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Intracranial aneurysm (IA) is an expansion of the weakened arterial wall that is often asymptomatic until rupture, resulting in subarachnoid hemorrhage. Here we describe the high prevalence of familial IA in a cohort of Newfoundland ancestry. We began to investigate the genetic etiology of IA in affected family members, as the inheritance of this disease is poorly understood.
Whole exome sequencing was completed for a cohort of 12 affected individuals from two multiplex families with a strong family history of IA. A filtering strategy was implemented to identify rare, shared variants. Filtered variants were prioritized based on validation by Sanger sequencing and segregation within the families.
In family R1352, six variants passed filtering; while in family R1256, 68 variants remained, so further filtering was pursued. Following validation by Sanger sequencing, top candidates were investigated in a set of population controls, namely, C4orf6 c.A1G (p.M1V) and SPDYE4c.C103T (p.P35S). Neither was detected in 100 Newfoundland control samples.
Rare and potentially deleterious variants were identified in both families, though incomplete segregation was identified for all filtered variants. Alternate methods of variant prioritization and broader considerations regarding the interplay of genetic and environmental factors are necessary in future studies of this disease.
Introduction: Although oral rehydration therapy is recommended for children with acute gastroenteritis (AGE) with none to some dehydration, intravenous (IV) rehydration is still commonly administered to these children in high-income countries. IV rehydration is associated with pain, anxiety, and emergency department (ED) revisits in children with AGE. A better understanding of the factors associated with IV rehydration is needed to inform knowledge translation strategies. Methods: This was a planned secondary analysis of the Pediatric Emergency Research Canada (PERC) and Pediatric Emergency Care Applied Research Network (PECARN) randomized, controlled trials of oral probiotics in children with AGE-associated diarrhea. Eligible children were aged 3-48 months and reported > 3 watery stools in a 24-hour period. The primary outcome was administration of IV rehydration at the index ED visit. We used mixed-effects logistic regression model to explore univariable and multivariable relationships between IV rehydration and a priori risk factors. Results: From the parent study sample of 1848 participants, 1846 had data available for analysis: mean (SD) age of 19.1 ± 11.4 months, 45.4% females. 70.2% (1292/1840) vomited within 24 hours of the index ED visit and 34.1% (629/1846) received ondansetron in the ED. 13.0% (240/1846) were administered IV rehydration at the index ED visit, and 3.6% (67/1842) were hospitalized. Multivariable predictors of IV rehydration were Clinical Dehydration Scale (CDS) score [compared to none: mild to moderate (OR: 8.1, CI: 5.5-11.8); severe (OR: 45.9, 95% CI: 20.1-104.7), P < 0.001], ondansetron in the ED (OR: 1.8, CI: 1.2-2.6, P = 0.003), previous healthcare visit for the same illness [compared to no prior visit: prior visit with no IV (OR: 1.9, 95% CI: 1.3-2.9); prior visit with IV (OR: 10.5, 95% CI: 3.2-34.8), P < 0.001], and country [compared to Canada: US (OR: 4.1, CI: 2.3-7.4, P < 0.001]. Significantly more participants returned to the ED with symptoms of AGE within 3 days if IV fluids were administered at the index visit [30/224 (13.4%) versus 88/1453 (6.1%), P < 0.001]. Conclusion: Higher CDS scores, antiemetic use, previous healthcare visits and country were independent predictors of IV rehydration which was also associated with increased ED revisits. Knowledge translation focused on optimizing the use of antiemetics (i.e. for those with dehydration) and reducing the geographic variation in IV rehydration use may improve the ED experience and reduce ED-revisits.
We sought to define the prevalence of echocardiographic abnormalities in long-term survivors of paediatric hematopoietic stem cell transplantation and determine the utility of screening in asymptomatic patients. We analysed echocardiograms performed on survivors who underwent hematopoietic stem cell transplantation from 1982 to 2006. A total of 389 patients were alive in 2017, with 114 having an echocardiogram obtained ⩾5 years post-infusion. A total of 95 patients had echocardiogram performed for routine surveillance. The mean time post-hematopoietic stem cell transplantation was 13 years. Of 95 patients, 77 (82.1%) had ejection fraction measured, and 10/77 (13.0%) had ejection fraction z-scores ⩽−2.0, which is abnormally low. Those patients with abnormal ejection fraction were significantly more likely to have been exposed to anthracyclines or total body irradiation. Among individuals who received neither anthracyclines nor total body irradiation, only 1/31 (3.2%) was found to have an abnormal ejection fraction of 51.4%, z-score −2.73. In the cohort of 77 patients, the negative predictive value of having a normal ejection fraction given no exposure to total body irradiation or anthracyclines was 96.7% at 95% confidence interval (83.3–99.8%). Systolic dysfunction is relatively common in long-term survivors of paediatric hematopoietic stem cell transplantation who have received anthracyclines or total body irradiation. Survivors who are asymptomatic and did not receive radiation or anthracyclines likely do not require surveillance echocardiograms, unless otherwise indicated.
