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Ciliopathies represent a major category of rare multisystem disease. Arriving at a specific diagnosis for a given patient is challenged by the significant genetic and clinical heterogeneity of these conditions. We report the outcome of the diagnostic odyssey of a child with obesity, renal, and retinal disease. Genome sequencing identified biallelic splice site variants in sodium channel and clathrin linker 1 (SCLT1), an emerging ciliopathy gene. We review the literature on all patients reported with biallelic SCLT1 variants highlighting a frequent clinical presentation that overlaps Bardet-Biedl and Senior-Loken syndromes. We also discuss current concepts in syndrome designation in light of these data., (© 2024 Wiley Periodicals LLC.)

Introduction: Genetic testing is used across medical disciplines leading to unprecedented demand for genetic services. This has resulted in excessive waitlists and unsustainable pressure on the standard model of genetic healthcare. Alternative models are needed; e-health tools represent scalable and evidence-based solution. We aim to evaluate the effectiveness of the Genetics Navigator, an interactive patient-centred digital platform that supports the collection of medical and family history, provision of pregenetic and postgenetic counselling and return of genetic testing results across paediatric and adult settings., Methods and Analysis: We will evaluate the effectiveness of the Genetics Navigator combined with usual care by a genetics clinician (physician or counsellor) to usual care alone in a randomised controlled trial. One hundred and thirty participants (adults patients or parents of paediatric patients) eligible for genetic testing through standard of care will be recruited across Ontario genetics clinics. Participants randomised into the intervention arm will use the Genetics Navigator for pretest and post-test genetic counselling and results disclosure in conjunction with their clinician. Participants randomised into the control arm will receive usual care, that is, clinician-delivered pretest and post-test genetic counselling, and results disclosure. The primary outcome is participant distress 2 weeks after test results disclosure. Secondary outcomes include knowledge, decisional conflict, anxiety, empowerment, quality of life, satisfaction, acceptability, digital health literacy and health resource use. Quantitative data will be analysed using statistical hypothesis tests and regression models. A subset of participants will be interviewed to explore user experience; data will be analysed using interpretive description. A cost-effectiveness analysis will examine the incremental cost of the Navigator compared with usual care per unit reduction in distress or unit improvement in quality of life from public payer and societal perspectives., Ethics and Dissemination: This study was approved by Clinical Trials Ontario. Results will be shared through stakeholder workshops, national and international conferences and peer-reviewed journals., Trial Registration Number: NCT06455384., Competing Interests: Competing interests: YB and MC are cofounders of Genetics Adviser., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

A 40-year-old man, newly diagnosed with cardiac sarcoidosis (CS) presented with symptomatic ventricular tachycardia three days after starting steroid-based immunosuppressive therapy (IT). There was no clear guideline indication for implantable cardioverter-defibrillator (ICD) before the initiation of IT. Shortly after ICD implantation and the initiation of anti-arrhythmic drugs, recurring ventricular arrhythmias required titration of the anti-arrhythmic drug therapy. One-year follow-up assessment showed no significant arrhythmias and complete PET scan FDG uptake suppression. This case, along with recent publications, suggests transient pro-arrhythmic effects of steroids in patients with CS, which are not appropriately addressed in the current guidelines. We believe ICD implantation should be considered in clinically manifest CS before initiating IT, particularly in cases with heterogeneous and/or extensive FDG uptake on PET scans., (© 2024 The Authors. Pacing and Clinical Electrophysiology published by Wiley Periodicals LLC.)

This work presents the design and validation of a vibrating coil magnetometer for the characterization of the field dependence of the critical current density of centimeter-sized bulk superconductors as an alternative to the destructive methods typically used. The magnetometer is also shown to be capable of measuring the magnetic moment in an applied field of up to 5 T for diverse magnetic materials, such as soft and hard ferromagnets and high-temperature superconducting pellets. The vibrating coil magnetometer was first optimized using finite element simulations and calibrated using a commercial vibrating sample magnetometer. The vibrating coil magnetometer was benchmarked with hysteresis measurements of a Nd2Fe14B disk made with a commercial hysteresisgraph, showing good agreement between the different setups. The magnetic hysteresis of a YBa2Cu3O7-x superconducting pellet was measured at 77 K, showing a penetration field of 1 T and an irreversibility field of 4 T. The field dependent critical current density of the superconductor was then inferred from the magnetic hysteresis measurements and extrapolated at low fields. Finally, the resulting critical current density was used to successfully reproduce the measured magnetization curve of the pellet at 2 T with finite element simulations., (© 2023 Author(s). Published under an exclusive license by AIP Publishing.)

The present work investigates the effectiveness of two heat treatment cycles-solution treatment + aging (STA) and direct aging (DA)-on optimizing the microstructure and enhancing the mechanical properties of 18Ni-300 maraging steel (300 MS) produced by additive-subtractive hybrid manufacturing (ASHM). The STA treatment led to a fully martensitic microstructure with minor remnants of the cellular substructures associated with the solidification conditions in ASHM. DA resulted in some reverted austenite and partial dissolution of the cellular morphologies into shorter fragments. Despite the contrasting microstructures, the tensile strength and the macro- and micro-hardness were comparable between STA and DA conditions. By contrast, the potential for improving the ductility was higher with the DA heat treatment. This is attributed to the higher reverted austenite content in the samples treated by DA, i.e., up to a maximum of 13.4% compared to less than 3.0% in the STA samples. For the DA sample with the highest reverted austenite content of 13.4%, the highest local and global fracture strain values of 30.1 and 5.9 ± 0.6% were measured, while the respective values were 23.4 and 4.4 ± 0.1% for the corresponding STA sample. This work suggests that DA of 300 MS produced by ASHM is sufficient to achieve comparable hardness and tensile strength to STA, whilst maintaining reasonable ductility. Avoiding the solution treatment cycle, with its appreciably higher temperatures, could benefit the dimensional stability and surface quality that are important for ASHM of 300 MS parts.

HostSeq was launched in April 2020 as a national initiative to integrate whole genome sequencing data from 10,000 Canadians infected with SARS-CoV-2 with clinical information related to their disease experience. The mandate of HostSeq is to support the Canadian and international research communities in their efforts to understand the risk factors for disease and associated health outcomes and support the development of interventions such as vaccines and therapeutics. HostSeq is a collaboration among 13 independent epidemiological studies of SARS-CoV-2 across five provinces in Canada. Aggregated data collected by HostSeq are made available to the public through two data portals: a phenotype portal showing summaries of major variables and their distributions, and a variant search portal enabling queries in a genomic region. Individual-level data is available to the global research community for health research through a Data Access Agreement and Data Access Compliance Office approval. Here we provide an overview of the collective project design along with summary level information for HostSeq. We highlight several statistical considerations for researchers using the HostSeq platform regarding data aggregation, sampling mechanism, covariate adjustment, and X chromosome analysis. In addition to serving as a rich data source, the diversity of study designs, sample sizes, and research objectives among the participating studies provides unique opportunities for the research community., (© 2023. The Author(s).)

