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66 Research products, page 1 of 7

  • Canada
  • 2017-2021
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  • Canadian Institutes of Health Research

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  • Restricted
    Authors: 
    Yannick Molgat-Seon; Sabina A. Guler; Carli M. Peters; Dragoş M. Vasilescu; Joseph H. Puyat; Harvey O. Coxson; Christopher J. Ryerson; Jordan A. Guenette;
    Publisher: Elsevier BV
    Project: NSERC , CIHR

    RATIONALE The pathophysiology of interstitial lung disease (ILD) impacts body composition, whereby ILD severity is linked to lower lean mass. OBJECTIVES To determine i) if pectoralis muscle area (PMA) is a surrogate for whole-body lean mass in ILD, ii) whether PMA is associated with ILD severity, and iii) if the longitudinal change in PMA is associated with pulmonary function and mortality in ILD. METHODS Patients with ILD (n = 164) were analyzed retrospectively. PMA was quantified from a chest computed tomography scan. Peripheral oxygen saturation (SpO2), 6-min walk distance (6MWD), and pulmonary function were obtained as part of routine clinical care. Dyspnea and quality of life were assessed using the UCSD Shortness of Breath Questionnaire and European Quality of Life 5 Dimensions questionnaire, respectively. RESULTS PMA was associated with whole-body lean mass (p  0.05). The annual negative PMA slope was associated with annual negative slopes in FVC, FEV1, and DLCO (all p < 0.05), but not FEV1/FVC (p = 0.46). Annual slope in PMA was associated with all-cause mortality (hazard ratio = -0.80, 95% CI:0.889-0.959; p < 0.001). CONCLUSION In patients with ILD, PMA is a suitable surrogate for whole-body lean mass. A lower PMA is associated with indices of ILD severity, which supports the notion that ILD progression may involve sarcopenia.

  • Restricted English
    Authors: 
    Sara García-Viñuales; Rashik Ahmed; Michele Sciacca; Valeria Lanza; Maria Laura Giuffrida; Stefania Zimbone; Valeria Romanucci; Armando Zarrelli; Corrado Bongiorno; Natalia Spinella; +4 more
    Publisher: American Chemical Society, Washington, D.C. , Stati Uniti d'America
    Country: Italy
    Project: CIHR , NSERC , EC | INCIPIT (665403)

    Alzheimer's disease (AD) is linked to the abnormal accumulation of amyloid ? peptide (A?) aggregates in the brain. Silybin B, a natural compound extracted from milk thistle (Silybum marianum), has been shown to significantly inhibit A? aggregation in vitro and to exert neuroprotective properties in vivo. However, further explorations of silybin B's clinical potential are currently limited by three main factors: (a) poor solubility, (b) instability in blood serum, and (c) only partial knowledge of silybin's mechanism of action. Here, we address these three limitations. We demonstrate that conjugation of a trehalose moiety to silybin significantly increases both water solubility and stability in blood serum without significantly compromising its antiaggregation properties. Furthermore, using a combination of biophysical techniques with different spatial resolution, that is, TEM, ThT fluorescence, CD, and NMR spectroscopy, we profile the interactions of the trehalose conjugate with both A? monomers and oligomers and evidence that silybin may shield the "toxic" surfaces formed by the N-terminal and central hydrophobic regions of A?. Finally, comparative analysis with silybin A, a less active diastereoisomer of silybin B, revealed how even subtle differences in chemical structure may entail different effects on amyloid inhibition. The resulting insight on the mechanism of action of silybins as aggregation inhibitors is anticipated to facilitate the future investigation of silybin's therapeutic potential.

  • Restricted
    Authors: 
    Natalie C. Marshall; Theo Klein; Maichael Thejoe; Niklas von Krosigk; Jayachandran N. Kizhakkedathu; B. Brett Finlay; Christopher M. Overall;
    Country: Netherlands
    Project: CIHR

