Immunological and Safety Considerations When Selecting the Dose Formulation of a Purified Inactivated Zika Virus Vaccine (PIZV).

We previously reported the first-in-human assessment of three doses (2, 5, and 10 µg) of purified inactivated Zika virus vaccine (PIZV or TAK-426) in the Phase 1 ZIK-101 study (NCT03343626). Here, we report dose selection based on extended safety and immunogenicity data (6 months post-vaccination) and discuss considerations (e.g.

Predicting Efficacy of a Purified Inactivated Zika Virus Vaccine in Flavivirus-Naïve Humans Using an Immunological Correlate of Protection in Non-Human Primates.

A traditional phase 3 clinical efficacy study for a Zika vaccine may be unfeasible because of the current low transmission of Zika virus (ZIKV). An alternative clinical development approach to evaluate Zika vaccine efficacy (VE) is therefore required, delineated in the US FDA's Accelerated Approval Program for licensure, which utilizes an anti-Zika neutralizing antibody (Zika NAb) titer correlated with non-human primate (NHP) protection as a surrogate endpoint. In this accelerated approval approach, the estimation of VE would be inferred from the percentage of phase 3 trial participants achieving the established surrogate endpoint.

An open-label, Phase 3 trial of TAK-003, a live attenuated dengue tetravalent vaccine, in healthy US adults: immunogenicity and safety when administered during the second half of a 24-month shelf-life.

Dengue is caused by a mosquito-transmitted flavivirus. The disease is now endemic to many tropical and subtropical regions, manifesting as approximately 96 million symptomatic cases of dengue each year. Clinical trials have shown TAK-003 (Qdenga®), a live attenuated dengue tetravalent vaccine, to be well-tolerated, immunogenic, and efficacious in adults with no prior exposure to dengue virus infection living in non-endemic regions, as well as in adults and children living in dengue-endemic areas.

Risks of Heart Failure, Stroke, and Bleeding in Atrial Fibrillation According to Heart Failure Phenotypes.

Background: The risks of heart failure (HF) events compared with stroke/systemic embolic events (SEE) or major bleeding (MB) in heart failure with reduced ejection fraction (HFrEF) vs heart failure with preserved ejection fraction (HFpEF) in a large atrial fibrillation (AF) population have not been well-studied.

Objectives: This study sought to assess HF outcomes, according to HF history and HF phenotypes (HFrEF vs HFpEF), and compare these events with SEE and MB, among patients with AF.

Methods: We analyzed patients enrolled in the ENGAGE-AF TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in AF-Thrombolysis in Myocardial Infarction 48) trial.

Persistence of Immunogenicity of a Purified Inactivated Zika Virus Vaccine Candidate in Healthy Adults: 2 Years of Follow-up Compared With Natural Infection.

Background: We report 2-year persistence of immune response to Takeda's prophylactic purified formalin-inactivated whole Zika virus vaccine candidate (TAK-426) compared with that observed after natural infection.

Methods: A randomized, observer-blind, placebo-controlled, dose-selection, phase 1 trial was conducted in 18-49-year-old adults at 9 centers (7 in the United States, 2 in Puerto Rico) from 13 November 2017 to 24 November 2020. Primary objectives were safety, tolerability, and immunogenicity of 3 increasing doses of TAK-426 administered as 2 doses 28 days apart to flavivirus (FV)-naive and FV-primed adults.

Edoxaban versus Warfarin in high-risk patients with atrial fibrillation: A comprehensive analysis of high-risk subgroups.

Background: To compare the efficacy and safety of edoxaban vs warfarin in high-risk subgroups.

Methods: ENGAGE AF-TIMI 48 was a multicenter randomized, double-blind, controlled trial in 21,105 patients with atrial fibrillation (AF) within 12 months and CHADS score >2 randomized to higher-dose edoxaban regimen (HDER) 60 mg/reduced 30 mg, lower-dose edoxaban regimen (LDER) 30 mg/reduced 15 mg, or warfarin, and followed for 2.8 years (median).

Meta-analysis and machine learning-augmented mixed effects cohort analysis of improved diets among 5847 medical trainees, providers and patients.

Objective: We sought to produce the first meta-analysis (of medical trainee competency improvement in nutrition counseling) informing the first cohort study of patient diet improvement through medical trainees and providers counseling patients on nutrition.

Design: (Part A) A systematic review and meta-analysis informing (Part B) the intervention analysed in the world's largest prospective multi-centre cohort study on hands-on cooking and nutrition education for medical trainees, providers and patients.

