Prospective Deep Learning-based Quantitative Assessment of Coronary Plaque by CT Angiography Compared with Intravascular Ultrasound.

AIMS: Coronary computed tomography angiography provides noninvasive assessment of coronary stenosis severity and flow impairment. Automated artificial intelligence analysis may assist in precise quantification and characterization of coronary atherosclerosis, enabling patient-specific risk determination and management strategies. This multicenter international study compared an automated deep-learning-based method for segmenting coronary atherosclerosis in coronary computed tomography angiography (CCTA) against the reference standard of intravascular ultrasound (IVUS). METHODS AND RESULTS: The study included clinically stable patients with known coronary artery disease from 15 centers in the U.S. and Japan. An artificial intelligence (AI)-enabled plaque analysis service was utilized to quantify and characterize total plaque (TPV), vessel, lumen, calcified plaque (CP), non-calcified plaque (NCP), and low attenuation plaque (LAP) volumes derived from CCTA and compared with IVUS measurements in a blinded, core laboratory-adjudicated fashion. In 237 patients, 432 lesions were assessed; mean lesion length was 24.5 mm. Mean IVUS-TPV was 186.0 mm3. AI-enabled plaque analysis on CCTA showed strong correlation and high accuracy when compared with IVUS; correlation coefficient, slope, and Y intercept for TPV were 0.91, 0.99, and 1.87, respectively; for CP volume 0.91, 1.05, and 5.32, respectively; and for NCP volume 0.87, 0.98, and 15.24, respectively. Bland-Altman analysis demonstrated strong agreement with little bias for these measurements. CONCLUSIONS: Artificial intelligence enabled CCTA quantification and characterization of atherosclerosis demonstrated strong agreement with IVUS reference standard measurements. This tool may prove effective for accurate evaluation of coronary atherosclerotic burden and cardiovascular risk assessment.[ClinicalTrails.gov identifier: NCT05138289].

Systematic Review of Intralesional Therapies for Cutaneous Warts.

Intralesional therapies are used for recalcitrant warts, but no Food and Drug Administration-approved treatment exists nor is there consensus regarding the most efficacious therapy. Therefore, this systematic review aims to summarize efficacy and adverse events reported in 62 randomized controlled trials (RCTs) of intralesional therapies for cutaneous warts. The most studied intralesional therapies included measles, mumps, rubella (MMR) vaccine (n = 24 studies), purified protein derivative (PPD) (n = 19 studies), vitamin D3 (n = 15 studies), and Candida antigen (n = 14 studies). Most studies included adult and pediatric patients or adults alone, with only 4 studies on pediatric patients alone. MMR vaccine was the most studied treatment (n = 853 patients). MMR had a complete response rate of 27-90%. The next most common treatment, PPD, had a complete response rate of 45-87%. Other treatments included Candida antigen and vitamin D3, with complete response rates of 25-84% and 40-96%, respectively. The most frequent side effects were injection-site reactions and flu-like symptoms. This systematic review represents a useful summary of intralesional therapy RCTs for clinician reference. This study also highlights the lack of large multi-institutional RCTs, despite many patients being treated for this widespread problem.

Independent Plastic Surgery Match Regional Trends Comparing In-person and Virtual Interview Cycles.

Background: There is a trend toward matching in a different region than previous training for the independent plastic surgery match cycles from 2019 to 2021, which differs from the trend to match within the same region for integrated plastic surgery programs. Notably, residency interviews transitioned from in-person to virtual in 2020 due to the coronavirus pandemic. Therefore, we compared in-person versus virtual interview match trends from 2019 to 2023. Methods: Zip codes and regions of each successfully matched plastic surgery applicant's medical school, residency, and plastic surgery program were gathered from publicly available data for the 2019 and 2020 in-person interview cycles and 2021, 2022, and 2023 virtual interview cycles. Results: Although regions did not differ significantly in the proportions of positions each year (P = 0.85), there was a trend toward fewer positions in each region from 2019 to 2022. Overall, applicants were more likely to match in a different region as their medical school or residency during virtual compared with in-person interviews (P = 0.002 and P = 0.04). Applicants matched to programs further from their medical school zip code in virtual interview years (P = 0.02). There was no significant difference in distance between surgical residencies and plastic surgery residencies between the two time periods (P = 0.51). Conclusions: Trends toward matching into a different region than prior training after the switch to virtual interviews could be attributed to applicant accessibility to interview broadly. However, this could also be due to the decreased number of independent residency positions over the years, requiring applicants to move regions and travel further from where they began their training.

