapy. Quinidine is a partial antagonist of the KCNT1 encoded channel; patients with MMPSI have been reported to have responded to doses ranging 34.4/kg/d - 60mg/kg/d. We present a case of MMPSI with a KCNTI mutation (c.G1283A:p.R428Q) trialled on quinidine. Methods: Following ineffective trials of 6 anti-seizure medications, this patient was trialled on oral quinidine. This patient was titrated up to a dose of 52mg/kg/d. Twenty-four hour EEG monitoring prior to quinidine therapy, and at target dose were compared. Results: Prior to initiation of quinidine, this patient experienced 22 electrographic seizures over 24 hours. At target dose, this patient experienced greater than 70 seizures over 24 hours. Conclusions: Quinidine has previously been reported to be effective in patients with MMPSI with the same and different mutations. We report the second case of a patient with MMPSI and KCNT1 mutation R428Q with poor clinical response to quinidine.
Oregon's Fort Rock Cave is iconic in respect to both the archaeology of the northern Great Basin and the history of debate about when the Great Basin was colonized. In 1938, Luther Cressman recovered dozens of sagebrush bark sandals from beneath Mt. Mazama ash that were later radiocarbon dated to between 10,500 and 9350 cal B.P. In 1970, Stephen Bedwell reported finding lithic tools associated with a date of more than 15,000 cal B.P., a date dismissed as unreasonably old by most researchers. Now, with evidence of a nearly 15,000-year-old occupation at the nearby Paisley Five Mile Point Caves, we returned to Fort Rock Cave to evaluate the validity of Bedwell's claim, assess the stratigraphic integrity of remaining deposits, and determine the potential for future work at the site. Here, we report the results of additional fieldwork at Fort Rock Cave undertaken in 2015 and 2016, which supports the early Holocene occupation, but does not confirm a pre–10,500 cal B.P. human presence.
Introduction: Trauma code activation is initiated by emergency physicians using physiologic and anatomic criteria, mechanism of injury and patient demographic factors in conjunction with data obtained from emergency medical service personnel. This enables rapid definitive treatment of trauma patients. Our objective was to identify factors associated with delayed trauma team activation. Methods: We conducted a health records review to supplement data from a regional trauma center database. We assessed consecutive cases from the trauma database from January 2008 to March 2014 including all cases in which a trauma code was activated by an emergency physician. We defined a delay in trauma code activation as a time greater than 30 minutes from time to arrival to trauma team activation. Data were collected in Microsoft Excel and analyzed in Statistical Analysis System (SAS). We conducted univariate analysis for factors potentially influencing trauma team activation and we subsequently used multiple logistic regression analysis models for delayed activation in relation to mortality, length of stay and time to operative management. Results: 1020 patients were screened from which 174 patients were excluded, as they were seen directly by the trauma team. 846 patients were included for our analysis. 4.1% (35/846) of trauma codes were activated after 30 minutes. Mean age was 40.8 years in the early group versus 49.2 in the delayed group p=0.01. There was no significant difference in type of injury, injury severity or time from injury between the two groups. Patients were over 70 years in 7.6% in the early activation group vs 17.1% in the delayed group (p=0.04). 77.7% of the early group were male vs 71.4% in the delayed group (p=0.39). There was no significant difference in mortality (15.2% vs 11.4% p=0.10), median length of stay (10 days in both groups p=0.94) or median time to operative management (331 minutes vs 277 minutes p=0.52). Conclusion: Delayed activation is linked with increasing age with no clear link with increased mortality. Given the severe injuries in the delayed cohort which required activation of the trauma team further emphasis on the older trauma patient and interventions to recognize this vulnerable population should be made. When assessing elderly trauma patients emergency physicians should have a low threshold to activate trauma teams.
Introduction: Atrial fibrillation (AF) is the most common sustained arrhythmia affecting 1-2% of the population. Oral anticoagulation (OAC) reduces stroke risk by 60-80% in AF patients, but only 50% of indicated patients receive OAC. Many patients present to the ED with AF due to arrhythmia symptoms, however; lack of OAC prescription in the ED has been identified as a significant gap in the care of AF patients. Methods: This was a multi-center, pragmatic, three-phase before-after study, in three Canadian sites. Patients who presented to the ED with electrocardiographically (ECG) documented, nonvalvular AF and were discharged home were included. Phase 1 was a retrospective chart review to determine OAC prescription of AF patients in each ED; Phase 2 was a low-intensity knowledge translation intervention where a simple OAC-prescription tool for ED physicians with subsequent short-term OAC prescription was used, as well as an AF patient education package and a letter to family physicians; phase 3 incorporated Phase 2 interventions, but added immediate follow-up in a community AF clinic. The primary outcome of the study was the rate of new OAC prescriptions at ED discharge in AF patients who were OAC eligible and were not on OAC at presentation. Results: A total of 632 patients were included from June, 2015-November, 2016. ED census ranged from 30000-68000 annual visits. Mean age was 71±15, 67±12, 67±13 years, respectively. 47.5% were women, most responsible ED diagnosis was AF in 75.8%. The mean CHA2DS2-VASc score was 2.6±1.8, with no difference amongst groups. There were 266 patients eligible for OAC and were not on this at presentation. In this group, the prescription of new OAC was 15.8% in Phase 1 as compared to 54% and 47%, in Phases 2 and 3, respectively. After adjustment for center, components of the CHA2DS2-VASc score, prior risk of bleeding and most responsible ED diagnosis, the odds ratio for new OAC prescription was 8.0 (95%CI (3.5,18.3) p<0.001) for Phase 3 vs 1, and 10.0 (95%CI (4.4,22.9) p<0.001), for Phase 2 vs 1). No difference in OAC prescription was seen between Phases 2 and 3. Conclusion: Use of a simple OAC-prescription tool was associated with an increase in new OAC prescription in the ED for eligible patients with AF. Further testing in a rigorous study design to assess the effect of this practice on stroke prevention in the AF patients who present to the ED is indicated.
