Using Magneto-Inertial Measurement Units to Pervasively Measure Hip Joint Motion during Sports.

The use of wireless sensors to measure motion in non-laboratory settings continues to grow in popularity. Thus far, most validated systems have been applied to measurements in controlled settings and/or for prescribed motions. The aim of this study was to characterize adolescent hip joint motion of elite-level athletes (soccer players) during practice and recreationally active peers (controls) in after-school activities using a magneto-inertial measurement unit (MIMU) system.

Validation of magneto-inertial measuring units for measuring hip joint angles.

Camera-based motion capture systems are the current gold standard for motion analysis. However, the use of wireless inertial sensor-based systems is increasing in popularity, largely due to convenient portability. The purpose of this study was to validate the use of wireless inertial sensors for measuring hip joint motion with a functional calibration requiring only one motion (walking) and neutral standing.

Effects of APOC3 Heterozygous Deficiency on Plasma Lipid and Lipoprotein Metabolism.

Objective- Apo (apolipoprotein) CIII inhibits lipoprotein lipase (LpL)-mediated lipolysis of VLDL (very-low-density lipoprotein) triglyceride (TG) and decreases hepatic uptake of VLDL remnants. The discovery that 5% of Lancaster Old Order Amish are heterozygous for the APOC3 R19X null mutation provided the opportunity to determine the effects of a naturally occurring reduction in apo CIII levels on the metabolism of atherogenic containing lipoproteins. Approach and Results- We conducted stable isotope studies of VLDL-TG and apoB100 in 5 individuals heterozygous for the null mutation APOC3 R19X (CT) and their unaffected (CC) siblings.

Genome-wide association analysis of common genetic variants of resistant hypertension.

Resistant hypertension (RHTN), defined as uncontrolled blood pressure (BP) ≥ 140/90 using three or more drugs or controlled BP (<140/90) using four or more drugs, is associated with adverse outcomes, including decline in kidney function. We conducted a genome-wide association analysis in 1194 White and Hispanic participants with hypertension and coronary artery disease from the INternational VErapamil-SR Trandolapril STudy-GENEtic Substudy (INVEST-GENES). Top variants associated with RHTN at p < 10 were tested for replication in 585 White and Hispanic participants with hypertension and subcortical strokes from the Secondary Prevention of Subcortical Strokes GENEtic Substudy (SPS3-GENES).

Children with myelomeningocele do not exhibit normal remodeling of tibia roundness with physical development.

Skeletal loading through daily movement is an important factor in the normal development of bones. This loading is affected by the neurological and muscle deficits that result from myelominingocele (MM). While children with MM have been shown to have atypical gait, decreased bone accrual, and increased fracture risk, it is still unclear what morphological bone differences exist and to what extent they relate to physical developmental and ambulation level.

Multisite Investigation of Outcomes With Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention.

Objectives: This multicenter pragmatic investigation assessed outcomes following clinical implementation of CYP2C19 genotype-guided antiplatelet therapy after percutaneous coronary intervention (PCI).

Background: CYP2C19 loss-of-function alleles impair clopidogrel effectiveness after PCI.

Methods: After clinical genotyping, each institution recommended alternative antiplatelet therapy (prasugrel, ticagrelor) in PCI patients with a loss-of-function allele.

Pharmacogenetic Associations of β1-Adrenergic Receptor Polymorphisms With Cardiovascular Outcomes in the SPS3 Trial (Secondary Prevention of Small Subcortical Strokes).

Background And Purpose: Functional polymorphisms (Ser49Gly and Arg389Gly) in have been associated with cardiovascular and β-blocker response outcomes. Herein we examined associations of these polymorphisms with major adverse cardiovascular events (MACE), with and without stratification by β-blocker treatment in patients with a history of stroke.

Methods: Nine hundred and twenty-six participants of the SPS3 trial's (Secondary Prevention of Small Subcortical Strokes) genetic substudy with hypertension were included.

Genome-wide analysis of clopidogrel active metabolite levels identifies novel variants that influence antiplatelet response.

Clopidogrel is one of the most commonly used therapeutics for the secondary prevention of cardiovascular events in patients with acute coronary syndromes. However, considerable interindividual variation in clopidogrel response has been documented, resulting in suboptimal therapy and an increased risk of recurrent events for some patients. In this investigation, we carried out the first genome-wide association study of circulating clopidogrel active metabolite levels in 513 healthy participants to directly measure clopidogrel pharmacokinetics.