Consumption of Bifidobacterium breve MCC1274 has been shown to improve memory and prevent brain atrophy in populations with mild cognitive impairment (MCI). Preclinical in vivo studies using Alzheimer's disease (AD) models indicate that this probiotic protects against brain inflammation. There is growing evidence that lipid droplets are associated with brain inflammation, and lipid-associated proteins called perilipins could play an important role in neurodegenerative diseases such as dementia. In this study, we found that B. breve MCC1274 cell extracts significantly decreased the expression of perilipin 4 ( PLIN4 ), which encodes a lipid droplet docking protein whose expression is known to be increased during inflammation in SH-SY5Y cells. Niacin, an MCC1274 cell extract component, increased PLIN4 expression by itself. Moreover, MCC1274 cell extracts and niacin blocked the PLIN4 induction caused by oxidative stress in SH-SY5Y cells, reduced lipid droplet formation, and prevented IL-6 cytokine production. These results offer a possible explanation for the effect of this strain on brain inflammation.

Decisions to set aside Structured Oral Examinations (SOE) are, almost invariably, based on their poor psychometric properties. However, considering the perspectives of the stakeholders might help us to understand its potential contribution. To explore this, we conducted focus groups and individual interviews with stakeholders: students, assessors, and administrators. Students and assessors perceived the SOE as a window on students' clinical reasoning, as an authentic assessment, but as a subjective and stressful method. Administrators emphasized the organizational consequences such as logistical challenges. Consequences must be considered when making decisions about SOE and our results support important positive consequences., Competing Interests: Competing InterestsThe authors declare no competing interests., (© The Author(s) under exclusive licence to International Association of Medical Science Educators 2023.)

This study investigated the application of an in envelope additive/subtractive (LPBF) manufacturing method (Matsuura LUMEX-Avance-25) to fabricate IN718 benchmarking coupons. The coupons were then examined comprehensively for surface finish both with and without high-speed micro-machining. The microstructure of the manufactured IN718 coupons was investigated thoroughly in the as-fabricated condition and following three different standard and one non-standard post-processing heat treatments. As built coupons revealed columnar grain morphology mainly along the <100> direction with a cellular dendritic sub-grain structure and without any strengthening precipitates. Grain size, aspect ratio, and texture were maintained after each of the applied four heat treatments. Only one of the standard heat treatments resulted in the δ phase formation. The other three heat treatments effectively dissolved the Laves phase preventing the δ formation while promoting the formation of γ′/γ″ precipitates. Despite the observed differences in their microstructures, all of the heat treatments resulted in similar yield and ultimate tensile strength values that ranged between 1103−1205 MPa and 1347−1387 MPa, respectively. These values are above the minimum requirements of 1034 MPa and 1241 MPa for the wrought material. The non-standard heat treatment provided the highest elongation of 24.0 ± 0.1% amongst all the heat-treated specimens without a significant loss in strength, while the standard heat treatment for the wrought parts resulted in the lowest elongation of 18.3 ± 0.7% due to the presence of δ phase.

Introduction: Despite the superior diagnostic performance of exome and genome sequencing compared with conventional genetic tests, evidence gaps related to clinical utility and cost effectiveness have limited their availability in routine clinical practice in many jurisdictions. To inform adoption and reimbursement policy, this protocol provides a chain of evidence approach to determining the diagnostic utility, clinical utility and cost-effectiveness of whole exome sequencing (WES) from seven medical genetic centres in two Canadian provinces., Methods and Analysis: Using a multicentre observational cohort design, we will extract data specific to the pre-WES diagnostic pathway and 1-year post-WES medical management from electronic medical records for 650 patients with rare disease of suspected genetic aetiology who receive WES. The date from the clinical record will be linked to provincial administrative health database to capture healthcare resource use and estimate costs. Our analysis will: (1) define and describe diagnostic testing pathways that occur prior to WES among patients with rare disease, (2) determine the diagnostic utility of WES, characterised as the proportion of patients for whom causative DNA variants are identified, (3) determine the clinical utility of WES, characterised as a change in medical management triggered by WES results, (4) determine the pattern and cost of health service utilisation prior and 1 year following WES among patients who receive a diagnosis, do not receive a diagnosis, or receive an uncertain diagnosis and (5) estimate the cost-effectiveness of WES compared with conventional diagnostic testing pathways, measured by the incremental cost per additional patient diagnosed by WES using simulation modelling., Ethics and Dissemination: This protocol was approved by Clinical Trials Ontario (CTO-1577) and research ethics boards at the University of Calgary (REB18-0744 and REB20-1449) and University of Alberta (Pro0009156). Findings will be disseminated through academic publications and policy reports., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Probiotics have been reported to ameliorate cognitive impairment., Objective: We investigated the effect of the probiotic strain Bifidobacterium breve MCC1274 (A1) in enhancing cognition and preventing brain atrophy of older patients with mild cognitive impairment (MCI)., Methods: In this RCT, 130 patients aged from 65 to 88 years old with suspected MCI received once daily either probiotic (B. breve MCC1274, 2×1010 CFU) or placebo for 24 weeks. Cognitive functions were assessed by ADAS-Jcog and MMSE tests. Participants underwent MRI to determine brain atrophy changes using Voxel-based Specific Regional Analysis System for Alzheimer's disease (VSRAD). Fecal samples were collected for the analysis of gut microbiota composition., Results: Analysis was performed on 115 participants as the full analysis set (probiotic 55, placebo 60). ADAS-Jcog subscale "orientation" was significantly improved compared to placebo at 24 weeks. MMSE subscales "orientation in time" and "writing" were significantly improved compared to placebo in the lower baseline MMSE (< 25) subgroup at 24 weeks. VSRAD scores worsened in the placebo group; probiotic supplementation tended to suppress the progression, in particular among those subjects with progressed brain atrophy (VOI Z-score ≥1.0). There were no marked changes in the overall composition of the gut microbiota by the probiotic supplementation., Conclusion: Improvement of cognitive function was observed on some subscales scores only likely due to the lower sensitiveness of these tests for MCI subjects. Probiotics consumption for 24 weeks suppressed brain atrophy progression, suggesting that B. breve MCC1274 helps prevent cognitive impairment of MCI subjects.

Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Objectives: A substantial proportion of individuals infected with SARS-CoV-2 do not experience noticeable symptoms typical of COVID-19. Our objectives were to evaluate the impact of the first wave of the pandemic in Québec by measuring SARS-CoV-2 antibody seroprevalence in a convenience sample of healthy blood donors and to study the association between seropositivity and the occurrence of COVID-19 symptoms., Methods: The study design was a cross-sectional serological survey with a nested case-control study. Residual blood samples from donations collected between May 25 and July 9, 2020 (well before vaccination rollout) in the province of Québec were tested for anti-Spike RBD antibodies by ELISA. Seropositive donors and a control group of seronegative donors were questioned about prior COVID-19 symptoms. All qualified blood donors were eligible for participation., Results: A total of 7691 blood donors were included in the study. After adjustments, the seroprevalence rate was 2.2% (95% CI 1.9-2.6). Seropositive donors reported one or more symptoms in a proportion of 52.2% (95% CI 44.2-60.1); this proportion was 19.1% (95% CI 13.4-26.1) among seronegative donors, suggesting that approximately 50-66% of all infections were asymptomatic. Univariate analysis of associations between symptoms and seropositivity revealed that except for rhinorrhea, all symptoms were significantly associated with seropositivity., Conclusion: Assuming that blood donors are fairly representative of the general adult population, this study shows that less than 3% of 18-69-year-olds have been infected during the first wave of the pandemic in the province of Québec. Our data also confirm that many infections escaped detection, including a substantial proportion that were asymptomatic.

