Safety and pharmacodynamics of an engineered E. coli Nissle for the treatment of phenylketonuria: a first-in-human phase 1/2a study.

Phenylketonuria (PKU) is a rare disease caused by biallelic mutations in the PAH gene that result in an inability to convert phenylalanine (Phe) to tyrosine, elevated blood Phe levels and severe neurological complications if untreated. Most patients are unable to adhere to the protein-restricted diet, and thus do not achieve target blood Phe levels. We engineered a strain of E.

Development of a mechanistic model to predict synthetic biotic activity in healthy volunteers and patients with phenylketonuria.

The development of therapeutics depends on predictions of clinical activity from pre-clinical data. We have previously described SYNB1618, an engineered bacterial therapeutic (synthetic biotic) for the treatment of Phenylketonuria (PKU), a rare genetic disease that leads to accumulation of plasma phenylalanine (Phe) and severe neurological complications. SYNB1618 consumes Phe in preclinical models, healthy human volunteers, and PKU patients.

Variability and Lability of Ammonia Levels in Healthy Volunteers and Patients With Cirrhosis: Implications for Trial Design and Clinical Practice.

Introduction: Ammonia levels are used to assess hepatic encephalopathy, but their levels are highly variable in clinical practice.

Methods: We studied factors associated with variation in ammonia values in cirrhotic patients without previous hepatic encephalopathy and healthy volunteers (HVs).

Results: Ammonia increased by 12% and 18% at 1 and 2 hour, respectively, after a protein meal in 64 cirrhotic patients (P < 0.

Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism.

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. We meta-analyzed GWAS data from 18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE.

An engineered Nissle improves hyperammonemia and survival in mice and shows dose-dependent exposure in healthy humans.

The intestine is a major source of systemic ammonia (NH); thus, capturing part of gut NH may mitigate disease symptoms in conditions of hyperammonemia such as urea cycle disorders and hepatic encephalopathy. As an approach to the lowering of blood ammonia arising from the intestine, we engineered the orally delivered probiotic Nissle 1917 to create strain SYNB1020 that converts NH to l-arginine (l-arg). We up-regulated arginine biosynthesis in SYNB1020 by deleting a negative regulator of l-arg biosynthesis and inserting a feedback-resistant l-arg biosynthetic enzyme.

ADP Platelet Hyperreactivity Predicts Cardiovascular Disease in the FHS (Framingham Heart Study).

Background: Platelet function is associated with adverse events in patients with cardiovascular disease (CVD).

Methods And Results: We examined associations of baseline platelet function with incident CVD events in the community-based FHS (Framingham Heart Study). Participants free of prevalent CVD and without recent aspirin treatment with available data in the Framingham Offspring cohort (1991-1995) and Omni cohort (1994-1998) were included.

Familial Hypercholesterolemia and Type 2 Diabetes in the Old Order Amish.

Alleles associated with lower levels of LDL cholesterol (LDL-C) have recently been associated with an increased risk of type 2 diabetes (T2D), highlighting the complex relationship between LDL-C and diabetes. This observation begs the question of whether LDL-C-raising alleles are associated with a decreased risk of T2D. This issue was recently addressed in a large familial hypercholesterolemia (FH) screening study, which reported a lower prevalence of self-reported diabetes in FH subjects than in age-matched relatives without FH.

Platelet function as a risk factor for venous thromboembolism in the Framingham Heart Study.

Introduction: The relationship of venous thromboembolism (VTE) with platelet reactivity is unclear. Platelet function plays a key role in arterial thrombosis. Evidence suggests antiplatelet agents also effects in reducing VTE.

Biomarkers for the prediction of venous thromboembolism in the community.

Venous and arterial thrombosis share common pathophysiology. Multiple biomarkers reflecting various biological pathways can predict arterial thrombosis. We studied whether this approach could identify persons at risk of first venous thromboembolism (VTE).

Epidemiology of venous thromboembolism in the Framingham Heart Study.

Background: Reports of the crude incidence of venous thromboembolism (VTE) in Western countries vary widely. Data regarding risk factors, incidence and recurrence of VTE from deeply-phenotyped community-based cohort studies are needed.

Objectives: To study the incidence, associated mortality, and predisposing factors of VTE in the prospective, longitudinal community-based Framingham Heart Study.

Renal Impairment and Prognosis of Patients with Atrial Fibrillation Undergoing Coronary Intervention - The AFCAS Trial.

Background: Renal impairment is a well-known risk factor for cardiovascular complications, but the effect of different stages of renal impairment on thrombotic/thromboembolic and bleeding complications in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) remains largely unknown. We sought to evaluate the incidence and clinical impact of four stages of renal impairment in patients with AF undergoing PCI.

Methods: We assessed renal function by estimated glomerular filtration rate (eGFR) and outcomes in 781 AF patients undergoing PCI by using the data from a prospective European multicenter registry.

CHADS2, CHA2DS2-VASc and HAS-BLED as predictors of outcome in patients with atrial fibrillation undergoing percutaneous coronary intervention.

Introduction: CHADS2 and CHA2DS2-VASc scores are used to estimate thromboembolic risk in atrial fibrillation (AF). HAS-BLED is recommended for bleeding risk prediction. Their value in predicting the outcome of AF patients after percutaneous coronary intervention (PCI) is unknown.