Interaction of AI-Enabled Quantitative Coronary Plaque Volumes on Coronary CT Angiography, FFRCT, and Clinical Outcomes: A Retrospective Analysis of the ADVANCE Registry.

BACKGROUND: Luminal stenosis, computed tomography-derived fractional-flow reserve (FFRCT), and high-risk plaque features on coronary computed tomography angiography are all known to be associated with adverse clinical outcomes. The interactions between these variables, patient outcomes, and quantitative plaque volumes have not been previously described. METHODS: Patients with coronary computed tomography angiography (n=4430) and one-year outcome data from the international ADVANCE (Assessing Diagnostic Value of Noninvasive FFRCT in Coronary Care) registry underwent artificial intelligence-enabled quantitative coronary plaque analysis. Optimal cutoffs for coronary total plaque volume and each plaque subtype were derived using receiver-operator characteristic curve analysis. The resulting plaque volumes were adjusted for age, sex, hypertension, smoking status, type 2 diabetes, hyperlipidemia, luminal stenosis, distal FFRCT, and translesional delta-FFRCT. Median plaque volumes and optimal cutoffs for these adjusted variables were compared with major adverse cardiac events, late revascularization, a composite of the two, and cardiovascular death and myocardial infarction. RESULTS: At one year, 55 patients (1.2%) had experienced major adverse cardiac events, and 123 (2.8%) had undergone late revascularization (>90 days). Following adjustment for age, sex, risk factors, stenosis, and FFRCT, total plaque volume above the receiver-operator characteristic curve-derived optimal cutoff (total plaque volume >564 mm3) was associated with the major adverse cardiac event/late revascularization composite (adjusted hazard ratio, 1.515 [95% CI, 1.093-2.099]; P=0.0126), and both components. Total percent atheroma volume greater than the optimal cutoff was associated with both major adverse cardiac event/late revascularization (total percent atheroma volume >24.4%; hazard ratio, 2.046 [95% CI, 1.474-2.839]; P<0.0001) and cardiovascular death/myocardial infarction (total percent atheroma volume >37.17%, hazard ratio, 4.53 [95% CI, 1.943-10.576]; P=0.0005). Calcified, noncalcified, and low-attenuation percentage atheroma volumes above the optimal cutoff were associated with all adverse outcomes, although this relationship was not maintained for cardiovascular death/myocardial infarction in analyses stratified by median plaque volumes. CONCLUSIONS: Analysis of the ADVANCE registry using artificial intelligence-enabled quantitative plaque analysis shows that total plaque volume is associated with one-year adverse clinical events, with incremental predictive value over luminal stenosis or abnormal physiology by FFRCT. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02499679.

Coronary computed tomography angiography derived fractional flow reserve and risk of recurrent angina: A 3-year follow-up study.