Settings: (A) Medical educational institutions.

Clinical Application of a Novel Genetic Risk Score for Ischemic Stroke in Patients With Cardiometabolic Disease.

Background: Genome-wide association studies have identified single-nucleotide polymorphisms that are associated with an increased risk of stroke. We sought to determine whether a genetic risk score (GRS) could identify subjects at higher risk for ischemic stroke after accounting for traditional clinical risk factors in 5 trials across the spectrum of cardiometabolic disease.

Methods: Subjects who had consented for genetic testing and who were of European ancestry from the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation), SOLID-TIMI 52 (Stabilization of Plaques Using Darapladib), SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus), PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin), and FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) trials were included in this analysis.

Two Clinical Prediction Tools to Improve Tuberculosis Contact Investigation.

Background: Efficient contact investigation strategies are needed for the early diagnosis of tuberculosis (TB) disease and treatment of latent TB infections.

Methods: Between September 2009 and August 2012, we conducted a prospective cohort study in Lima, Peru, in which we enrolled and followed 14 044 household contacts of adults with pulmonary TB. We used information from a subset of this cohort to derive 2 clinical prediction tools that identify contacts of TB patients at elevated risk of progressing to active disease by training multivariable models that predict (1) coprevalent TB among all household contacts and (2) 1-year incident TB among adult contacts.

Predicting Benefit From Evolocumab Therapy in Patients With Atherosclerotic Disease Using a Genetic Risk Score: Results From the FOURIER Trial.

Background: The ability of a genetic risk score to predict risk in established cardiovascular disease and identify individuals who derive greater benefit from PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition has not been established.

Methods: We studied 14 298 patients with atherosclerotic cardiovascular disease from the FOURIER trial (Further Cardiovascular Outcomes Researh With PCSK9 Inhibition in Subjects With Elevated Risk). A 27-single-nucleotide polymorphism genetic risk score defined low (quintile 1), intermediate (quintiles 2-4), and high (quintile 5) genetic risk.

Efficacy and safety of edoxaban compared with warfarin according to the burden of diseases in patients with atrial fibrillation: insights from the ENGAGE AF-TIMI 48 trial.

Aims: Non-vitamin K antagonist oral anticoagulants represent a new option for prevention of embolic events in patients with atrial fibrillation (AF). However, little is known about the impact of non-cardiac comorbidities on the efficacy and safety profile of these drugs.

Methods And Results: In a post hoc analysis of the ENGAGE AF-TIMI 48 trial, we analysed 21 105 patients with AF followed for an average of 2.

Comparison of Events Across Bleeding Scales in the ENGAGE AF-TIMI 48 Trial.

Background: Numerous scales exist for the classification of major bleeding events. Limited data compare the most commonly used bleeding scales within a single at-risk cohort of patients with atrial fibrillation. Here, we analyze bleeding outcomes according to the ISTH (International Society on Thrombosis and Hemostasis), TIMI (Thrombolysis in Myocardial Infarction), GUSTO (Global Usage of Strategies to Open Occluded Arteries), and BARC (Bleeding Academic Research Consortium) bleeding scales in the ENGAGE AF (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation)-TIMI 48 trial (NCT00781391) of edoxaban versus warfarin.

Edoxaban Versus Warfarin in Patients With Atrial Fibrillation and History of Liver Disease.

Background: Patients with liver disease have increased risk of thrombosis and bleeding but are typically excluded from trials of direct oral anticoagulant agents.

Objectives: This study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), clinical efficacy and safety of edoxaban versus warfarin in patients with atrial fibrillation (AF) and history of liver disease.

Methods: ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction Study 48) was a randomized, double-blind trial comparing edoxaban with warfarin in patients with AF followed for 2.

Association of the coronary artery disease risk gene GUCY1A3 with ischaemic events after coronary intervention.

Aim: A common genetic variant at the GUCY1A3 coronary artery disease locus has been shown to influence platelet aggregation. The risk of ischaemic events including stent thrombosis varies with the efficacy of aspirin to inhibit platelet reactivity. This study sought to investigate whether homozygous GUCY1A3 (rs7692387) risk allele carriers display higher on-aspirin platelet reactivity and risk of ischaemic events early after coronary intervention.

Performance of the ABC Scores for Assessing the Risk of Stroke or Systemic Embolism and Bleeding in Patients With Atrial Fibrillation in ENGAGE AF-TIMI 48.

