Relationship Between Severity of Ischemia and Coronary Artery Disease for Different Stress Test Modalities in the ISCHEMIA Trial.

Background: The relationship between the extent and severity of stress-induced ischemia and the extent and severity of anatomic coronary artery disease (CAD) in patients with obstructive CAD is multifactorial and includes the intensity of stress achieved, type of testing used, presence and extent of prior infarction, collateral blood flow, plaque characteristics, microvascular disease, coronary vasomotor tone, and genetic factors. Among chronic coronary disease participants with site-determined moderate or severe ischemia, we investigated associations between ischemia severity on stress testing and the extent of CAD on coronary computed tomography angiography.

Methods: Clinically indicated stress testing included nuclear imaging, echocardiography, cardiac magnetic resonance imaging, or nonimaging exercise tolerance test.

Artificial Intelligence Efficacy as a Function of Trainee Interpreter Proficiency: Lessons from a Randomized Controlled Trial.

Background And Purpose: Recently, artificial intelligence tools have been deployed with increasing speed in educational and clinical settings. However, the use of artificial intelligence by trainees across different levels of experience has not been well-studied. This study investigates the impact of artificial intelligence assistance on the diagnostic accuracy for intracranial hemorrhage and large-vessel occlusion by medical students and resident trainees.

The BLISTER Score: A Novel, Externally Validated Tool for Predicting Cardiac Implantable Electronic Device Infections, and Its Cost-Utility Implications for Antimicrobial Envelope Use.

Background: Antimicrobial envelopes reduce the incidence of cardiac implantable electronic device infections, but their cost restricts routine use in the United Kingdom. Risk scoring could help to identify which patients would most benefit from this technology.

Methods: A novel risk score (BLISTER [Blood results, Long procedure time, Immunosuppressed, Sixty years old (or younger), Type of procedure, Early re-intervention, Repeat procedure]) was derived from multivariate analysis of factors associated with cardiac implantable electronic device infection.

De novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8.

The RGD (Arg-Gly-Asp)-binding integrins αvβ6 and αvβ8 are clinically validated cancer and fibrosis targets of considerable therapeutic importance. Compounds that can discriminate between homologous αvβ6 and αvβ8 and other RGD integrins, stabilize specific conformational states, and have high thermal stability could have considerable therapeutic utility. Existing small molecule and antibody inhibitors do not have all these properties, and hence new approaches are needed.

design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8.

The RGD (Arg-Gly-Asp)-binding integrins αvβ6 and αvβ8 are clinically validated cancer and fibrosis targets of considerable therapeutic importance. Compounds that can discriminate between the two closely related integrin proteins and other RGD integrins, stabilize specific conformational states, and have sufficient stability enabling tissue restricted administration could have considerable therapeutic utility. Existing small molecules and antibody inhibitors do not have all of these properties, and hence there is a need for new approaches.

Noninvasive Plaque Imaging to Accelerate Coronary Artery Disease Drug Development.

Coronary artery disease (CAD) remains the leading cause of adult mortality globally. Targeting known modifiable risk factors has had substantial benefit, but there remains a need for new approaches. Improvements in invasive and noninvasive imaging techniques have enabled an increasing recognition of distinct quantitative phenotypes of coronary atherosclerosis that are prognostically relevant.

Biomarker correlates with response to NY-ESO-1 TCR T cells in patients with synovial sarcoma.

Autologous T cells transduced to express a high affinity T-cell receptor specific to NY-ESO-1 (letetresgene autoleucel, lete-cel) show promise in the treatment of metastatic synovial sarcoma, with 50% overall response rate. The efficacy of lete-cel treatment in 45 synovial sarcoma patients (NCT01343043) has been previously reported, however, biomarkers predictive of response and resistance remain to be better defined. This post-hoc analysis identifies associations of response to lete-cel with lymphodepleting chemotherapy regimen (LDR), product attributes, cell expansion, cytokines, and tumor gene expression.

Axial Length Distributions in Patients With Genetically Confirmed Inherited Retinal Diseases.

Purpose: We investigated axial length (AL) distributions in inherited retinal diseases (IRDs), comparing them with reference cohorts.