BACKGROUND: The association between coronary computed tomography angiography (CTA) derived fractional flow reserve (FFRCT) and risk of recurrent angina in patients with new onset stable angina pectoris (SAP) and stenosis by CTA is uncertain. METHODS: Multicenter 3-year follow-up study of patients presenting with symptoms suggestive of new onset SAP who underwent first-line CTA evaluation and subsequent standard-of-care treatment. All patients had at least one ≥30 â€‹% coronary stenosis. A per-patient lowest FFRCT-value ≤0.80 represented an abnormal test result. Patients with FFRCT ≤0.80 who underwent revascularization were categorized according to completeness of revascularization: 1) Completely revascularized (CR-FFRCT), all vessels with FFRCT ≤0.80 revascularized; or 2) incompletely revascularized (IR-FFRCT) ≥1 vessels with FFRCT ≤0.80 non-revascularized. Recurrent angina was evaluated using the Seattle Angina Questionnaire. RESULTS: Amongst 769 patients (619 [80 â€‹%] stenosis ≥50 â€‹%, 510 [66 â€‹%] FFRCT ≤0.80), 174 (23 â€‹%) reported recurrent angina at follow-up. An FFRCT ≤0.80 vs â€‹> â€‹0.80 associated to increased risk of recurrent angina, relative risk (RR): 1.82; 95 â€‹% CI: 1.31-2.52, p â€‹< â€‹0.001. Risk of recurrent angina in CR-FFRCT (n â€‹= â€‹135) was similar to patients with FFRCT >0.80, 13 â€‹% vs 15 â€‹%, RR: 0.93; 95 â€‹% CI: 0.62-1.40, p â€‹= â€‹0.72, while IR-FFRCT (n â€‹= â€‹90) and non-revascularized patients with FFRCT ≤0.80 (n â€‹= â€‹285) had increased risk, 37 â€‹% vs 15 â€‹% RR: 2.50; 95 â€‹% CI: 1.68-3.73, p â€‹< â€‹0.001 and 30 â€‹% vs 15 â€‹%, RR: 2.03; 95 â€‹% CI: 1.44-2.87, p â€‹< â€‹0.001, respectively. Use of antianginal medication was similar across study groups. CONCLUSION: In patients with SAP and coronary stenosis by CTA undergoing standard-of-care guided treatment, FFRCT provides information regarding risk of recurrent angina.

Searching for Structure: Characterizing the Protein Conformational Landscape with Clustering-Based Algorithms.

The identification and characterization of the main conformations from a protein population are a challenging and inherently high-dimensional problem. Here, we evaluate the performance of the Secondary sTructural Ensembles with machine LeArning (StELa) double-clustering method, which clusters protein structures based on the relationship between the φ and ψ dihedral angles in a protein backbone and the secondary structure of the protein, thus focusing on the local properties of protein structures. The classification of states as vectors composed of the clusters' indices arising naturally from the Ramachandran plot is followed by the hierarchical clustering of the vectors to allow for the identification of the main features of the corresponding free energy landscape (FEL). We compare the performance of StELa with the established root-mean-squared-deviation (RMSD)-based clustering algorithm, which focuses on global properties of protein structures and with Combinatorial Averaged Transient Structure (CATS), the combinatorial averaged transient structure clustering method based on distributions of the φ and ψ dihedral angle coordinates. Using ensembles of conformations from molecular dynamics simulations of intrinsically disordered proteins (IDPs) of various lengths (tau protein fragments) or short fragments from a globular protein, we show that StELa is the clustering method that identifies many of the minima and relevant energy states around the minima from the corresponding FELs. In contrast, the RMSD-based algorithm yields a large number of clusters that usually cover most of the FEL, thus being unable to distinguish between states, while CATS does not sample well the FELs for long IDPs and fragments from globular proteins.

Age- and Sex-Specific Nomographic CT Quantitative Plaque Data From a Large International Cohort.

BACKGROUND: With growing adoption of coronary computed tomographic angiography (CTA), there is increasing evidence for and interest in the prognostic importance of atherosclerotic plaque volume. Manual tools for plaque segmentation are cumbersome, and their routine implementation in clinical practice is limited. OBJECTIVES: The aim of this study was to develop nomographic quantitative plaque values from a large consecutive multicenter cohort using coronary CTA. METHODS: Quantitative assessment of total atherosclerotic plaque and plaque subtype volumes was performed in patients undergoing clinically indicated coronary CTA, using an Artificial Intelligence-Enabled Quantitative Coronary Plaque Analysis tool. RESULTS: A total of 11,808 patients were included in the analysis; their mean age was 62.7 ± 12.2 years, and 5,423 (45.9%) were women. The median total plaque volume was 223 mm3 (IQR: 29-614 mm3) and was significantly higher in male participants (360 mm3; IQR: 78-805 mm3) compared with female participants (108 mm3; IQR: 10-388 mm3) (P < 0.0001). Total plaque increased with age in both male and female patients. Younger patients exhibited a higher prevalence of noncalcified plaque. The distribution of total plaque volume and its components was reported in every decile by age group and sex. CONCLUSIONS: The authors developed pragmatic age- and sex-stratified percentile nomograms for atherosclerotic plaque measures using findings from coronary CTA. The impact of age and sex on total plaque and its components should be considered in the risk-benefit analysis when treating patients. Artificial Intelligence-Enabled Quantitative Coronary Plaque Analysis work flows could provide context to better interpret coronary computed tomographic angiographic measures and could be integrated into clinical decision making.