    The human genome encodes ∼20 mitochondrial proteases, yet we know little of how they sculpt the mitochondrial proteome, particularly during important mitochondrial events such as the initiation of apoptosis. To characterize global mitochondrial proteolysis we refined our technique, terminal amine isotopic labeling of substrates, for mitochondrial SILAC (MS-TAILS) to identify proteolysis across mitochondria and parent cells in parallel. Our MS-TAILS analyses identified 45% of the mitochondrial proteome and identified protein amino (N)-termini from 26% of mitochondrial proteins, the highest reported coverage of the human mitochondrial N-terminome. MS-TAILS revealed 97 previously unknown proteolytic sites. MS-TAILS also identified mitochondrial targeting sequence (MTS) removal by proteolysis during protein import, confirming 101 MTS sites and identifying 135 new MTS sites, revealing a wobbly requirement for the MTS cleavage motif. To examine the relatively unknown initial cleavage events occurring before the well-studied activation of caspase-3 in intrinsic apoptosis, we quantitatively compared N-terminomes of mitochondria and their parent cells before and after initiation of apoptosis at very early time points. By identifying altered levels of >400 N-termini, MS-TAILS analyses implicated specific mitochondrial pathways including protein import, fission, and iron homeostasis in apoptosis initiation. Notably, both staurosporine and Bax activator molecule-7 triggered in common 7 mitochondrial and 85 cellular cleavage events that are potentially part of an essential core of apoptosis-initiating events. All mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium with the dataset identifier PXD009054.

  • Publication . Article . Other literature type . 2020
    Restricted English
    Authors: 
    Emmanuelle Ranza; Werner J. Z’Graggen; Mathias Lidgren; Maurice Beghetti; Michel Guipponi; Stylianos E. Antonarakis; Michael Absoud; Sushma Goyal; Deb K. Pal; Christian Korff;
    Country: Switzerland
    Project: CIHR

    Anoxic-epileptic seizures (AES) are rare outcomes of common childhood reflex anoxic syncope that trigger a true epileptic seizure. The term AES was coined by Stephenson in 1983, to differentiate these events from convulsive syncopes and the more common reflex anoxic syncopes. A genetic susceptibility for AES has been postulated; but, its molecular basis has up to now been elusive. We report here two illustrative cases and show the association of de novo SCN8A variants and AES. One of them had focal or generalized seizures and autonomic symptoms triggered by orthostatism; the second had breath-holding spells triggered by pain or exercise leading to tonic-clonic seizures; both had repeatedly normal EEGs and a family history of reflex syncope. The data of three additional AES patients further suggest, for the first time, a link between SCN8A pathogenic variants and AES. The neurodevelopment of four patients was abnormal. Four of the five SCN8A mutations observed here were previously described in patients with seizure disorders. Seizures responded particularly well to sodium channel blockers. Our observation enriches the spectrum of seizures linked with SCN8A pathogenic variants.

  • Publication . Article . 2021
    Restricted
    Authors: 
    Faizan Khan; Tobias Tritschler; Susan R Kahn; Marc A Rodger;
    Publisher: Elsevier BV
    Project: CIHR , SNSF | Development of a novel, e... (177999)

    Venous thromboembolism, comprising both deep vein thrombosis and pulmonary embolism, is a chronic illness that affects nearly 10 million people every year worldwide. Strong provoking risk factors for venous thromboembolism include major surgery and active cancer, but most events are unprovoked. Diagnosis requires a sequential work-up that combines assessment of clinical pretest probability for venous thromboembolism using a clinical score (eg, Wells score), D-dimer testing, and imaging. Venous thromboembolism can be considered excluded in patients with both a non-high clinical pretest probability and normal D-dimer concentrations. When required, ultrasonography should be done for a suspected deep vein thrombosis and CT or ventilation-perfusion scintigraphy for a suspected pulmonary embolism. Direct oral anticoagulants (DOACs) are the first-line treatment for almost all patients with venous thromboembolism (including those with cancer). After completing 3-6 months of initial treatment, anticoagulation can be discontinued in patients with venous thromboembolism provoked by a major transient risk factor. Patients whose long-term risk of recurrent venous thromboembolism outweighs the long-term risk of major bleeding, such as those with active cancer or men with unprovoked venous thromboembolism, should receive indefinite anticoagulant treatment. Pharmacological venous thromboembolism prophylaxis is generally warranted in patients undergoing major orthopaedic or cancer surgery. Ongoing research is focused on improving diagnostic strategies for suspected deep vein thrombosis, comparing different DOACs, developing safer anticoagulants, and further individualising approaches for the prevention and management of venous thromboembolism.