Alzheimer's disease (AD) is the most common form of dementia and aging is the most common risk factor for developing the disease. The etiology of AD is not known but AD may be considered as a clinical syndrome with multiple causal pathways contributing to it. The amyloid cascade hypothesis, claiming that excess production or reduced clearance of amyloid-beta (Aβ) and its aggregation into amyloid plaques, was accepted for a long time as the main cause of AD. However, many studies showed that Aβ is a frequent consequence of many challenges/pathologic processes occurring in the brain for decades. A key factor, sustained by experimental data, is that low-grade infection leading to production and deposition of Aβ, which has antimicrobial activity, precedes the development of clinically apparent AD. This infection is chronic, low grade, largely clinically silent for decades because of a nearly efficient antimicrobial immune response in the brain. A chronic inflammatory state is induced that results in neurodegeneration. Interventions that appear to prevent, retard or mitigate the development of AD also appear to modify the disease. In this review, we conceptualize further that the changes in the brain antimicrobial immune response during aging and especially in AD sufferers serve as a foundation that could lead to improved treatment strategies for preventing or decreasing the progression of AD in a disease-modifying treatment., Competing Interests: Prof. Dr Tamas Fulop reports grants from CIHR, during the conduct of the study; personal fees from Pfizer and Sanofi, outside the submitted work. Dr Ton Bunt is a share holder of Izumi Biosciences INC, outside the submitted work. In addition, Dr Ton Bunt is a co-inventor for patent US-2014235631-A1 pending and an inventor for a patent WO/2019/183403. Professor Annelise E Barron reports grant (# 5DP1AG072438) from NIH/NIA, during the conduct of the study. In addition, Professor Annelise E Barron has a patent US20190015361A1 pending to Stanford University not related to this study. The authors report no other conflicts of interest in this work., (© 2021 Fulop et al.)

Background: Progress in the field of evolutionary forest ecology has been hampered by the huge challenge of phenotyping trees across their ranges in their natural environments, and the limitation in high-resolution environmental information., Findings: The GenTree Platform contains phenotypic and environmental data from 4,959 trees from 12 ecologically and economically important European forest tree species: Abies alba Mill. (silver fir), Betula pendula Roth. (silver birch), Fagus sylvatica L. (European beech), Picea abies (L.) H. Karst (Norway spruce), Pinus cembra L. (Swiss stone pine), Pinus halepensis Mill. (Aleppo pine), Pinus nigra Arnold (European black pine), Pinus pinaster Aiton (maritime pine), Pinus sylvestris L. (Scots pine), Populus nigra L. (European black poplar), Taxus baccata L. (English yew), and Quercus petraea (Matt.) Liebl. (sessile oak). Phenotypic (height, diameter at breast height, crown size, bark thickness, biomass, straightness, forking, branch angle, fructification), regeneration, environmental in situ measurements (soil depth, vegetation cover, competition indices), and environmental modeling data extracted by using bilinear interpolation accounting for surrounding conditions of each tree (precipitation, temperature, insolation, drought indices) were obtained from trees in 194 sites covering the species' geographic ranges and reflecting local environmental gradients., Conclusion: The GenTree Platform is a new resource for investigating ecological and evolutionary processes in forest trees. The coherent phenotyping and environmental characterization across 12 species in their European ranges allow for a wide range of analyses from forest ecologists, conservationists, and macro-ecologists. Also, the data here presented can be linked to the GenTree Dendroecological collection, the GenTree Leaf Trait collection, and the GenTree Genomic collection presented elsewhere, which together build the largest evolutionary forest ecology data collection available., (© The Author(s) 2021. Published by Oxford University Press GigaScience.)

Objectives: Educators and researchers recently implemented developmental progress assessment (DPA) in the context of competency-based education. To reap its anticipated benefits, much still remains to be understood about its implementation. In this study, we aimed to determine the nature and extent of the current evidence on DPA, in an effort to broaden our understanding of the major goals and intended outcomes of DPA as well as the lessons learned from how it has been executed in, or applied across, educational contexts., Methods: We conducted a scoping study based on the methodology of Arksey and O'Malley. Our search strategy yielded 2494 articles. These articles were screened for inclusion and exclusion (90% agreement), and numerical and qualitative data were extracted from 56 articles based on a pre-defined set of charting categories. The thematic analysis of the qualitative data was completed with iterative consultations and discussions until consensus was achieved for the interpretation of the results., Results: Tools used to document DPA include scales, milestones and portfolios. Performances were observed in clinical or standardised contexts. We identified seven major themes in our qualitative thematic analysis: (a) underlying aims of DPA; (b) sources of information; (c) barriers; (d) contextual factors that can act as barriers or facilitators to the implementation of DPA; (e) facilitators; (f) observed outcomes, and (g) documented validity evidences., Conclusions: Developmental progress assessment seems to fill a need in the training of future competent health professionals. However, moving forward with a widespread implementation of DPA, factors such as lack of access to user-friendly technology and time to observe performance may render its operationalisation burdensome in the context of competency-based medical education., (© 2020 John Wiley & Sons Ltd and The Association for the Study of Medical Education.)

Background: Cerebellar atrophy is a nonspecific imaging finding observed in a number of neurological disorders. Genetic ataxias associated with cerebellar atrophy are a heterogeneous group of conditions, rendering the approach to diagnosis challenging., Objectives: To define the spectrum of genetic ataxias associated with cerebellar atrophy in a Canadian cohort and the diagnostic yield of exome sequencing for this group of conditions., Methods: A total of 92 participants from 66 families with cerebellar atrophy were recruited for this multicenter prospective cohort study. Exome sequencing was performed for all participants between 2011 and 2017 as part of 1 of 2 national research programs, Finding of Rare Genetic Disease Genes or Enhanced Care for Rare Genetic Diseases in Canada., Results: A genetic diagnosis was established in 53% of families (35/66). Pathogenic variants were found in 21 known genes, providing a diagnosis for 31/35 families (89%), and in 4 novel genes, accounting for 4/35 families (11%). Of the families, 31/66 (47%) remained without a genetic diagnosis. The most common diagnoses were channelopathies, which were established in 9/35 families (26%). Additional clinical findings provided useful clues to specific diagnoses., Conclusions: We report on the high frequency of channelopathies as a cause of genetic ataxias associated with cerebellar atrophy and the utility of exome sequencing for this group of conditions., Competing Interests: This work was performed by the Care4Rare Canada Consortium funded by Genome Canada and the Ontario Genomics Institute (OGI‐147), the Canadian Institutes of Health Research, Ontario Research Fund, Genome Alberta, Genome British Columbia, Genome Quebec, Children's Hospital of Eastern Ontario Foundation, and The Hospital for Sick Children. The authors have no conflicts of interest to declare., (© 2020 International Parkinson and Movement Disorder Society.)