Methods: AL measurements from IRD natural history study participants were included and compared with reference cohorts (TwinsUK, Raine Study Gen2-20, and published studies). Comparing with the Raine Study cohort, formal odds ratios (ORs) for AL ≥ 26 mm or AL ≤ 22 mm were derived for each IRD (Firth's logistic regression model, adjusted for age and sex).

Interferon-γ primes macrophages for pathogen ligand-induced killing via a caspase-8 and mitochondrial cell death pathway.

Cell death plays an important role during pathogen infections. Here, we report that interferon-γ (IFNγ) sensitizes macrophages to Toll-like receptor (TLR)-induced death that requires macrophage-intrinsic death ligands and caspase-8 enzymatic activity, which trigger the mitochondrial apoptotic effectors, BAX and BAK. The pro-apoptotic caspase-8 substrate BID was dispensable for BAX and BAK activation.

Prognostic significance of plaque location in non-obstructive coronary artery disease: from the CONFIRM registry.

Aim: Obstructive coronary artery disease (CAD) in proximal coronary segments is associated with a poor prognosis. However, the relative importance of plaque location regarding the risk for major adverse cardiovascular events (MACE) in patients with non-obstructive CAD has not been well defined.

Methods And Results: From the Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter (CONFIRM) registry, 4644 patients without obstructive CAD were included in this study.

Shortened relative leukocyte telomere length is associated with all-cause mortality in type 2 diabetes- analysis from the Hong Kong Diabetes Register.

Aims: Few studies have investigated the relationship between rLTL and mortality in patients with type 2 diabetes in a large prospective study, particularly in the Asian population. This study investigates the relationship between rLTL and the risk of death in Chinese patients with type 2 diabetes.

Methods: Consecutive Chinese patients with type 2 diabetes (N = 5349) from the Hong Kong Diabetes Register with stored baseline DNA and available follow-up data were studied.

Monoallelic Mutations in Suggest a Novel Role in Human Heterotaxy and Ciliary Dysfunction.

Background: Human heterotaxy is a group of congenital disorders characterized by misplacement of one or more organs according to the left-right axis. The genetic causes of human heterotaxy are highly heterogeneous.

Methods: We performed exome sequencing in a cohort of 26 probands with heterotaxy followed by gene burden analysis for the enrichment of novel rare damaging mutations.

Point of Care Clinical Risk Score to Improve the Negative Diagnostic Utility of an Agatston Score of Zero: Averting the Need for Coronary Computed Tomography Angiography.

Background: Coronary artery calcification is a marker of underlying atherosclerotic vascular disease. The absence of coronary artery calcification is associated with a low prevalence of obstructive coronary artery disease (CAD), but it cannot be ruled out completely. We sought to develop a clinical tool that can be added to Agatston score of zero to rule out obstructive CAD with high accuracy.

Stress Myocardial Perfusion PET Provides Incremental Risk Prediction in Patients with and Patients without Diabetes.

Purpose: To evaluate the prognostic value of myocardial perfusion PET in patients with and patients without diabetes mellitus.

Materials And Methods: The authors performed a retrospective analysis of prospectively acquired data from a multicenter registry cohort of 7061 patients, including 1966 with diabetes mellitus, who underwent clinically indicated rest-stress rubidium 82 (Rb) myocardial perfusion PET. The mean patient age (±standard deviation) was 63.

Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis.

Background: Metagenomic next-generation sequencing (NGS) of cerebrospinal fluid (CSF) has the potential to identify a broad range of pathogens in a single test.

Methods: In a 1-year, multicenter, prospective study, we investigated the usefulness of metagenomic NGS of CSF for the diagnosis of infectious meningitis and encephalitis in hospitalized patients. All positive tests for pathogens on metagenomic NGS were confirmed by orthogonal laboratory testing.

Search for Resonant and Nonresonant Higgs Boson Pair Production in the bb[over ¯]τ^{+}τ^{-} Decay Channel in pp Collisions at sqrt[s]=13 TeV with the ATLAS Detector.

A search for resonant and nonresonant pair production of Higgs bosons in the bb[over ¯]τ^{+}τ^{-} final state is presented. The search uses 36.1  fb^{-1} of pp collision data with sqrt[s]=13  TeV recorded by the ATLAS experiment at the LHC in 2015 and 2016.