  • Restricted
    Authors: 
    Päivi Vieira; Jessie M. Cameron; Elisa Rahikkala; Riikka Keski-Filppula; Lin-Hua Zhang; Saikat Santra; Allison Matthews; Päivi Myllynen; Matti Nuutinen; Jukka S. Moilanen; +4 more
    Country: Netherlands
    Project: CIHR

    Abstract Clinical and laboratory data were collected from three Finnish patients including a sibling pair and another unrelated child with unexplained childhood hypoglycemia. Transient elevation of alanine transaminase, lactate and tricarboxylic acid cycle intermediates, especially fumarate, were noticed in urine organic acid analysis. Exome sequencing was performed for the patients and their parents. A novel homozygous PCK1 c.925G>A (p.G309R) mutation was detected in all affected individuals. COS-1 cells transfected with mutant PCK1 transcripts were used to study the pathogenic nature of the detected variant. The COS-1 transfected cells showed the mutant gene to be incapable of producing a normally functioning cytosolic phosphoenolpyruvate carboxykinase (PEPCK) enzyme. This report further delineates the clinical phenotype of isolated cytosolic PEPCK deficiency and offers a metabolic pattern helping to recognize these patients. Cytosolic PEPCK deficiency should be considered in the differential diagnosis of children presenting with hypoglycemia, hepatic dysfunction and elevated tricarboxylic acid intermediates in urinary organic acid analysis.

  • Restricted
    Authors: 
    Benyamin Rotberg; Erzsébet Horváth-Puhó; Simone N. Vigod; Joel G. Ray; Henrik Toft Sørensen; Eyal Cohen;
    Publisher: Wiley
    Project: CIHR

    Background: The birth of a child with a major congenital anomaly may create chronic caregiving stress for mothers, yet little is known about their psychiatric outcomes. Aims: To evaluate the association of the birth of a child with a major congenital anomaly with subsequent maternal psychiatric risk. Methods: This Danish nationwide cohort study included mothers who gave birth to an infant with a major congenital anomaly (n = 19 220) between 1997 and 2015. Comparators were randomly selected mothers, matched on maternal age, year of delivery and parity (n = 195 399). The primary outcome was any new-onset psychiatric diagnosis. Secondary outcomes included specific psychiatric diagnoses, psychiatric in-patient admissions and redeemed psychoactive medicines. Cox models were used to estimate hazard ratios (HRs), adjusted for socioeconomic and medical variables. Results: Mothers of affected infants had an elevated risk for a new-onset psychiatric disorder vs. the comparison group (adjusted HR, 1.16, 95% CI 1.11–1.22). The adjusted HR was particularly elevated during the first postpartum year (1.65, 95% CI 1.42–1.90), but remained high for years, especially among mothers of children with multiorgan anomalies (1.37, 95% CI 1.18–1.57). The risk was also elevated for most specific psychiatric diagnoses, admissions and medicines. Conclusions: Mothers who give birth to a child with a major congenital anomaly are at increased risk of new-onset psychiatric disorders, especially shortly after birth and for mothers of children with more severe anomalies. Our study highlights the need to screen for mental illness in this high-risk population, as well as to integrate adult mental health services and paediatric care.

  • Restricted English
    Authors: 
    Austin Larson; Shanti Balasubramaniam; John Christodoulou; Lindsay C. Burrage; Ronit Marom; Brett H. Graham; George A. Diaz; Emma Glamuzina; Natalie Hauser; Bryce Heese; +8 more
    Country: Netherlands
    Project: CIHR

    Elevations of specific acylcarnitines in blood reflect carboxylase deficiencies, and have utility in newborn screening for life-threatening organic acidemias and other inherited metabolic diseases. In this report, we describe a newly-identified association of biochemical features of multiple carboxylase deficiency in individuals harboring mitochondrial DNA (mtDNA) mutations in MT-ATP6 and in whom organic acidemias and multiple carboxylase deficiencies were excluded. Using retrospective chart review, we identified eleven individuals with abnormally elevated propionylcarnitine (C3) or hydroxyisovalerylcarnitine (C5OH) with mutations in MT-ATP6, most commonly m.8993T. >. G in high heteroplasmy or homoplasmy. Most patients were ascertained on newborn screening; most had normal enzymatic or molecular genetic testing to exclude biotinidase and holocarboxylase synthetase deficiencies. MT-ATP6 is associated with some cases of Leigh disease; clinical outcomes in our cohort ranged from death from neurodegenerative disease in early childhood to clinically and developmentally normal after several years of follow-up. These cases expand the biochemical phenotype associated with MT-ATP6 mutations, especially m.8993T. >. G, to include acylcarnitine abnormalities mimicking carboxylase deficiency states. Clinicians should be aware of this association and its implications for newborn screening, and consider mtDNA sequencing in patients exhibiting similar acylcarnitine abnormalities that are biotin-unresponsive and in whom other enzymatic deficiencies have been excluded.

