Fixed-Dose Four-Factor Prothrombin Complex Concentrate for Reversal of Anticoagulation: Evaluation of Efficacy, Safety, and Cost Savings.

Background: Four-factor prothrombin complex concentrate (4F-PCC) is used for warfarin reversal and off-label management of bleeding in patients taking direct oral anticoagulants (DOACs). Dosing strategies that optimize hemostatic efficacy and cost, such as fixed dosing of 4F-PCC, are still under evaluation. The objective of this study was to retrospectively evaluate the efficacy, safety, and cost savings of fixed-dosing of 4F-PCC (1,500 IU for warfarin, 2,000 IU for DOACs).

Best practice guidelines on reference interval harmonization in Canada: Evidence-based recommendations from the CSCC working group on reference interval harmonization (CSCC WG-hRI).

Unnecessary variation in reference intervals across clinical laboratories increases the risk of inconsistent or misinformed clinical decision-making. Development of harmonized or common reference intervals for assays that demonstrate minimal bias across measurement procedures and laboratories is an important step towards standardized quality healthcare. The aim of this document is to recommend evidence-based harmonized reference intervals for routine clinical laboratory tests that can be implemented in hospital and community settings across Canada.

NF1-specific growth charts for head circumference over the first three years of life.

Background And Objectives: Macrocephaly is among the most common findings in neurofibromatosis type 1 (NF1) and may be associated with other clinical manifestations of the genetic syndrome. NF1-specific growth charts that account for expected macrocephaly may increase sensitivity to detect atypical growth. We aimed to produce NF1-specific growth charts of head circumference for the age range of 0 to 3 years and to assess their potential clinical impact.

A systematic protocol to identify "clinical controls" for pediatric neuroimaging research from clinically acquired brain MRIs.

Progress at the intersection of artificial intelligence and pediatric neuroimaging necessitates large, heterogeneous datasets to generate robust and generalizable models. Retrospective analysis of clinical brain magnetic resonance imaging (MRI) scans offers a promising avenue to augment prospective research datasets, leveraging the extensive repositories of scans routinely acquired by hospital systems in the course of clinical care. Here, we present a systematic protocol for identifying "scans with limited imaging pathology" through machine-assisted manual review of radiology reports.

Copy Number Variant Architecture of Child Psychopathology and Cognitive Development in the ABCD Study.

Objective: Late childhood is a crucial period for individuals with psychiatric disorders. While common single-nucleotide polymorphisms explain a large proportion of inherited risk, structural variations including copy number variants (CNVs) play a significant role in the genetic architecture of neurodevelopmental disorders. The relevance of CNVs to child psychopathology and cognitive function in the general population remains underexplored.

Presence, Severity, and Functional Associations of Incomplete Hippocampal Inversion in 22q11.2 Deletion Syndrome.

Background: The hippocampus is smaller and functionally disrupted in individuals with 22q11.2 deletion syndrome (22q11DS), but the cause remains unclear. During gestational weeks 20 to 30, an inversion in the dentate gyrus and cornu ammonis occurs.

Ceramide metabolism alterations contribute to Tumor Necrosis Factor-induced melanoma dedifferentiation and predict resistance to immune checkpoint inhibitors in advanced melanoma patients.

Introduction: Advanced cutaneous melanoma is a skin cancer characterized by a poor prognosis and high metastatic potential. During metastatic spread, melanoma cells often undergo dedifferentiation toward an invasive phenotype, resulting in reduced expression of microphthalmia-associated transcription factor (MITF)-dependent melanoma antigens and facilitating immune escape. Tumor Necrosis Factor (TNF) is known to be a key factor in melanoma dedifferentiation.

Cortico-striatal differences in the epigenome in attention-deficit/ hyperactivity disorder.

While epigenetic modifications have been implicated in ADHD through studies of peripheral tissue, to date there has been no examination of the epigenome of the brain in the disorder. To address this gap, we mapped the methylome of the caudate nucleus and anterior cingulate cortex in post-mortem tissue from fifty-eight individuals with or without ADHD. While no single probe showed adjusted significance in differential methylation, several differentially methylated regions emerged.

Stability and Analytical Characterization of Voriconazole as Measured by Immunoassay.

Background: Voriconazole is a broad-spectrum triazole antifungal agent recommended for invasive fungal diseases, including invasive aspergillosis. Therapeutic drug monitoring via voriconazole target trough concentration is important to ensure efficacy while preventing toxicity. Our aim was to determine the stability of voriconazole as adapted and measured by an immunoassay.

Evaluation of Busulfan as a Third-Party Immunoassay on a Clinical Chemistry Analyzer.

Background: Busulfan is widely used in conditioning regimens to prepare patients for hematopoietic stem cell transplantation. Therapeutic drug monitoring (TDM) is critical due to large inter- and intra-individual variability in busulfan pharmacokinetics, and the risk of adverse consequences of toxicity including hepatic veno-occlusive disease. Busulfan is most commonly measured by liquid chromatography-mass spectrometry (LC-MS/MS), which is not as widely available in clinical laboratories as automated routine clinical chemistry analyzers.

Mining the Gap: Deriving Pregnancy Reference Intervals for Hematology Parameters Using Clinical Datasets.