Alzheimer's disease (AD) is the most prevalent dementia in the world. Its cause(s) are presently largely unknown. The most common explanation for AD, now, is the amyloid cascade hypothesis, which states that the cause of AD is senile plaque formation by the amyloid β peptide, and the formation of neurofibrillary tangles by hyperphosphorylated tau. A second, burgeoning theory by which to explain AD is based on the infection hypothesis. Much experimental and epidemiological data support the involvement of infections in the development of dementia. According to this mechanism, the infection either directly or via microbial virulence factors precedes the formation of amyloid β plaques. The amyloid β peptide, possessing antimicrobial properties, may be beneficial at an early stage of AD, but becomes detrimental with the progression of the disease, concomitantly with alterations to the innate immune system at both the peripheral and central levels. Infection results in neuroinflammation, leading to, and sustained by, systemic inflammation, causing eventual neurodegeneration, and the senescence of the immune cells. The sources of AD-involved microbes are various body microbiome communities from the gut, mouth, nose, and skin. The infection hypothesis of AD opens a vista to new therapeutic approaches, either by treating the infection itself or modulating the immune system, its senescence, or the body's metabolism, either separately, in parallel, or in a multi-step way.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The dataset presented here was collected by the GenTree project (EU-Horizon 2020), which aims to improve the use of forest genetic resources across Europe by better understanding how trees adapt to their local environment. This dataset of individual tree-core characteristics including ring-width series and whole-core wood density was collected for seven ecologically and economically important European tree species: silver birch (Betula pendula), European beech (Fagus sylvatica), Norway spruce (Picea abies), European black poplar (Populus nigra), maritime pine (Pinus pinaster), Scots pine (Pinus sylvestris), and sessile oak (Quercus petraea). Tree-ring width measurements were obtained from 3600 trees in 142 populations and whole-core wood density was measured for 3098 trees in 125 populations. This dataset covers most of the geographical and climatic range occupied by the selected species. The potential use of it will be highly valuable for assessing ecological and evolutionary responses to environmental conditions as well as for model development and parameterization, to predict adaptability under climate change scenarios.

Background: Probiotics use has been associated with modulation of inflammation and considered as a possible intervention for CNS diseases such as mild cognitive impairment (MCI) and dementia., Objective: We aimed to test the effect of the probiotic strain, Bifidobacterium breve A1 (MCC1274), to restore cognition in a physically healthy, suspected MCI population., Methods: In this randomized, double-blind, placebo-controlled trial, 80 healthy older adults suffering from MCI were divided into two even groups to receive once daily either probiotic (B. breve A1, 2×1010 CFU) or placebo for 16 weeks using a computer-generated algorithm. Cognitive functions were assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Japanese version of the MCI Screen (JMCIS) tests before and after the study as primary and secondary endpoints, respectively., Results: 79 participants completed the study, and no adverse events were observed. RBANS total score was significantly improved in probiotic group compared with placebo (mean between-group difference 11.3 [95% CI 6.7 to 15.8]; p < 0.0001) after 16 weeks of consumption, in particular with significant improvement in domain scores of immediate memory, visuospatial/constructional, and delayed memory (p < 0.0001), in both intention-to-treat (ITT) analysis and per-protocol (PP) analysis. JMCIS score was also improved versus placebo in ITT analysis (p = 0.052) and PP analysis (p = 0.036)., Conclusion: Study results indicate B. breve A1 is a safe and effective approach for improving memory functions of suspected MCI subjects.

MSTO1 encodes a cytosolic mitochondrial fusion protein, misato homolog 1 or MSTO1. While the full genotype-phenotype spectrum remains to be explored, pathogenic variants in MSTO1 have recently been reported in a small number of patients presenting with a phenotype of cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic and pigmentary retinopathy. The proposed underlying pathogenic mechanism of MSTO1-related disease is suggestive of impaired mitochondrial fusion secondary to a loss of function of MSTO1. Disorders of mitochondrial fusion and fission have been shown to also lead to mitochondrial DNA (mtDNA) depletion, linking them to the mtDNA depletion syndromes, a clinically and genetically diverse class of mitochondrial diseases characterized by a reduction of cellular mtDNA content. However, the consequences of pathogenic variants in MSTO1 on mtDNA maintenance remain poorly understood. We present extensive phenotypic and genetic data from 12 independent families, including 15 new patients harbouring a broad array of bi-allelic MSTO1 pathogenic variants, and we provide functional characterization from seven MSTO1-related disease patient fibroblasts. Bi-allelic loss-of-function variants in MSTO1 manifest clinically with a remarkably consistent phenotype of childhood-onset muscular dystrophy, corticospinal tract dysfunction and early-onset non-progressive cerebellar atrophy. MSTO1 protein was not detectable in the cultured fibroblasts of all seven patients evaluated, suggesting that pathogenic variants result in a loss of protein expression and/or affect protein stability. Consistent with impaired mitochondrial fusion, mitochondrial networks in fibroblasts were found to be fragmented. Furthermore, all fibroblasts were found to have depletion of mtDNA ranging from 30 to 70% along with alterations to mtDNA nucleoids. Our data corroborate the role of MSTO1 as a mitochondrial fusion protein and highlight a previously unrecognized link to mtDNA regulation. As impaired mitochondrial fusion is a recognized cause of mtDNA depletion syndromes, this novel link to mtDNA depletion in patient fibroblasts suggests that MSTO1-deficiency should also be considered a mtDNA depletion syndrome. Thus, we provide mechanistic insight into the disease pathogenesis associated with MSTO1 mutations and further define the clinical spectrum and the natural history of MSTO1-related disease.

Hepatitis E virus (HEV) is the most common cause of acute hepatitis worldwide including large water-borne outbreaks, zoonotic infections and transfusion transmissions. Several countries have initiated or are considering blood donor screening in response to high HEV-RNA donation prevalence leading to transfusion-transmission risk. Because HEV transmission is more common through food sources, the efficacy of blood donor screening alone may be limited. HEV-nucleic acids in 101 489 blood donations in the United States and Canada were studied. A risk-based decision-making framework was used to evaluate the quantitative risks and cost-benefit of HEV-blood donation screening in Canada comparing three scenarios: no screening, screening blood for all transfused patients or screening blood for only those at greatest risk. HEV-RNA prevalence in the United States was one per 16 908 (95% confidence interval [CI], 1:5786-1:81987), whereas Canadian HEV-RNA prevalence was one per 4615 (95% CI, 1:2579-1:9244). Although 4-fold greater, Canadian HEV-RNA prevalence was not significantly higher than in the United States. Viral loads ranged from 20 to 3080 international units per mL; all successfully typed infections were genotype 3. No HEV-RNA false-positive donations were identified for 100 percent specificity. Without donation screening, heart and lung transplant recipients had the greatest HEV-infection risk (1:366962) versus kidney transplant recipients with the lowest (1:2.8 million) at costs of $225 546 to $561 810 per quality-adjusted life-year (QALY) gained for partial or universal screening, respectively. Higher cost per QALY would be expected in the United States. Thus, HEV prevalence in North America is lower than in countries performing blood donation screening, and if implemented, is projected to be costly under any scenario., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Biomonitoring studies of vulnerable populations in low- and middle-income countries are limited because traditional sampling methods are challenging to implement in low-resource settings. The present study examined the feasibility, precision, and accuracy of dried blood spots (DBS) for human biomonitoring of nonessential elements (cadmium [Cd], mercury [Hg], and lead [Pb]) in an area of northern Tanzania with artisanal and small-scale gold mining activities. Pregnant women (n = 44) were recruited in Geita during antenatal clinic visits, and DBS from capillary blood were collected on filter paper. As a gold-standard comparison, venous blood was sampled from the same participants and compared with the DBS. Venous blood, DBS, and quality control samples were analyzed for chemical elements by inductively coupled plasma mass spectrometry. Field blanks were very clean for most elements, generally only twice as high as corresponding laboratory filter blanks. No significant differences were found between duplicate DBS samples taken from the same participants, with near perfect intraclass correlation coefficients (0.99) for Cd, Hg, and Pb, indicating excellent reliability. Moreover, correlation was strong (r 2 > 0.9) and significant (p < 0.0001) between DBS and the quantitative venous blood, with regression line slopes close to 1.0 (0.847, 0.976, and 0.969 for Cd, Hg, and Pb, respectively), indicating high accuracy of the DBS method compared with the gold-standard approach. The DBS method is minimally invasive and was a feasible, precise, and accurate means of measuring exposure to Cd, Hg, and Pb in pregnant women in a low-resource setting. Environ Toxicol Chem 2019;38:1285-1293. © 2019 SETAC., (© 2019 SETAC.)