  • Restricted English
    Authors: 
    Hanbin Choi; Jens Peter Andersen; Robert S. Molday;
    Project: CIHR

    ATP8A2 is a P4-ATPase (adenosine triphosphate) that actively flips phosphatidylserine and phosphatidylethanolamine from the exoplasmic to the cytoplasmic leaflet of cell membranes to generate and maintain phospholipid asymmetry. Mutations in the ATP8A2 gene have been reported to cause severe autosomal recessive neurological diseases in humans characterized by intellectual disability, hypotonia, chorea, and hyperkinetic movement disorders with or without optic and cerebellar atrophy. To determine the effect of disease-associated missense mutations on ATP8A2, we expressed six variants with the accessory subunit CDC50A in HEK293T cells. The level of expression, cellular localization, and functional activity were analyzed by western blot analysis, immunofluorescence microscopy, and ATPase activity assays. Two variants (p.Ile376Met and p.Lys429Met) expressed at normal ATP8A2 levels and preferentially localized to the Golgi-recycling endosomes, but were devoid of ATPase activity. Four variants (p.Lys429Asn, pAla544Pro, p.Arg625Trp, and p.Trp702Arg) expressed poorly, localized to the endoplasmic reticulum, and lacked ATPase activity. The expression of these variants was increased twofold by the addition of the proteasome inhibitor MG132. We conclude that the p.Ile376Met and p.Lys429Met variants fold in a native-like conformation, but lack key amino acid residues required for ATP-dependent lipid transport. In contrast, the p.Lys429Asn, pAla544Pro, p.Arg625Trp, and p.Trp702Arg variants are highly misfolded and undergo rapid proteosomal degradation.

  • Restricted English
    Authors: 
    Faizan Khan; Tobias Tritschler; Miriam Kimpton; Philip S. Wells; Clive Kearon; Jeffrey I. Weitz; Harry R. Büller; Gary E. Raskob; Walter Ageno; Francis Couturaud; +27 more
    Countries: Italy, Netherlands, Italy
    Project: CIHR

    BACKGROUND The long-term risk for major bleeding in patients receiving extended (beyond the initial 3 to 6 months) anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain. PURPOSE To determine the incidence of major bleeding during extended anticoagulation of up to 5 years among patients with a first unprovoked VTE, overall, and in clinically important subgroups. DATA SOURCES MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception to 23 July 2021. STUDY SELECTION Randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding among patients with a first unprovoked VTE who were to receive oral anticoagulation for a minimum of 6 additional months after completing at least 3 months of initial anticoagulant treatment. DATA EXTRACTION Two reviewers independently abstracted data and assessed study quality. Unpublished data required for analyses were obtained from authors of included studies. DATA SYNTHESIS Among the 14 RCTs and 13 cohort studies included in the analysis, 9982 patients received a vitamin K antagonist (VKA) and 7220 received a direct oral anticoagulant (DOAC). The incidence of major bleeding per 100 person-years was 1.74 events (95% CI, 1.34 to 2.20 events) with VKAs and 1.12 events (CI, 0.72 to 1.62 events) with DOACs. The 5-year cumulative incidence of major bleeding with VKAs was 6.3% (CI, 3.6% to 10.0%). Among patients receiving either a VKA or a DOAC, the incidence of major bleeding was statistically significantly higher among those who were older than 65 years or had creatinine clearance less than 50 mL/min, a history of bleeding, concomitant use of antiplatelet therapy, or a hemoglobin level less than 100 g/L. The case-fatality rate of major bleeding was 8.3% (CI, 5.1% to 12.2%) with VKAs and 9.7% (CI, 3.2% to 19.2%) with DOACs. LIMITATION Data were insufficient to estimate incidence of major bleeding beyond 1 year of extended anticoagulation with DOACs. CONCLUSION In patients with a first unprovoked VTE, the long-term risks and consequences of anticoagulant-related major bleeding are considerable. This information will help inform patient prognosis and guide decision making about treatment duration for unprovoked VTE. PRIMARY FUNDING SOURCE Canadian Institutes of Health Research. (PROSPERO: CRD42019128597).