Background: Physiological changes during pregnancy invalidate use of general population reference intervals (RIs) for pregnant people. The complete blood count (CBC) is commonly ordered during pregnancy, but few studies have established pregnancy RIs suitable for contemporary Canadian mothers. Prospective RI studies are challenging to perform during pregnancy while retrospective techniques fall short as pregnancy and health status are not readily available in the laboratory information system (LIS).

Reference Interval Harmonization: Harnessing the Power of Big Data Analytics to Derive Common Reference Intervals across Populations and Testing Platforms.

Background: Harmonization in laboratory medicine is essential for consistent and accurate clinical decision-making. There is significant and unwarranted variation in reference intervals (RIs) used by laboratories for assays with established analytical traceability. The Canadian Society of Clinical Chemists (CSCC) Working Group on Reference Interval Harmonization (hRI-WG) aims to establish harmonized RIs (hRIs) for laboratory tests and support implementation.

Evaluation of an Association Between Enoxaparin Dose per Estimated Blood Volume and Clinically Relevant Bleeding in Low-Weight Trauma Patients.

Background: The optimal dosing for enoxaparin venous thromboembolism (VTE) prophylaxis in low-weight trauma patients is unknown. Estimated blood volume (EBV) has shown promise as a dose modifier.

Objective: To characterize the association of enoxaparin dose per EBV with the prevalence of VTE and bleeding in low-weight trauma patients.

Pediatric reference interval verification for 16 biochemical markers on the Alinity ci system in the CALIPER cohort of healthy children and adolescents.

Objectives: Special chemistry parameters are useful in the diagnosis and management of inherited disorders, liver disease, and immunopathology. Evidence-based pediatric reference intervals (RIs) are required for appropriate clinical decision-making and need to be verified as new assays are developed. This study aimed to evaluate the applicability of pediatric RIs established for biochemical markers on the ARCHITECT for use on newer Alinity assays.

Rare copy number variants in males and females with childhood attention-deficit/hyperactivity disorder.

While childhood attention-deficit/hyperactivity disorder (ADHD) is more prevalent in males than females, genetic contributors to this effect have not been established. Here, we explore sex differences in the contribution of common and/or rare genetic variants to ADHD. Participants were from the Adolescent Brain and Cognitive Development study (N = 1253 youth meeting DSM-5 criteria for ADHD [mean age = 11.

Mapping the cortico-striatal transcriptome in attention deficit hyperactivity disorder.

Despite advances in identifying rare and common genetic variants conferring risk for ADHD, the lack of a transcriptomic understanding of cortico-striatal brain circuitry has stymied a molecular mechanistic understanding of this disorder. To address this gap, we mapped the transcriptome of the caudate nucleus and anterior cingulate cortex in post-mortem tissue from 60 individuals with and without ADHD. Significant differential expression of genes was found in the anterior cingulate cortex and, to a lesser extent, the caudate.

Management of cancer-associated thrombosis with thrombocytopenia: Impact of the ISTH guidance statement.

Background: Optimal management of cancer-associated thrombosis (CAT) in patients with thrombocytopenia remains difficult given competing risks of recurrent thrombosis and increased bleeding. We determine the impact of the ISTH Scientific and Standardization Committee (SCC) guidance on CAT management and thrombocytopenia on platelet transfusion, bleeding, and recurrent thrombosis.

Methods: A retrospective review was performed of patients with CAT and thrombocytopenia who required anticoagulation for VTE for 11 months before and after implementation of the ISTH SCC guidance.

Continuous reference intervals for pediatric testosterone, sex hormone binding globulin and free testosterone using quantile regression.

Testosterone (T), sex hormone binding globulin (SHBG), free testosterone (FT) and bioavailable testosterone (BAT) are commonly employed tests in pediatric endocrinology and all require age-dependent reference intervals for interpretation. The common methods used to derive these reference intervals require decisions about data shape and/or age partition thresholds, which can result in sharp differences between age groups, particularly for pubescent children. Partitioning also results in a form of data loss, where data from one age-bin is completed disconnected from the adjacent age-bins.

Pediatric cannabis intoxication trends in the pre and post-legalization era.

Introduction: On April 13, 2017, a bill to legalize cannabis was introduced to the Canadian Parliament and presented to the public. On October 17, 2018, Canada legalized recreational cannabis use. We assessed intoxication severity, reflected by ICU admission rates, risk factors and other characteristics in children who presented to the emergency department (ED) with cannabis intoxication, before and after legalization.

Cardiac Biomarkers in Pediatrics: An Undervalued Resource.

Background: The clinical use of common cardiac biomarkers, such as brain natriuretic peptides and troponins, has traditionally been limited to adult populations in the assessment of heart failure and acute coronary syndrome, respectively. While many have discounted the value of these markers in pediatric populations, emerging evidence suggests they may be useful in the diagnosis and prognostication of many cardiac and noncardiac pathologies in neonates, children, and adolescents, and an increasing number of pediatric hospitals are routinely measuring cardiac markers in their clinical practice.

Content: This review summarizes and critically evaluates the current literature regarding the application of cardiac biomarkers for clinical decision-making in the pediatric population.