Prospective Evaluation of Genetic Variation in Platelet Endothelial Aggregation Receptor 1 Reveals Aspirin-Dependent Effects on Platelet Aggregation Pathways.

Genetic variation in the platelet endothelial aggregation receptor 1 (PEAR1) gene, most notably rs12041331, is implicated in altered on-aspirin platelet aggregation and increased cardiovascular event risk. We prospectively tested the effects of aspirin administration at commonly prescribed doses (81, 162, and 324 mg/day) on agonist-induced platelet aggregation by rs12041331 genotype in 67 healthy individuals. Prior to aspirin administration, rs12041331 minor allele carriers had significantly reduced adenosine diphosphate (ADP)-induced platelet aggregation compared with noncarriers (P = 0.

Identifying clinically relevant sources of variability: The clopidogrel challenge.

High interindividual variability in clinical outcomes following clopidogrel's standard dosing regimen continues to be a challenge even two decades after its approval. CYP2C19 polymorphisms, obesity, older age, diabetes, and drug-drug interactions have been identified as risk factors for adverse events and treatment failure. We conducted a mechanism-based pharmacokinetic/pharmacodynamic analysis, where we integrated knowledge on in vitro enzyme kinetic, physiological, genetic, and demographic information to characterize changes in platelet reactivity from baseline following clopidogrel antiplatelet therapy.

A systematic analysis and comparison of warfarin initiation strategies.

Objective: Randomized trials have reported inconsistent evidence on the effectiveness of algorithms that use genotypes to initiate warfarin therapy. The Clarification of Optimal Anticoagulation through Genetics (COAG) trial initiated therapy on the basis of predicted maintenance doses, with a pharmacogenetic-guided algorithm in one study group and a clinically guided algorithm in the other. The European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) consortium initiated therapy on the basis of loading doses, with an algorithm-based prediction in one study group and a fixed-dose regimen in the other.

Development of a physiology-directed population pharmacokinetic and pharmacodynamic model for characterizing the impact of genetic and demographic factors on clopidogrel response in healthy adults.

Clopidogrel (Plavix®), is a widely used antiplatelet agent, which shows high inter-individual variability in treatment response in patients following the standard dosing regimen. In this study, a physiology-directed population pharmacokinetic/pharmacodynamic (PK/PD) model was developed based on clopidogrel and clopidogrel active metabolite (clop-AM) data from the PAPI and the PGXB2B studies using a step-wise approach in NONMEM (version 7.2).

Oxylipid Profile of Low-Dose Aspirin Exposure: A Pharmacometabolomics Study.

Background: While aspirin is a well-established and generally effective anti-platelet agent, considerable inter-individual variation in drug response exists, for which mechanisms are not completely understood. Metabolomics allows for extensive measurement of small molecules in biological samples, enabling detailed mapping of pathways involved in drug response.

Methods And Results: We used a mass-spectrometry-based metabolomics platform to investigate the changes in the serum oxylipid metabolome induced by an aspirin intervention (14 days, 81 mg/day) in healthy subjects (n=156).

The Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study: Variation in Platelet Response to Clopidogrel and Aspirin.

Clopidogrel and aspirin are commonly prescribed anti-platelet medications indicated for patients who have experienced, or are at risk for, ischemic cardiovascular events. The Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study was designed to characterize determinants of clopidogrel and dual anti-platelet therapy (DAPT) response in a healthy cohort of Old Order Amish from Lancaster, PA. Following a loading dose, clopidogrel was taken once a day for 7 days.

The Impact of Inpatient Versus Outpatient Initiation on Early Warfarin Dosing.

Background And Objectives: Dosing algorithms for warfarin incorporate clinical and genetic factors but may not account for the numerous comorbidities affecting patients who start warfarin while hospitalized. We aimed to determine whether these algorithms perform differently when warfarin is initiated for inpatients compared with outpatients.

Patients And Methods: We analyzed a prospective cohort of 1015 participants from the Clarification of Optimal Anticoagulation through Genetics (COAG) trial who were randomized to either pharmacogenetically or clinically guided warfarin dosing algorithms.

CYP2C19 metabolizer status and clopidogrel efficacy in the Secondary Prevention of Small Subcortical Strokes (SPS3) study.