Is There an Age When Myocardial Perfusion Imaging May No Longer Be Prognostically Useful?

Background: Heart disease continues to be the leading cause of death, and the prevalence of coronary artery disease is expected to increase as the population ages. It is important to understand the clinical utility of medical tests, or its lack thereof, in the aging population. The objective of this study was to understand the incremental prognostic value of positron emission tomographic (PET) myocardial perfusion imaging in the elderly (≥85 years of age).

Prognostic Significance of Nonobstructive Left Main Coronary Artery Disease in Women Versus Men: Long-Term Outcomes From the CONFIRM (Coronary CT Angiography Evaluation For Clinical Outcomes: An International Multicenter) Registry.

Background: Patients with obstructive (≥50% stenosis) left main (LM) coronary artery disease (CAD) are at high risk for adverse events; prior studies have also documented worse outcomes among women than men with severe multivessel/LM CAD. However, the prognostic significance of nonobstructive (1%-49% stenosis) LM CAD, including sex-specific differences, has not been previously examined.

Methods And Results: In the long-term CONFIRM (Coronary CT Angiography Evaluation For Clinical Outcomes: An International Multicenter) registry, patients underwent elective coronary computed tomographic angiography for suspected CAD and were followed for 5 years.

Relationship of Hypertension to Coronary Atherosclerosis and Cardiac Events in Patients With Coronary Computed Tomographic Angiography.

Hypertension is an atherosclerosis factor and is associated with cardiovascular risk. We investigated the relationship between hypertension and the presence, extent, and severity of coronary atherosclerosis in coronary computed tomographic angiography and cardiac events risk. Of 17 181 patients enrolled in the CONFIRM registry (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry) who underwent ≥64-detector row coronary computed tomographic angiography, we identified 14 803 patients without known coronary artery disease.

Kidney-Failure Risk Projection for the Living Kidney-Donor Candidate.

Background: Evaluation of candidates to serve as living kidney donors relies on screening for individual risk factors for end-stage renal disease (ESRD). To support an empirical approach to donor selection, we developed a tool that simultaneously incorporates multiple health characteristics to estimate a person's probable long-term risk of ESRD if that person does not donate a kidney.

Methods: We used risk associations from a meta-analysis of seven general population cohorts, calibrated to the population-level incidence of ESRD and mortality in the United States, to project the estimated long-term incidence of ESRD among persons who do not donate a kidney, according to 10 demographic and health characteristics.

Intrarenal and Urinary Th9 and Th22 Cytokine Gene Expression in Lupus Nephritis.

Objective: We studied the urinary sediment mRNA level of Th9- and Th22-related cytokines in patients with systemic lupus erythematosus (SLE).

Methods: We quantified urinary mRNA levels of interleukin (IL) 9, IL-10, IL-22, and their corresponding transcription factors in 73 patients with active lupus nephritis, 13 patients with hypertensive nephrosclerosis (HTN), and 25 healthy subjects.

Results: There was no detectable IL-9 mRNA in all samples.

Prognostic and therapeutic implications of statin and aspirin therapy in individuals with nonobstructive coronary artery disease: results from the CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter registry) registry.

Objective: We sought to examine the risk of mortality associated with nonobstructive coronary artery disease (CAD) and to determine the impact of baseline statin and aspirin use on mortality.

Approach And Results: Coronary computed tomographic angiography permits direct visualization of nonobstructive CAD. To date, the prognostic implications of nonobstructive CAD and the potential benefit of directing therapy based on nonobstructive CAD have not been carefully examined.

PBPK modeling to unravel nonlinear pharmacokinetics of verapamil to estimate the fractional clearance for verapamil N-demethylation in the recirculating rat liver preparation.

We applied physiologically based pharmacokinetic (PBPK) modeling to study the dose-dependent metabolism and excretion of verapamil and its preformed metabolite, norverapamil, to unravel the kinetics of norverapamil formation via N-demethylation. Various initial verapamil (1, 50, and 100 μM) and preformed norverapamil (1.5 and 5 μM) concentrations, perfused at 12 ml/min, were investigated in the perfused rat liver preparation.