Mountain pine beetle (Dendroctonus ponderosae Hopkins; Coleoptera: Curculionidae) is a major disturbance agent in pine (Pinus Linnaeus; Pinaceae) ecosystems of western North America. Adaptation to local climates has resulted in primarily univoltine generation time across a thermally diverse latitudinal gradient. We hypothesised that voltinism patterns have been shaped by selection for slower developmental rates in southern populations inhabiting warmer climates. To investigate traits responsible for latitudinal differences we measured lifestage-specific development of southern mountain pine beetle eggs, larvae, and pupae across a range of temperatures. Developmental rate curves were fit using maximum posterior likelihood estimation with a Bayesian prior to improve fit stability. When compared to previously published data for a northern population, optimal development of southern individuals occurred at higher temperatures, with higher development thresholds, as compared with northern individuals. Observed developmental rates of the southern and northern populations were similar across studied lifestages at 20 °C, and southern lifestages were generally faster at temperature extremes (10 °C, 27 °C). At 25 °C southern fourth instars were significantly slower than northern fourth instars. Our results suggest that evolved traits in the fourth instar and remaining unstudied lifestage, teneral (i.e., preemergent) adult, likely influence latitudinal differences in mountain pine beetle generation time.
Public Health England has set a definition for free sugars in the UK in order to estimate intakes of free sugars in the National Diet and Nutrition Survey. This follows the recommendation from the Scientific Advisory Committee on Nutrition in its 2015 report on Carbohydrates and Health that a definition of free sugars should be adopted. The definition of free sugars includes: all added sugars in any form; all sugars naturally present in fruit and vegetable juices, purées and pastes and similar products in which the structure has been broken down; all sugars in drinks (except for dairy-based drinks); and lactose and galactose added as ingredients. The sugars naturally present in milk and dairy products, fresh and most types of processed fruit and vegetables and in cereal grains, nuts and seeds are excluded from the definition.
A range of endophenotypes characterise psychosis, however there has been limited work understanding if and how they are inter-related.
This multi-centre study includes 8754 participants: 2212 people with a psychotic disorder, 1487 unaffected relatives of probands, and 5055 healthy controls. We investigated cognition [digit span (N = 3127), block design (N = 5491), and the Rey Auditory Verbal Learning Test (N = 3543)], electrophysiology [P300 amplitude and latency (N = 1102)], and neuroanatomy [lateral ventricular volume (N = 1721)]. We used linear regression to assess the interrelationships between endophenotypes.
The P300 amplitude and latency were not associated (regression coef. −0.06, 95% CI −0.12 to 0.01, p = 0.060), and P300 amplitude was positively associated with block design (coef. 0.19, 95% CI 0.10–0.28, p < 0.001). There was no evidence of associations between lateral ventricular volume and the other measures (all p > 0.38). All the cognitive endophenotypes were associated with each other in the expected directions (all p < 0.001). Lastly, the relationships between pairs of endophenotypes were consistent in all three participant groups, differing for some of the cognitive pairings only in the strengths of the relationships.
The P300 amplitude and latency are independent endophenotypes; the former indexing spatial visualisation and working memory, and the latter is hypothesised to index basic processing speed. Individuals with psychotic illnesses, their unaffected relatives, and healthy controls all show similar patterns of associations between endophenotypes, endorsing the theory of a continuum of psychosis liability across the population.
Academic health systems and their investigators are challenged to systematically assure clinical research regulatory compliance. This challenge is heightened in the emerging era of centralized single Institutional Review Boards for multicenter studies, which rely on monitoring programs at each participating site.
To describe the development, implementation, and outcome measurement of an institution-wide paired training curriculum and internal monitoring program for clinical research regulatory compliance.
Standard operating procedures (SOPs) were developed to facilitate investigator and research professional adherence to institutional policies, federal guidelines, and international standards. An SOP training curriculum was developed and implemented institution-wide. An internal monitoring program was launched, utilizing risk-based monitoring plans of pre-specified frequency and intensity, assessed upon Institutional Review Boards approval of each prospective study. Monitoring plans were executed according to an additional SOP on internal monitoring, with monitoring findings captured in a REDCap database.
We observed few major violations across 3 key domains of clinical research conduct and demonstrated a meaningful decrease in the rates of nonmajor violations in each, over the course of 2 years.
The paired training curriculum and monitoring program is a successful institution-wide clinical research regulatory compliance model that will continue to be refined.
This paper reports three cases of severe post-stapedectomy granuloma, emphasising the variable presentation of this devastating complication and the challenges of its management.
A retrospective review was conducted of three cases of post-stapedectomy granuloma requiring surgical debulking between 2010 and 2015. Clinical symptoms, serial imaging, histopathology and post-operative outcomes were considered.