Background: The ABC (age, biomarker, clinical history)-stroke and ABC-bleeding risk scores incorporate clinical variables and cardiovascular biomarkers to estimate risk of stroke or systemic embolic events and bleeding, respectively, in patients with atrial fibrillation. These scores have been proposed for routine clinical use, but their performance in external cohorts remains uncertain.

Methods: ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a multinational randomized trial of the oral factor Xa inhibitor edoxaban in patients with atrial fibrillation and a CHADS score ≥2.

Outdoor particulate matter (PM10) exposure and lung cancer risk in the EAGLE study.

Objective: Cohort studies in Europe, but not in North-America, showed an association between exposure to outdoor particulate matter with aerodynamic diameter ≤10 μm (PM10) and lung cancer risk. Only a case-control study on lung cancer and PM10 in South Korea has so far been performed. For the first time in Europe we analyzed quantitatively this association using a case-control study design in highly polluted areas in Italy.

Edoxaban in atrial fibrillation patients with established coronary artery disease: Insights from ENGAGE AF-TIMI 48.

Background:: The relative efficacy and safety profile of the oral Factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation and established coronary artery disease (CAD) has not been analyzed.

Materials And Methods:: In the ENGAGE AF-TIMI 48 trial, two edoxaban regimens were compared with warfarin in 21,105 patients with atrial fibrillation and CHADS ⩾2. We analyzed the primary trial endpoints (efficacy: stroke or systemic embolic event, safety: International Society on Thrombosis and Haemostasis major bleeding) in patients with versus without CAD, and used interaction testing to assess for treatment effect modification.

Nitric Oxide Decreases Acute Kidney Injury and Stage 3 Chronic Kidney Disease after Cardiac Surgery.

Rationale: No medical intervention has been identified that decreases acute kidney injury and improves renal outcome at 1 year after cardiac surgery.

Objectives: To determine whether administration of nitric oxide reduces the incidence of postoperative acute kidney injury and improves long-term kidney outcomes after multiple cardiac valve replacement requiring prolonged cardiopulmonary bypass.

Methods: Two hundred and forty-four patients undergoing elective, multiple valve replacement surgery, mostly due to rheumatic fever, were randomized to receive either nitric oxide (treatment) or nitrogen (control).

Gastrointestinal Bleeding With Edoxaban Versus Warfarin: Results From the ENGAGE AF-TIMI 48 Trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction).

Background: The ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction) compared higher-dose edoxaban regimen (HD-ER) and lower-dose edoxaban regimen with well-managed warfarin in 21 105 patients with atrial fibrillation. The risk factors and clinical impact of gastrointestinal bleeding (GIB) in this trial have not been described in detail.

Methods And Results: This analysis was undertaken to identify risk factors for major GIB (MGIB) and compare the severity and outcomes of GIB with edoxaban and warfarin.

Clinical events after interruption of anticoagulation in patients with atrial fibrillation: An analysis from the ENGAGE AF-TIMI 48 trial.

Background: Patients with atrial fibrillation (AF) who interrupt anticoagulation are at high risk of thromboembolism and death.

Methods And Results: Patients enrolled in the ENGAGE AF-TIMI 48 trial (randomized comparison of edoxaban vs. warfarin) who interrupted study anticoagulant for >3 days were identified.

Accounting for adaptation and intensity in projecting heat wave-related mortality.

Background: How adaptation and intensity of heat waves affect heat wave-related mortality is unclear, making health projections difficult.

Methods: We estimated the effect of heat waves, the effect of the intensity of heat waves, and adaptation on mortality in 209 U.S.

Ambient Temperature and Sudden Infant Death Syndrome in the United States.

Background: Sudden infant death syndrome (SIDS) is a leading cause of infant mortality in the United States. While thermal stress is implicated in many risk factors for SIDS, the association between ambient temperature and SIDS remains unclear.

Methods: We obtained daily individual-level infant mortality data and outdoor temperature data from 1972 to 2006 for 210 US cities.

Valvular Heart Disease Patients on Edoxaban or Warfarin in the ENGAGE AF-TIMI 48 Trial.

Background: The use of non-vitamin K antagonist oral anticoagulants (NOACs) instead of vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) and coexisting valvular heart disease (VHD) is of substantial interest.

Objectives: This study explored outcomes in patients with AF with and without VHD in the ENGAGE AF-TIMI 48 (Effective Anticoagulation with factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48) trial, comparing edoxaban with warfarin.

Methods: Valvular heart disease was defined as history or baseline echocardiography evidence of at least moderate aortic/mitral regurgitation, aortic stenosis, or prior valve surgery (bioprosthesis replacement, valve repair, valvuloplasty).