Background: Banked human milk (BHM) offers potential health benefits to premature babies. BHM is pasteurized to mitigate infectious risks, but pasteurization is ineffective against sporulating bacteria such as Bacillus cereus . Sepsis related to Bacillus cereus in premature infants is severe and can often be fatal. Even if a causal link has never been established, BHM has been suggested as a potential source of infection in premature infants., Objective: Our aim was to estimate the potential risk of Bacillus cereus infection in preterm infants caused by the ingestion of contaminated pasteurized BHM using different post-pasteurization release criteria (i.e., 9 sampling of 100 microliters versus the HMBANA guideline of 1 sampling of 100 microliters per pool)., Methods: In the absence of scientific evidence regarding the risk of Bacillus cereus infection by the ingestion of BHM in premature infants, risk assessment using Monte Carlo simulation with the exponential dose-response model was performed. Three scenarios of infectious risk (annual incidence rate of 0.01%, 0.13%, and 0.2%) with 18 variations of the B. cereus virulent dose (from 0.5 CFU/ml to 200 CFU/ml) were simulated., Results: The mean risk differential between the two methods of post-pasteurization bacteriological control for realistic infectious doses of 30 to 200 CFU/ml ranges from 0.036 to 0.0054, 0.47 to 0.070, and 0.72 to 0.11 per million servings, for each of the three scenarios., Conclusion: Simulation highlights the very small risk of Bacillus cereus infection following the ingestion of pasteurized BHM, even in the worst case scenarios, and suggests that a 100-microliter sample for post-pasteurization culture is sufficient.

This article was migrated. The article was marked as recommended. Introduction Continuous Professional Development (CPD) is an important part of a physician's professional life. Yet, providing effective in-service training solutions is a persistent challenge for CPD planners. Methods Primary care physicians are frequently confronted with skin lesionsthey feel ill-prepared to manage. A dermatology Learning-by-concordance (LbC) online activity was developed and offered to family physicians for CPD credit. We were interested in finding out whether this online tool was suitable for CPD. Following a pilot phase, the on-line activity was launched and 45 geographically dispersed primary care physicians completed it. They participated in a telephone conference a week later with an expert to discuss outstanding questions. Evaluation was carried out by a survey that was available immediately after the last case. Results Participants found the on-line training tool user friendly and should be implemented on a larger scale. Participants found the dermatology concepts discussed allowed them to increase their knowledge and apply it to their practice. Discussion Among the strengths of LbC is that the learning task resemble those of a primary physician's daily practice. Finally, our study reveals that LbC is easily integrated in busy work schedules and thus is an effective learning solution for CPD., (Copyright: © 2018 Lecours J et al.)

The inherited peripheral neuropathies (IPNs) are characterized by marked clinical and genetic heterogeneity and include relatively frequent presentations such as Charcot-Marie-Tooth disease and hereditary motor neuropathy, as well as more rare conditions where peripheral neuropathy is associated with additional features. There are over 250 genes known to cause IPN-related disorders but it is estimated that in approximately 50% of affected individuals a molecular diagnosis is not achieved. In this study, we examine the diagnostic utility of whole-exome sequencing (WES) in a cohort of 50 families with 1 or more affected individuals with a molecularly undiagnosed IPN with or without additional features. Pathogenic or likely pathogenic variants in genes known to cause IPN were identified in 24% (12/50) of the families. A further 22% (11/50) of families carried sequence variants in IPN genes in which the significance remains unclear. An additional 12% (6/50) of families had variants in novel IPN candidate genes, 3 of which have been published thus far as novel discoveries (KIF1A, TBCK, and MCM3AP). This study highlights the use of WES in the molecular diagnostic approach of highly heterogeneous disorders, such as IPNs, places it in context of other published neuropathy cohorts, while further highlighting associated benefits for discovery., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Recent clinical whole exome sequencing (WES) cohorts have identified unanticipated multiple genetic diagnoses in single patients. However, the frequency of multiple genetic diagnoses in families is largely unknown., Aims: We set out to identify the rate of multiple genetic diagnoses in probands and their families referred for analysis in two national research programs in Canada., Materials & Methods: We retrospectively analyzed WES results for 802 undiagnosed probands referred over the past 5 years in either the FORGE or Care4Rare Canada WES initiatives., Results: Of the 802 probands, 226 (28.2%) were diagnosed based on mutations in known disease genes. Eight (3.5%) had two or more genetic diagnoses explaining their clinical phenotype, a rate in keeping with the large published studies (average 4.3%; 1.4 - 7.2%). Seven of the 8 probands had family members with one or more of the molecularly diagnosed diseases. Consanguinity and multisystem disease appeared to increase the likelihood of multiple genetic diagnoses in a family., Conclusion: Our findings highlight the importance of comprehensive clinical phenotyping of family members to ultimately provide accurate genetic counseling., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Paediatric mild traumatic brain injury (mTBI) is a public health burden. Clinicians urgently need evidence-based guidance to manage mTBI, but gold standards for diagnosing and predicting the outcomes of mTBI are lacking. The objective of the Advancing Concussion Assessment in Pediatrics (A-CAP) study is to assess a broad pool of neurobiological and psychosocial markers to examine associations with postinjury outcomes in a large sample of children with either mTBI or orthopaedic injury (OI), with the goal of improving the diagnosis and prognostication of outcomes of paediatric mTBI., Methods and Analysis: A-CAP is a prospective, longitudinal cohort study of children aged 8.00-16.99 years with either mTBI or OI, recruited during acute emergency department (ED) visits at five sites from the Pediatric Emergency Research Canada network. Injury information is collected in the ED; follow-up assessments at 10 days and 3 and 6 months postinjury measure a variety of neurobiological and psychosocial markers, covariates/confounders and outcomes. Weekly postconcussive symptom ratings are obtained electronically. Recruitment began in September 2016 and will occur for approximately 24 months. Analyses will test the major hypotheses that neurobiological and psychosocial markers can: (1) differentiate mTBI from OI and (2) predict outcomes of mTBI. Models initially will focus within domains (eg, genes, imaging biomarkers, psychosocial markers), followed by multivariable modelling across domains. The planned sample size (700 mTBI, 300 OI) provides adequate statistical power and allows for internal cross-validation of some analyses., Ethics and Dissemination: The ethics boards at all participating institutions have approved the study and all participants and their parents will provide informed consent or assent. Dissemination will follow an integrated knowledge translation plan, with study findings presented at scientific conferences and in multiple manuscripts in peer-reviewed journals., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Hepatitis E virus (HEV) is a virus of emerging importance to transfusion medicine as studies on blood donors and other populations demonstrate that the prevalence of endemic cases is higher than previously recognized and the risk to vulnerable transfusion recipients is not insignificant., Study Design and Methods: We carried out an HEV prevalence study on 13,993 Canadian blood donors with polymerase chain reaction (PCR) testing on all donors and antibody testing on a subset of 4102 donors. HEV antibody-positive and age- and sex-matched antibody-negative donors were invited to participate in a scripted telephone interview about risk factors., Results: There were no PCR-positive samples found (95% confidence interval [CI], 0%-0.026%). The seroprevalence of HEV in our tested population was 5.9% (95% CI, 5.16%-6.59%). HEV antibody positivity was associated with male sex and increasing age. In case-control analysis history of living outside Canada (odds ratio [OR], 2.9; 95% CI, 1.56-5.32) and contact with farm animals (OR, 1.5; 95% CI, 1.01-2.28) were associated with HEV seropositivity., Conclusion: This is the largest data set to date on HEV infection in Canada. Results suggest low lifetime exposure to HEV and that infectious donations are rare., (© 2017 AABB.)