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The following results are related to Canada. Are you interested to view more results? Visit OpenAIRE - Explore.
66 Research products, page 1 of 7
  • Restricted
    Authors: 
    Yannick Molgat-Seon; Sabina A. Guler; Carli M. Peters; Dragoş M. Vasilescu; Joseph H. Puyat; Harvey O. Coxson; Christopher J. Ryerson; Jordan A. Guenette;
    Publisher: Elsevier BV
    Project: NSERC , CIHR

    RATIONALE The pathophysiology of interstitial lung disease (ILD) impacts body composition, whereby ILD severity is linked to lower lean mass. OBJECTIVES To determine i) if pectoralis muscle area (PMA) is a surrogate for whole-body lean mass in ILD, ii) whether PMA is associated with ILD severity, and iii) if the longitudinal change in PMA is associated with pulmonary function and mortality in ILD. METHODS Patients with ILD (n = 164) were analyzed retrospectively. PMA was quantified from a chest computed tomography scan. Peripheral oxygen saturation (SpO2), 6-min walk distance (6MWD), and pulmonary function were obtained as part of routine clinical care. Dyspnea and quality of life were assessed using the UCSD Shortness of Breath Questionnaire and European Quality of Life 5 Dimensions questionnaire, respectively. RESULTS PMA was associated with whole-body lean mass (p  0.05). The annual negative PMA slope was associated with annual negative slopes in FVC, FEV1, and DLCO (all p < 0.05), but not FEV1/FVC (p = 0.46). Annual slope in PMA was associated with all-cause mortality (hazard ratio = -0.80, 95% CI:0.889-0.959; p < 0.001). CONCLUSION In patients with ILD, PMA is a suitable surrogate for whole-body lean mass. A lower PMA is associated with indices of ILD severity, which supports the notion that ILD progression may involve sarcopenia.

  • Restricted English
    Authors: 
    Sara García-Viñuales; Rashik Ahmed; Michele Sciacca; Valeria Lanza; Maria Laura Giuffrida; Stefania Zimbone; Valeria Romanucci; Armando Zarrelli; Corrado Bongiorno; Natalia Spinella; +4 more
    Publisher: American Chemical Society, Washington, D.C. , Stati Uniti d'America
    Country: Italy
    Project: CIHR , NSERC , EC | INCIPIT (665403)

    Alzheimer's disease (AD) is linked to the abnormal accumulation of amyloid ? peptide (A?) aggregates in the brain. Silybin B, a natural compound extracted from milk thistle (Silybum marianum), has been shown to significantly inhibit A? aggregation in vitro and to exert neuroprotective properties in vivo. However, further explorations of silybin B's clinical potential are currently limited by three main factors: (a) poor solubility, (b) instability in blood serum, and (c) only partial knowledge of silybin's mechanism of action. Here, we address these three limitations. We demonstrate that conjugation of a trehalose moiety to silybin significantly increases both water solubility and stability in blood serum without significantly compromising its antiaggregation properties. Furthermore, using a combination of biophysical techniques with different spatial resolution, that is, TEM, ThT fluorescence, CD, and NMR spectroscopy, we profile the interactions of the trehalose conjugate with both A? monomers and oligomers and evidence that silybin may shield the "toxic" surfaces formed by the N-terminal and central hydrophobic regions of A?. Finally, comparative analysis with silybin A, a less active diastereoisomer of silybin B, revealed how even subtle differences in chemical structure may entail different effects on amyloid inhibition. The resulting insight on the mechanism of action of silybins as aggregation inhibitors is anticipated to facilitate the future investigation of silybin's therapeutic potential.

  • Restricted
    Authors: 
    Natalie C. Marshall; Theo Klein; Maichael Thejoe; Niklas von Krosigk; Jayachandran N. Kizhakkedathu; B. Brett Finlay; Christopher M. Overall;
    Country: Netherlands
    Project: CIHR