Introduction: Point of care ultrasound (PoCUS) has become an established tool in the initial management of patients with undifferentiated hypotension in the emergency department (ED). Current established protocols (e.g. RUSH and ACES) were developed by expert user opinion, rather than objective, prospective data. Recently the SHoC Protocol was published, recommending 3 core scans; cardiac, lung, and IVC; plus other scans when indicated clinically. We report the abnormal ultrasound findings from our international multicenter randomized controlled trial, to assess if the recommended 3 core SHoC protocol scans were chosen appropriately for this population. Methods: Recruitment occurred at seven centres in North America (4) and South Africa (3). Screening at triage identified patients (SBP<100 or shock index>1) who were randomized to PoCUS or control (standard care with no PoCUS) groups. All scans were performed by PoCUS-trained physicians within one hour of arrival in the ED. Demographics, clinical details and study findings were collected prospectively. A threshold incidence for positive findings of 10% was established as significant for the purposes of assessing the appropriateness of the core recommendations. Results: 138 patients had a PoCUS screen completed. All patients had cardiac, lung, IVC, aorta, abdominal, and pelvic scans. Reported abnormal findings included hyperdynamic LV function (59; 43%); small collapsing IVC (46; 33%); pericardial effusion (24; 17%); pleural fluid (19; 14%); hypodynamic LV function (15; 11%); large poorly collapsing IVC (13; 9%); peritoneal fluid (13; 9%); and aortic aneurysm (5; 4%). Conclusion: The 3 core SHoC Protocol recommendations included appropriate scans to detect all pathologies recorded at a rate of greater than 10 percent. The 3 most frequent findings were cardiac and IVC abnormalities, followed by lung. It is noted that peritoneal fluid was seen at a rate of 9%. Aortic aneurysms were rare. This data from the first RCT to compare PoCUS to standard care for undifferentiated hypotensive ED patients, supports the use of the prioritized SHoC protocol, though a larger study is required to confirm these findings.
Driving anxiety can range from driving reluctance to driving phobia, and 20% of young older adults experience mild driving anxiety, whereas 6% report moderate to severe driving anxiety. However, we do not know what impact driving anxiety has on health and well-being, especially among older drivers. This is problematic because there is a growing proportion of older adult drivers and a potential for driving anxiety to result in premature driving cessation that can impact on health and mortality. The purpose of the current study was to examine the impact of driving anxiety on young older adults’ health and well-being.
Data were taken from a longitudinal study of health and aging that included 2,473 young older adults aged 55–70 years. The outcome measures were mental and physical health (SF-12) and quality of life (WHOQOL-8).
Hierarchical multiple regression analyses demonstrated that driving anxiety was associated with poorer mental health, physical health, and quality of life, over and above the effect of socio-demographic variables. Sex moderated the effect of driving anxiety on mental health and quality of life in that, as driving anxiety increased, men and women were more likely to have lower mental health and quality of life, but women were more likely to have higher scores compared to men.
Further research is needed to investigate whether driving anxiety contributes to premature driving cessation. If so, self-regulation of driving and treating driving anxiety could be important in preventing or reducing the declines in health and quality of life associated with driving cessation for older adults affected by driving anxiety.
The Large Synoptic Survey Telescope (LSST), the next-generation optical imaging survey sited at Cerro Pachon in Chile, will provide an unprecedented database of astronomical measurements. The LSST design, with an 8.4m (6.7m effective) primary mirror, a 9.6 sq. deg. field of view, and a 3.2 Gigapixel camera, will allow about 10,000 sq. deg. of sky to be covered twice per night, every three to four nights on average, with typical 5-sigma depth for point sources of r=24.5 (AB). With over 800 observations in ugrizy bands over a 10-year period, these data will enable a deep stack reaching r=27.5 (about 5 magnitudes deeper than SDSS) and faint time-domain astronomy. The measured properties of newly discovered and known astrometric and photometric transients will be publicly reported within 60 sec after observation. The vast database of about 30 trillion observations of 40 billion objects will be mined for the unexpected and used for precision experiments in astrophysics. In addition to a brief introduction to LSST, we discuss a number of astro-statistical challenges that need to be overcome to extract maximum information and science results from LSST dataset.
Nutrition in the second year is important as this is a period of rapid growth and development. Milk is a major food for young children and this analysis evaluated the impact of the type of milk consumed on nutrient intakes and nutritional status. Data from the Diet and Nutrition Survey of Infants and Young Children were used to investigate the intakes of key nutrients, and Fe and vitamin D status, of children aged 12–18 months, not breastfed, and consuming >400 g/d fortified milk (n 139) or >400 g/d of whole cows’ milk (n 404). Blood samples from eligible children for measurement of Hb (n 113), serum ferritin and plasma 25-hydroxyvitamin D (25(OH)D) concentrations (n 105) were available for approximately 20 % of children. Unpaired Mann–Whitney tests were used to compare nutrient intakes and status between consumers of fortified and cows’ milk. Mean daily total dietary intakes of Fe, Zn, vitamin A and vitamin D were significantly higher in the fortified milk group. Mean daily total dietary intakes of energy, protein, Ca, iodine, Na and saturated fat were significantly higher in the cows’ milk group. Hb was not different between groups. The fortified milk group had significantly higher serum ferritin (P = 0·049) and plasma 25(OH)D (P = 0·014). This analysis demonstrates significantly different nutrient intakes and status between infants consuming >400 g/d fortified milk v. those consuming >400 g/d whole cows’ milk. These results indicate that fortified milks can play a significant role in improving the quality of young children's diets in their second year of life.