Background: During a major outbreak of West Nile virus (WNV) infection in the province of Quebec in 2012, public health authorities (PHAs) suspected underrecognition of West Nile neurologic disease (WNND). With data on acute infections detected in blood donors, an estimate of the degree of underrecognition was produced., Study Design and Methods: All 2012 donors were tested for WNV infection with the use of reverse transcription-polymerase chain reaction (RT-PCR). With the number of cases detected, the number of donors tested, our estimate of the duration of viremia, an estimate of the population at risk, and the ratio of WNND to total cases, an expected number of WNND cases was calculated. A Monte Carlo simulation was used to estimate the range of several of these variables., Results: Seventeen RT-PCR-positive donors were found among 52,309 donations tested. In the base case, the total number of cases was 16,095 and the expected number of WNND cases was 115. In the Monte Carlo simulation, the mean number of expected WNND cases was 136, and the median was 129. Since only 85 cases were reported to PHAs, it is estimated that between 26 and 37.5% of cases occurring in the province went undetected., Conclusion: The observation that close to one-third of cases of WNND went undetected because of the omission of appropriate laboratory testing indicates the need for improvement in the investigation of acute neurologic syndrome of suspected infectious etiology in Québec., (© 2017 AABB.)

Mutations in GLE1 cause two recessive subtypes of arthrogryposis multiplex congenita (AMC), a condition characterized by joint contractures at birth, and all previously reported patients died in the perinatal period. GLE1 related AMC has been almost exclusively reported in the Finnish population and is caused by a relatively common pathogenic splicing mutation in that population. Here, we report two non-Finnish brothers with novel compound heterozygous splicing mutations in GLE1, one of whom has survived to 12 years of age. We also demonstrate low levels of residual wild type transcript in fibroblasts from the surviving brother, suggesting that this residual wild-type transcript may contribute to the relatively longer-term survival in this family. We provide a detailed clinical report on the surviving patient, providing the first insight into the natural history of this rare neuromuscular disease. We also suggest that lethal congenital contracture syndrome 1 (LCCS1) and lethal arthrogryposis with anterior horn disease (LAAHD), the two AMC subtypes related to GLE1, do not have sufficient clinical or molecular differentiation to be considered allelic disorders. Rather, GLE1 mutations cause a variable spectrum of AMC severity including a non-lethal variant described herein., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: To examine the diagnostic performance of array comparative genomic hybridization (CGH) for fetal cardiac anomalies in two medium-sized Canadian prenatal genetics clinics., Methods: We prospectively recruited 22 pregnant women with fetal structural cardiac anomalies, normal rapid aneuploidy detection, and FISH for 22q11.2 testing for array CGH analysis., Results: One case had an 8p deletion that was also visible on karyotype and included the GATA4 gene, which has been associated with congenital heart disease. Two cases had inherited pathogenic copy number variants (CNVs) of variable expressivity and penetrance: one was a duplication of 16p11.2 and the other a deletion of 15q11.2. One case had the incidental finding of being a carrier of a recessive disease unrelated to the cardiac anomaly., Conclusions: Of these prospectively recruited cases of fetal cardiac anomalies, 14% had a pathogenic result on array CGH. Pathogenic CNVs of variable penetrance and expressivity were a significant proportion of the positive results identified. These CNVs are generally associated with neurodevelopmental issues and may or may not have been associated with the fetus' underlying congenital heart disease. Array CGH increases the diagnostic yield in this group of patients; however, certain CNVs remain a challenge for counselling in the prenatal setting., (Copyright © 2016 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Cerebro-Costo-Mandibular syndrome (CCMS) is a rare autosomal dominant condition comprising branchial arch-derivative malformations with striking rib-gaps. Affected patients often have respiratory difficulties, associated with upper airway obstruction, reduced thoracic capacity, and scoliosis. We describe a series of 12 sporadic and 4 familial patients including 13 infants/children and 3 adults. Severe micrognathia and reduced numbers of ribs with gaps are consistent findings. Cleft palate, feeding difficulties, respiratory distress, tracheostomy requirement, and scoliosis are common. Additional malformations such as horseshoe kidney, hypospadias, and septal heart defect may occur. Microcephaly and significant developmental delay are present in a small minority of patients. Key radiological findings are of a narrow thorax, multiple posterior rib gaps and abnormal costo-transverse articulation. A novel finding in 2 patients is bilateral accessory ossicles arising from the hyoid bone. Recently, specific mutations in SNRPB, which encodes components of the major spliceosome, have been found to cause CCMS. These mutations cluster in an alternatively spliced regulatory exon and result in altered SNRPB expression. DNA was available from 14 patients and SNRPB mutations were identified in 12 (4 previously reported). Eleven had recurrent mutations previously described in patients with CCMS and one had a novel mutation in the alternative exon. These results confirm the specificity of SNRPB mutations in CCMS and provide further evidence for the role of spliceosomal proteins in craniofacial and thoracic development., (© 2016 Wiley Periodicals, Inc.)