    The human genome encodes ∼20 mitochondrial proteases, yet we know little of how they sculpt the mitochondrial proteome, particularly during important mitochondrial events such as the initiation of apoptosis. To characterize global mitochondrial proteolysis we refined our technique, terminal amine isotopic labeling of substrates, for mitochondrial SILAC (MS-TAILS) to identify proteolysis across mitochondria and parent cells in parallel. Our MS-TAILS analyses identified 45% of the mitochondrial proteome and identified protein amino (N)-termini from 26% of mitochondrial proteins, the highest reported coverage of the human mitochondrial N-terminome. MS-TAILS revealed 97 previously unknown proteolytic sites. MS-TAILS also identified mitochondrial targeting sequence (MTS) removal by proteolysis during protein import, confirming 101 MTS sites and identifying 135 new MTS sites, revealing a wobbly requirement for the MTS cleavage motif. To examine the relatively unknown initial cleavage events occurring before the well-studied activation of caspase-3 in intrinsic apoptosis, we quantitatively compared N-terminomes of mitochondria and their parent cells before and after initiation of apoptosis at very early time points. By identifying altered levels of >400 N-termini, MS-TAILS analyses implicated specific mitochondrial pathways including protein import, fission, and iron homeostasis in apoptosis initiation. Notably, both staurosporine and Bax activator molecule-7 triggered in common 7 mitochondrial and 85 cellular cleavage events that are potentially part of an essential core of apoptosis-initiating events. All mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium with the dataset identifier PXD009054.

  • Publication . Article . Other literature type . 2020
    Restricted English
    Authors: 
    Emmanuelle Ranza; Werner J. Z’Graggen; Mathias Lidgren; Maurice Beghetti; Michel Guipponi; Stylianos E. Antonarakis; Michael Absoud; Sushma Goyal; Deb K. Pal; Christian Korff;
    Country: Switzerland
    Project: CIHR

    Anoxic-epileptic seizures (AES) are rare outcomes of common childhood reflex anoxic syncope that trigger a true epileptic seizure. The term AES was coined by Stephenson in 1983, to differentiate these events from convulsive syncopes and the more common reflex anoxic syncopes. A genetic susceptibility for AES has been postulated; but, its molecular basis has up to now been elusive. We report here two illustrative cases and show the association of de novo SCN8A variants and AES. One of them had focal or generalized seizures and autonomic symptoms triggered by orthostatism; the second had breath-holding spells triggered by pain or exercise leading to tonic-clonic seizures; both had repeatedly normal EEGs and a family history of reflex syncope. The data of three additional AES patients further suggest, for the first time, a link between SCN8A pathogenic variants and AES. The neurodevelopment of four patients was abnormal. Four of the five SCN8A mutations observed here were previously described in patients with seizure disorders. Seizures responded particularly well to sodium channel blockers. Our observation enriches the spectrum of seizures linked with SCN8A pathogenic variants.

  • Publication . Article . 2021
    Restricted
    Authors: 
    Faizan Khan; Tobias Tritschler; Susan R Kahn; Marc A Rodger;
    Publisher: Elsevier BV
    Project: CIHR , SNSF | Development of a novel, e... (177999)

    Venous thromboembolism, comprising both deep vein thrombosis and pulmonary embolism, is a chronic illness that affects nearly 10 million people every year worldwide. Strong provoking risk factors for venous thromboembolism include major surgery and active cancer, but most events are unprovoked. Diagnosis requires a sequential work-up that combines assessment of clinical pretest probability for venous thromboembolism using a clinical score (eg, Wells score), D-dimer testing, and imaging. Venous thromboembolism can be considered excluded in patients with both a non-high clinical pretest probability and normal D-dimer concentrations. When required, ultrasonography should be done for a suspected deep vein thrombosis and CT or ventilation-perfusion scintigraphy for a suspected pulmonary embolism. Direct oral anticoagulants (DOACs) are the first-line treatment for almost all patients with venous thromboembolism (including those with cancer). After completing 3-6 months of initial treatment, anticoagulation can be discontinued in patients with venous thromboembolism provoked by a major transient risk factor. Patients whose long-term risk of recurrent venous thromboembolism outweighs the long-term risk of major bleeding, such as those with active cancer or men with unprovoked venous thromboembolism, should receive indefinite anticoagulant treatment. Pharmacological venous thromboembolism prophylaxis is generally warranted in patients undergoing major orthopaedic or cancer surgery. Ongoing research is focused on improving diagnostic strategies for suspected deep vein thrombosis, comparing different DOACs, developing safer anticoagulants, and further individualising approaches for the prevention and management of venous thromboembolism.