Background: The role of the CYP2C19 genotype on clopidogrel efficacy has been studied widely, with data suggesting reduced clopidogrel efficacy in loss-of-function variant carriers taking clopidogrel after percutaneous coronary intervention; however, data are limited regarding the association between CYP2C19 genetic variants and outcomes in stroke patients. We investigated whether CYP2C19 metabolizer status affects the risk of recurrent stroke or major bleeding in subcortical stroke patients taking dual antiplatelet therapy with aspirin and clopidogrel.

Methods And Results: CYP2C19*2 and CYP2C19*17 were genotyped in 522 patients treated with dual antiplatelet therapy from the Secondary Prevention of Small Subcortical Strokes (SPS3) study.

An approach for determining quantitative measures for bone volume and bone mass in the pediatric spina bifida population.

Background: The pediatric spina bifida population suffers from decreased mobility and recurrent fractures. This study aimed to develop a method for quantifying bone mass along the entire tibia in youth with spina bifida. This will provide information about all potential sites of bone deficiencies.

Pharmacometabolomics reveals that serotonin is implicated in aspirin response variability.

While aspirin is generally effective for prevention of cardiovascular disease, considerable variation in drug response exists, resulting in some individuals displaying high on-treatment platelet reactivity. We used pharmacometabolomics to define pathways implicated in variation of response to treatment. We profiled serum samples from healthy subjects pre- and postaspirin (14 days, 81 mg/day) using mass spectrometry.

Null mutation in hormone-sensitive lipase gene and risk of type 2 diabetes.

Background: Lipolysis regulates energy homeostasis through the hydrolysis of intracellular triglycerides and the release of fatty acids for use as energy substrates or lipid mediators in cellular processes. Genes encoding proteins that regulate energy homeostasis through lipolysis are thus likely to play an important role in determining susceptibility to metabolic disorders.

Methods: We sequenced 12 lipolytic-pathway genes in Old Order Amish participants whose fasting serum triglyceride levels were at the extremes of the distribution and identified a novel 19-bp frameshift deletion in exon 9 of LIPE, encoding hormone-sensitive lipase (HSL), a key enzyme for lipolysis.

Effectiveness of clopidogrel dose escalation to normalize active metabolite exposure and antiplatelet effects in CYP2C19 poor metabolizers.

Carriers of two copies of the loss-of-function CYP2C19*2 variant convert less clopidogrel into its active metabolite, resulting in diminished antiplatelet responses and higher cardiovascular event rates. To evaluate whether increasing the daily clopidogrel dose in poor metabolizers (PM) overcomes the effect of the CYP2C19 * 2 variant, we enrolled 18 healthy participants in a genotype-stratified, multi-dose, three-period, fixed-sequence crossover study. Six participants with the *1/*1 extensive (EM), *1/*2 intermediate (IM), and *2/*2 poor metabolizer genotypes each received 75 mg, 150 mg, and 300 mg each for 8 days.

Implementation of pharmacogenetics: the University of Maryland Personalized Anti-platelet Pharmacogenetics Program.

Despite a substantial evidence base, implementation of pharmacogenetics into routine patient care has been slow due to a number of non-trivial practical barriers. We implemented a Personalized Anti-platelet Pharmacogenetics Program (PAP3) for cardiac catheterization patients at the University of Maryland Medical Center and the Baltimore Veterans Administration Medical Center Patients' are offered CYP2C19 genetic testing, which is performed in our Clinical Laboratory Improvement Amendment (CLIA)-certified Translational Genomics Laboratory. Results are returned within 5 hr along with clinical decision support that includes interpretation of results and prescribing recommendations for anti-platelet therapy based on the Clinical Pharmacogenetics Implementation Consortium guidelines.

A pharmacogenetic versus a clinical algorithm for warfarin dosing.

Background: The clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin has been tested only in small clinical trials or observational studies, with equivocal results.

Methods: We randomly assigned 1015 patients to receive doses of warfarin during the first 5 days of therapy that were determined according to a dosing algorithm that included both clinical variables and genotype data or to one that included clinical variables only. All patients and clinicians were unaware of the dose of warfarin during the first 4 weeks of therapy.

Purine pathway implicated in mechanism of resistance to aspirin therapy: pharmacometabolomics-informed pharmacogenomics.

Although aspirin is a well-established antiplatelet agent, the mechanisms of aspirin resistance remain poorly understood. Metabolomics allows for measurement of hundreds of small molecules in biological samples, enabling detailed mapping of pathways involved in drug response. We defined the metabolic signature of aspirin exposure in subjects from the Heredity and Phenotype Intervention Heart Study.