An accurate diagnosis is an integral component of patient care for children with rare genetic disease. Recent advances in sequencing, in particular whole-exome sequencing (WES), are identifying the genetic basis of disease for 25-40% of patients. The diagnostic rate is probably influenced by when in the diagnostic process WES is used. The Finding Of Rare Disease GEnes (FORGE) Canada project was a nation-wide effort to identify mutations for childhood-onset disorders using WES. Most children enrolled in the FORGE project were toward the end of the diagnostic odyssey. The two primary outcomes of FORGE were novel gene discovery and the identification of mutations in genes known to cause disease. In the latter instance, WES identified mutations in known disease genes for 105 of 362 families studied (29%), thereby informing the impact of WES in the setting of the diagnostic odyssey. Our analysis of this dataset showed that these known disease genes were not identified prior to WES enrollment for two key reasons: genetic heterogeneity associated with a clinical diagnosis and atypical presentation of known, clinically recognized diseases. What is becoming increasingly clear is that WES will be paradigm altering for patients and families with rare genetic diseases., (© 2015 The Authors. Clinical Genetics published by John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The prevalence of women experiencing the genitourinary syndrome of menopause is expected to escalate due to the rising numbers of menopausal women. In no other time in history has it been more important for nurses to possess current knowledge regarding menopause management.

Background: Human babesiosis, caused by the intraerythrocytic protozoan parasite Babesia microti, is primarily transmitted by tick bites and is also transmitted by transfusion. Infections have been identified in U.S. blood donors close to Canadian borders. We aimed to assess the risk of transfusion-transmitted babesiosis in Canada by examining infections in ticks and seroprevalence in blood donors., Study Design and Methods: Passive surveillance (receipt of ticks submitted by the public) was used to identify regions for tick drag sampling (active surveillance, 2009-2014). All ticks were tested for B. microti using an indirect immunofluorescent antibody assay (Imugen, Inc.). Between July and December 2013, blood donations from selected sites (southern Manitoba, Ontario, Québec, New Brunswick, and Nova Scotia) near endemic U.S. regions were tested for antibody to B. microti. Donors completed a questionnaire about risk travel and possible tick exposure., Results: Of approximately 12,000 ticks submitted, 14 were B. microti positive (10 in Manitoba, one in Ontario, one in Québec, two in New Brunswick). From active tick surveillance, six of 361 ticks in Manitoba were positive (1.7%), three of 641 (0.5%) in Québec, and none elsewhere. There were 26,260 donors at the selected sites of whom 13,993 (53%) were tested. None were positive for antibody to B. microti. In 2013, 47% of donors visited forested areas in Canada, and 41% traveled to the United States., Conclusion: The data do not suggest that laboratory-based testing is warranted at this time. However, there are indicators that B. microti may be advancing into Canada and ongoing monitoring of tick populations and donor seroprevalence is indicated., (© 2015 AABB.)

Objectives: An obstetric comorbidity index has been developed recently with superior performance characteristics relative to general comorbidity measures in an obstetric population. This study aimed to externally validate this index and to examine the impact of including hospitalisation/delivery records only when estimating comorbidity prevalence and discriminative performance of the obstetric comorbidity index., Design: Validation study., Setting: Alberta, Canada., Population: Pregnant women who delivered a live or stillborn infant in hospital (n = 5995)., Methods: Administrative databases were linked to create a population-based cohort. Comorbid conditions were identified from diagnoses for the delivery hospitalisation, all hospitalisations and all healthcare contacts (i.e. hospitalisations, emergency room visits and physician visits) that occurred during pregnancy and 3 months pre-conception. Logistic regression was used to test the discriminative performance of the comorbidity index., Main Outcome Measures: Maternal end-organ damage and extended length of stay for delivery., Results: Although prevalence estimates for comorbid conditions were consistently lower in delivery records and hospitalisation data than in data for all healthcare contacts, the discriminative performance of the comorbidity index was constant for maternal end-organ damage [all healthcare contacts area under the receiver operating characteristic curve (AUC) = 0.70; hospitalisation data AUC = 0.67; delivery data AUC = 0.65] and extended length of stay for delivery (all healthcare contacts AUC = 0.60; hospitalisation data AUC = 0.58; delivery data AUC = 0.58)., Conclusions: The obstetric comorbidity index shows similar performance characteristics in an external population and is a valid measure of comorbidity in an obstetric population. Furthermore, the discriminative performance of the comorbidity index was similar for comorbidities ascertained at the time of delivery, in hospitalisation data or through all healthcare contacts., (© 2015 The Authors. BJOG An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.)

Purpose and Scope: The aim of this Position Statement is to provide recommendations for Canadian medical geneticists, clinical laboratory geneticists, genetic counsellors and other physicians regarding the use of genome-wide sequencing of germline DNA in the context of clinical genetic diagnosis. This statement has been developed to facilitate the clinical translation and development of best practices for clinical genome-wide sequencing for genetic diagnosis of monogenic diseases in Canada; it does not address the clinical application of this technology in other fields such as molecular investigation of cancer or for population screening of healthy individuals., Methods of Statement Development: Two multidisciplinary groups consisting of medical geneticists, clinical laboratory geneticists, genetic counsellors, ethicists, lawyers and genetic researchers were assembled to review existing literature and guidelines on genome-wide sequencing for clinical genetic diagnosis in the context of monogenic diseases, and to make recommendations relevant to the Canadian context. The statement was circulated for comment to the Canadian College of Medical Geneticists (CCMG) membership-at-large and, following incorporation of feedback, approved by the CCMG Board of Directors. The CCMG is a Canadian organisation responsible for certifying medical geneticists and clinical laboratory geneticists, and for establishing professional and ethical standards for clinical genetics services in Canada., Results and Conclusions: Recommendations include (1) clinical genome-wide sequencing is an appropriate approach in the diagnostic assessment of a patient for whom there is suspicion of a significant monogenic disease that is associated with a high degree of genetic heterogeneity, or where specific genetic tests have failed to provide a diagnosis; (2) until the benefits of reporting incidental findings are established, we do not endorse the intentional clinical analysis of disease-associated genes other than those linked to the primary indication; and (3) clinicians should provide genetic counselling and obtain informed consent prior to undertaking clinical genome-wide sequencing. Counselling should include discussion of the limitations of testing, likelihood and implications of diagnosis and incidental findings, and the potential need for further analysis to facilitate clinical interpretation, including studies performed in a research setting. These recommendations will be routinely re-evaluated as knowledge of diagnostic and clinical utility of clinical genome-wide sequencing improves. While the document was developed to direct practice in Canada, the applicability of the statement is broader and will be of interest to clinicians and health jurisdictions internationally., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: We here examined whether plasma desmosterol-to-cholesterol ratio (DES/CHO) is decreased in patients with Alzheimer's disease (AD) and investigated the association between plasma DES/CHO and longitudinal cognitive decline., Methods: Plasma DES/CHO of AD patients and age-matched controls in a Japanese cross-sectional cohort was determined. Plasma DES/CHO at baseline and follow-up visits was assessed in relation to cognitive decline in Japanese and Swedish longitudinal cohorts., Results: Plasma DES/CHO was significantly reduced in Japanese AD patients and significantly correlated with Mini-Mental State Examination (MMSE) score. The longitudinal analysis revealed that plasma DES/CHO in AD patients shows a significant decrease at follow-up intervals. The decline in plasma DES/CHO is larger in the AD group with rapid progression than in that with slow progression. The changes in plasma DES/CHO significantly correlated with changes in the MMSE score., Conclusion: Plasma DES/CHO is decreased in AD patients and may serve as a longitudinal surrogate marker associated with cognitive decline.