Intra-operatively, extensive granulation tissue with erosion of the otic capsule was found. There was spread along the VIIth and VIIIth cranial nerves to the cochlear nucleus in one patient. Post-operative clinical improvement was demonstrable, corroborated by diminution of contrast enhancement on serial magnetic resonance imaging. Facial nerve function recovered, tinnitus amelioration was variable and some otalgia persisted. Post-operative complications included grade IV facial weakness and late Pseudomonas aeruginosa meningitis, which all resolved.
To the authors’ knowledge, this paper reports the only case of post-stapedectomy granuloma tracking to the brainstem. Otalgia was present in all our cases, and may be deemed a red flag symptom of progressive bony destruction and otic capsule involvement. Although granuloma remains rare, it should be considered in any patient with worsening otological symptoms following stapes surgery.
The stability of a tidewater terminus is controlled by glacial dynamics, calving processes and sedimentary processes at the grounding line. An investigation of grounding-line sediment dynamics and morainal-bank sediment budgets in Glacier Bay, Alaska, U.S.A., has yielded data that enable us to determine the debris fluxes of Grand pacific, Margerie and Muir Glaciers. Debris flux ranges from 105 to 106 m3 a−1, one to two orders of magnitude lower than the glacifluvial sediment fluxes (106−107 m3 a−1). Combined, these fluxes represent the highest yields known for glacierized basins. Large debris fluxes reflect the combined effects of rapid glacier flow, driven by the maritime climate of southeast Alaska, and highly erodible bedrock. Englacial-debris distribution is affected by valley width and relief, both of which control the availability of sediment. The number of tributaries controls the distribution and volume of debris in englacial and supraglacial moraines. At the terminus, iceberg-rafting removes up to two orders of magnitude more sediment from the ice-proximal environment than is deposited by melt-out or is dumped during calving events. Rough estimates of the sediment flux by deforming beds suggests that soft-bed deformation may deliver up to an order of magnitude more sediment to the terminus than is released from within the glacier ice.
Investigations of grounding-line sedimentation in front of tidewater termini of temperate valley glaciers demonstrate that sediment yields and dynamics provide a second-order control on glacier stability by influencing water depth at the grounding line. Sediment is delivered to the grounding line by two routes: (1) debris transported in, on and beneath the glacier, and (2) sediment transported in glacial outwash streams. Glacial streams in Glacier Bay, Alaska, U.S.A., deliver 106 to 107 m3 year−1 of sediment to the grounding lines. The glacial debris flux transports 105 to 106 m3 year−1 of debris to the ice cliffs, where approximately 10% is released at the grounding line, the remainder being transported downfjord by iceberg-rafting. An additional 105 m3 year−1 of sediment may be transported to the grounding line by shearing and advection of a deformable bed.
Background: The diagnosis of a sports-related concussion is often dependent on the athlete self-reporting their symptoms. It has been suggested that improving youth athlete knowledge and attitudes toward concussion may increase self-reporting behaviour. The objective of this study was to determine if a novel Concussion-U educational program improves knowledge of and attitudes about concussion among a cohort of elite male Bantam and Midget AAA hockey players. Methods: Fifty-seven male Bantam and Midget AAA-level hockey players (mean age=14.52±1.13 years) were recruited from the local community. Each participant completed a modified version of the Rosenbaum Concussion Knowledge and Attitudes Survey–Student Version immediately before and after a Concussion-U educational presentation. Follow-up sessions were arranged 4 to 6 months after the presentation, and assessed retention of knowledge and attitude changes. Results: Forty-three players completed all three surveys. Concussion knowledge and attitude scores significantly (p<0.01) increased from pre- to post-presentation by 12.79 and 8.41%, respectively. At long-term follow-up, knowledge levels remained significantly (p<0.01) higher than baseline by 8.49%. Mean attitude scores were also increased at follow-up; however, this increase was not statistically significant. Conclusions: A Concussion-U educational program led to an immediate improvement in concussion knowledge and attitudes among elite male Bantam and Midget AAA hockey players. Increased knowledge was maintained at long-term follow-up, but improved attitude was not. Future studies should investigate whether similar educational programs influence symptom reporting and concussion incidence. In addition, they should focus on how to maintain improved concussion attitudes.
In southern Africa, wetlands of different types are an integral part of the drainage network, yet evolve and are sensitive to different combinations of geologic, climatic, geomorphic, edaphic and hydrologic controls. Understanding of these controls can help in the interpretation of environmental and climatic records from different wetland types, given that wetland sensitivity to environmental and climatic changes may vary throughout their ‘life cycle’. The chapter discusses inland wetland records from dated sites in South Africa in order to consider their significance for reconstructing late glacial and Holocene climates; and the relationship of wetlands to preservation of the Pleistocene archaeological record. Wetlands are sensitive to degradation under contemporary environmental and climatic changes, which may impact on their hydrological and ecological function as well as the integrity of associated archaeological sites.