  • Restricted
    Authors: 
    Päivi Vieira; Jessie M. Cameron; Elisa Rahikkala; Riikka Keski-Filppula; Lin-Hua Zhang; Saikat Santra; Allison Matthews; Päivi Myllynen; Matti Nuutinen; Jukka S. Moilanen; +4 more
    Country: Netherlands
    Project: CIHR

    Abstract Clinical and laboratory data were collected from three Finnish patients including a sibling pair and another unrelated child with unexplained childhood hypoglycemia. Transient elevation of alanine transaminase, lactate and tricarboxylic acid cycle intermediates, especially fumarate, were noticed in urine organic acid analysis. Exome sequencing was performed for the patients and their parents. A novel homozygous PCK1 c.925G>A (p.G309R) mutation was detected in all affected individuals. COS-1 cells transfected with mutant PCK1 transcripts were used to study the pathogenic nature of the detected variant. The COS-1 transfected cells showed the mutant gene to be incapable of producing a normally functioning cytosolic phosphoenolpyruvate carboxykinase (PEPCK) enzyme. This report further delineates the clinical phenotype of isolated cytosolic PEPCK deficiency and offers a metabolic pattern helping to recognize these patients. Cytosolic PEPCK deficiency should be considered in the differential diagnosis of children presenting with hypoglycemia, hepatic dysfunction and elevated tricarboxylic acid intermediates in urinary organic acid analysis.

  • Restricted
    Authors: 
    Benyamin Rotberg; Erzsébet Horváth-Puhó; Simone N. Vigod; Joel G. Ray; Henrik Toft Sørensen; Eyal Cohen;
    Publisher: Wiley
    Project: CIHR

    Background: The birth of a child with a major congenital anomaly may create chronic caregiving stress for mothers, yet little is known about their psychiatric outcomes. Aims: To evaluate the association of the birth of a child with a major congenital anomaly with subsequent maternal psychiatric risk. Methods: This Danish nationwide cohort study included mothers who gave birth to an infant with a major congenital anomaly (n = 19 220) between 1997 and 2015. Comparators were randomly selected mothers, matched on maternal age, year of delivery and parity (n = 195 399). The primary outcome was any new-onset psychiatric diagnosis. Secondary outcomes included specific psychiatric diagnoses, psychiatric in-patient admissions and redeemed psychoactive medicines. Cox models were used to estimate hazard ratios (HRs), adjusted for socioeconomic and medical variables. Results: Mothers of affected infants had an elevated risk for a new-onset psychiatric disorder vs. the comparison group (adjusted HR, 1.16, 95% CI 1.11–1.22). The adjusted HR was particularly elevated during the first postpartum year (1.65, 95% CI 1.42–1.90), but remained high for years, especially among mothers of children with multiorgan anomalies (1.37, 95% CI 1.18–1.57). The risk was also elevated for most specific psychiatric diagnoses, admissions and medicines. Conclusions: Mothers who give birth to a child with a major congenital anomaly are at increased risk of new-onset psychiatric disorders, especially shortly after birth and for mothers of children with more severe anomalies. Our study highlights the need to screen for mental illness in this high-risk population, as well as to integrate adult mental health services and paediatric care.

  • Restricted English
    Authors: 
    Austin Larson; Shanti Balasubramaniam; John Christodoulou; Lindsay C. Burrage; Ronit Marom; Brett H. Graham; George A. Diaz; Emma Glamuzina; Natalie Hauser; Bryce Heese; +8 more
    Country: Netherlands
    Project: CIHR

    Elevations of specific acylcarnitines in blood reflect carboxylase deficiencies, and have utility in newborn screening for life-threatening organic acidemias and other inherited metabolic diseases. In this report, we describe a newly-identified association of biochemical features of multiple carboxylase deficiency in individuals harboring mitochondrial DNA (mtDNA) mutations in MT-ATP6 and in whom organic acidemias and multiple carboxylase deficiencies were excluded. Using retrospective chart review, we identified eleven individuals with abnormally elevated propionylcarnitine (C3) or hydroxyisovalerylcarnitine (C5OH) with mutations in MT-ATP6, most commonly m.8993T. >. G in high heteroplasmy or homoplasmy. Most patients were ascertained on newborn screening; most had normal enzymatic or molecular genetic testing to exclude biotinidase and holocarboxylase synthetase deficiencies. MT-ATP6 is associated with some cases of Leigh disease; clinical outcomes in our cohort ranged from death from neurodegenerative disease in early childhood to clinically and developmentally normal after several years of follow-up. These cases expand the biochemical phenotype associated with MT-ATP6 mutations, especially m.8993T. >. G, to include acylcarnitine abnormalities mimicking carboxylase deficiency states. Clinicians should be aware of this association and its implications for newborn screening, and consider mtDNA sequencing in patients exhibiting similar acylcarnitine abnormalities that are biotin-unresponsive and in whom other enzymatic deficiencies have been excluded.