Objective: Insulin is regularly used in hospitalized patients for glycemic control but is associated with significant risks. The goals of this study were to describe the strengths and weaknesses of a university health centre in the safe use of insulin, to collect improvement proposals from health professionals involved in the management of insulin therapy and to assess inpatient glycemic control., Methods: This is a qualitative study. Physicians, nurses and pharmacists practising at the Centre Hospitalier Universitaire de Sherbrooke (CHUS) for at least 2 years were invited to join focus groups on safe insulin treatment. Themes up for discussion were roles of professionals in insulin therapy, problems encountered, solutions put forward and strengths of the hospital. The Quality Hyperglycemia Score (QHS) was assessed using an existing cohort of inpatients who were prescribed insulin., Results: A total of 5 focus groups were held in February and March of 2012, involving 31 healthcare professional participants. Several groups pointed out the same problems, namely, lack of access to useful information for optimal management of insulin therapy and lack of communication among personnel on different work shifts. Results of the QHS suggest room for improvement in blood glucose control at our institution., Conclusion: These focus groups allowed better identification of the management problems related to the use of insulin in our health institution and possible interventions to solve them. The QHS will be reassessed to measure quality of inpatient glycemic control over time., (Copyright © 2014 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.)

Several studies have shown that housing conditions and environmental exposure to a series of stimuli lead to behavior improvement in several species. While more works have been focused on illustrating changes of the proteome and transcriptome following enriched environment exposure in mice, little has been done to understand changes in the brain metabolome in this paradigm due to the complexity of this type of analysis. In this paper, lipidomics focused on phospholipids and gangliosides were conducted for brain tissues of mice exposed to enriched or impoverished conditions. We optimized previously reported method and established a reliable relative comparison method for phospholipids and gangliosides in brain tissue using prefractionation with weak anion exchange cartridge. We used liquid chromatography mass spectrometry to explore metabolic signatures of the cerebral cortex and hippocampus after confirming the animals had significant memory differences using the fear conditioning paradigm and brain immunohistochemistry. Although both cerebral cortex and hippocampus regions did not show major alterations in ganglioside composition, we found significant differences in a series of phospholipids containing 22:6 fatty acid in the prefrontal cortex, indicating that environmental enrichment and impoverished housing conditions might be a relevant paradigm to study aberrant lipid metabolism of docosahexaenoic acid consumption. Our study highlights the hypothesis-generating potential of lipidomics and identifies novel region-specific lipid changes possibly linked not only to change of memory function in these models, but also to help us better understand how lipid changes may contribute to memory disorders.

DING proteins, named after their conserved N-terminus, form an overlooked protein family whose members were generally discovered through serendipity. It is characterized by an unusually high sequence conservation, even between distantly related species, and by an outstanding diversity of activities and ligands. They all share a demonstrated capacity to bind phosphate with high affinity or at least a predicted phosphate-binding site. However, DING protein genes are conspicuously absent from databases. The many novel family members identified in recent years have confirmed that DING proteins are ubiquitous not only in animals and plants but probably also in prokaryotes. At the functional level, there is increasing evidence that they participate in many health-related processes such as cancers as well as bacterial (Pseudomonas) and viral (HIV) infections, by mechanisms that are now beginning to be understood. They thus represent potent targets for the development of novel therapeutic approaches, especially against HIV. The few genomic sequences that are now available are starting to give some clues on why DING protein genes and mRNAs are well conserved and difficult to clone. This could open a new era of research, of both fundamental and applied importance.

A minimally invasive diagnostic assay for early detection of Alzheimer's disease (AD) is required to select optimal patient groups in clinical trials, monitor disease progression and response to treatment, and to better plan patient clinical care. Blood is an attractive source for biomarkers due to minimal discomfort to the patient, encouraging greater compliance in clinical trials and frequent testing. MiRNAs belong to the class of non-coding regulatory RNA molecules of ∼22 nt length and are now recognized to regulate ∼60% of all known genes through post-transcriptional gene silencing (RNAi). They have potential as useful biomarkers for clinical use because of their stability and ease of detection in many tissues, especially blood. Circulating profiles of miRNAs have been shown to discriminate different tumor types, indicate staging and progression of the disease and to be useful as prognostic markers. Recently their role in neurodegenerative diseases, both as diagnostic biomarkers as well as explaining basic disease etiology has come into focus. Here we report the discovery and validation of a unique circulating 7-miRNA signature (hsa-let-7d-5p, hsa-let-7g-5p, hsa-miR-15b-5p, hsa-miR-142-3p, hsa-miR-191-5p, hsa-miR-301a-3p and hsa-miR-545-3p) in plasma, which could distinguish AD patients from normal controls (NC) with >95% accuracy (AUC of 0.953). There was a >2 fold difference for all signature miRNAs between the AD and NC samples, with p-values<0.05. Pathway analysis, taking into account enriched target mRNAs for these signature miRNAs was also carried out, suggesting that the disturbance of multiple enzymatic pathways including lipid metabolism could play a role in AD etiology.

Purpose: Birth cohorts are a common tool used in epidemiological studies about pregnancy; yet these datasets systematically miss pregnancies that are spontaneously lost or terminated. This study examined the feasibility of linking administrative and clinical datasets from Alberta Canada to identify a pregnancy cohort that includes spontaneous and medical pregnancy losses., Methods: Deterministic linkage was used to link data from twelve clinical and administrative datasets for women who conceived between November 2007 and February 2008. Descriptive statistics were used to characterize the relative contribution of each dataset to the overall dataset., Results: Overall, 6,477 unique pregnancies were eligible for inclusion, resulting in a live birth rate of 94.1%, a stillbirth rate of 0.5%, a fetal death rate of 4.1%, and an estimated 1.3% of the cohort moving out of the study area. No single dataset could identify all pregnancies. Individual databases identified 2.0-99.1% of the cohort. Fetal deaths were most frequently identified in outpatient physician claims, emergency room visits, ultrasound data, or from the cytogenetic laboratory., Conclusions: Linkage of clinical and administrative databases to identify pregnancy is feasible and can overcome many limitations associated with the use of a single dataset; however, fetal deaths continue to be under-ascertained., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: The aim of this research was to determine the impact of observed versus hypothesized service utilization on the cost of first trimester screening (FTS) and prenatal diagnosis for trisomy 21 in a Canadian province., Methods: A population-based pregnancy cohort was created by linking 12 clinical and administrative databases. Care trajectories were derived to examine utilization patterns for FTS, prenatal diagnosis, and pregnancy termination. A literature review was conducted to determine what utilization parameters were used in economic evaluations of FTS. Local cost data was applied to observed and hypothesized care trajectories., Results: The observed mean cost per fetus with trisomy 21 detected prenatally using FTS was $129,606.04 compared with $27,021.45 for women who did not access FTS. Observed utilization of FTS and prenatal diagnosis among screen positive women and termination of pregnancy following prenatal diagnosis of trisomy 21 were substantially lower than hypothesized in existing cost effectiveness studies. Cost estimates were sensitive to hypothetical changes in utilization of prenatal screening, prenatal diagnosis, and pregnancy termination., Conclusion: Literature-based estimates of the cost-effectiveness of prenatal screening may not accurately represent current local practice due to potentially unrealistic assumptions about what proportion of women will proceed to invasive testing and ultimately terminate an affected pregnancy., (© 2013 John Wiley & Sons, Ltd.)