  • Restricted English
    Authors: 
    Hanbin Choi; Jens Peter Andersen; Robert S. Molday;
    Project: CIHR

    ATP8A2 is a P4-ATPase (adenosine triphosphate) that actively flips phosphatidylserine and phosphatidylethanolamine from the exoplasmic to the cytoplasmic leaflet of cell membranes to generate and maintain phospholipid asymmetry. Mutations in the ATP8A2 gene have been reported to cause severe autosomal recessive neurological diseases in humans characterized by intellectual disability, hypotonia, chorea, and hyperkinetic movement disorders with or without optic and cerebellar atrophy. To determine the effect of disease-associated missense mutations on ATP8A2, we expressed six variants with the accessory subunit CDC50A in HEK293T cells. The level of expression, cellular localization, and functional activity were analyzed by western blot analysis, immunofluorescence microscopy, and ATPase activity assays. Two variants (p.Ile376Met and p.Lys429Met) expressed at normal ATP8A2 levels and preferentially localized to the Golgi-recycling endosomes, but were devoid of ATPase activity. Four variants (p.Lys429Asn, pAla544Pro, p.Arg625Trp, and p.Trp702Arg) expressed poorly, localized to the endoplasmic reticulum, and lacked ATPase activity. The expression of these variants was increased twofold by the addition of the proteasome inhibitor MG132. We conclude that the p.Ile376Met and p.Lys429Met variants fold in a native-like conformation, but lack key amino acid residues required for ATP-dependent lipid transport. In contrast, the p.Lys429Asn, pAla544Pro, p.Arg625Trp, and p.Trp702Arg variants are highly misfolded and undergo rapid proteosomal degradation.

  • Restricted English
    Authors: 
    Faizan Khan; Tobias Tritschler; Miriam Kimpton; Philip S. Wells; Clive Kearon; Jeffrey I. Weitz; Harry R. Büller; Gary E. Raskob; Walter Ageno; Francis Couturaud; +27 more
    Countries: Italy, Netherlands, Italy
    Project: CIHR

    BACKGROUND The long-term risk for major bleeding in patients receiving extended (beyond the initial 3 to 6 months) anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain. PURPOSE To determine the incidence of major bleeding during extended anticoagulation of up to 5 years among patients with a first unprovoked VTE, overall, and in clinically important subgroups. DATA SOURCES MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception to 23 July 2021. STUDY SELECTION Randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding among patients with a first unprovoked VTE who were to receive oral anticoagulation for a minimum of 6 additional months after completing at least 3 months of initial anticoagulant treatment. DATA EXTRACTION Two reviewers independently abstracted data and assessed study quality. Unpublished data required for analyses were obtained from authors of included studies. DATA SYNTHESIS Among the 14 RCTs and 13 cohort studies included in the analysis, 9982 patients received a vitamin K antagonist (VKA) and 7220 received a direct oral anticoagulant (DOAC). The incidence of major bleeding per 100 person-years was 1.74 events (95% CI, 1.34 to 2.20 events) with VKAs and 1.12 events (CI, 0.72 to 1.62 events) with DOACs. The 5-year cumulative incidence of major bleeding with VKAs was 6.3% (CI, 3.6% to 10.0%). Among patients receiving either a VKA or a DOAC, the incidence of major bleeding was statistically significantly higher among those who were older than 65 years or had creatinine clearance less than 50 mL/min, a history of bleeding, concomitant use of antiplatelet therapy, or a hemoglobin level less than 100 g/L. The case-fatality rate of major bleeding was 8.3% (CI, 5.1% to 12.2%) with VKAs and 9.7% (CI, 3.2% to 19.2%) with DOACs. LIMITATION Data were insufficient to estimate incidence of major bleeding beyond 1 year of extended anticoagulation with DOACs. CONCLUSION In patients with a first unprovoked VTE, the long-term risks and consequences of anticoagulant-related major bleeding are considerable. This information will help inform patient prognosis and guide decision making about treatment duration for unprovoked VTE. PRIMARY FUNDING SOURCE Canadian Institutes of Health Research. (PROSPERO: CRD42019128597).