Association of plasma NRP2 and VEGF-C levels with prostate cancer disease severity.

BACKGROUND: Neuropilin 2 (NRP2) expression in tissue is an independent prognostic factor for aggressive prostate cancer. Since the NRP2 pathway activation is thought to occur in part through secondary resistance, quantification of NRP2 in initial tissue biopsy specimens collected at diagnosis may have limited utility in identifying patients at highest risk for morbidity and mortality. Given that metastatic tissue is only occasionally obtained for analysis, there is a need for development of a plasma biomarker indicative of NRP2 pathway activation to potentially inform prostate cancer prognosis. Therefore, we investigated if plasma levels of NRP2 or vascular endothelial growth factor C (VEGF-C), a known soluble ligand of NRP2, are prognostic for prostate cancer. We hypothesized that plasma NRP2 and VEGF-C would be associated with more advanced disease or relapsed disease. METHODS: NRP2 and VEGF-C levels were quantified by enzyme-linked immunoassay in plasma samples obtained from 145 prostate cancer patients in an opportunistic biobank. These patients were either (1) newly diagnosed (N = 28), (2) in remission (N = 56), or (3) relapsed disease (N = 61). Plasma samples from 15 adult males without known malignancy served as a comparator cohort. Statistical analysis was performed to investigate the association of plasma NRP2/VEGF-C with patient outcomes, adjusting for age, race, prostate-specific antigen (PSA), Gleason score, and tumor stage at diagnosis. RESULTS: Neither NRP2 nor VEGF-C levels were significantly different in cancer patients compared to noncancer controls. We observed no clear association between plasma NRP2 and disease severity. Increased plasma VEGF-C was significantly associated with disease remission and correlated with Stage I/II and intermediate-risk Gleason score. Neither NRP2 nor VEGF-C correlated with PSA level. CONCLUSIONS: Although tissue NRP2 expression correlates with severe disease, this was not observed for plasma NRP2. Plasma NRP2 levels did not correlate with disease severity or relapse. VEGF-C was highest in patients in remission and with less severe disease. Future investigation is needed to identify noninvasive methods to assess tumor NRP2 status.

Derivation and validation of a novel functional FFRCT score incorporating the burden of coronary stenosis severity and flow impairment to predict clinical events.

BACKGROUND: A score combining the burden of stenosis severity on coronary computed tomography angiography (CCTA) and flow impairment by fractional flow reserve derived from computed tomography (FFRCT) may be a better predictor of clinical events than either parameter alone. METHODS: The Functional FFRCT Score (FFS) combines CCTA and FFRCT parameters in an allocated point-based system. The feasibility of the FFS was assessed in cohort of 72 stable chest pain patients with matched CCTA and FFRCT datasets. Validation was performed using 2 cohorts: (a) 4468 patients from the ADVANCE Registry to define its association with revascularization and major adverse cardiovascular events (MACE); (b) 212 patients from the FORECAST trial to determine predictors of MACE. RESULTS: The median calculation time for the FFS was 10 (interquartile range 6-17) seconds, with strong intra-operator and inter-operator agreement (Cohen's Kappa 0.89 (±0.37, p â€‹< â€‹0.001) and 0.83 (±0.04, p â€‹< â€‹0.001, respectively). The FFS correlated strongly with both the CT-SYNTAX and the Functional CT-SYNTAX scores (rS â€‹= â€‹0.808 for both, p â€‹< â€‹0.001). In the ADVANCE cohort the FFS had good discriminatory abilities for revascularization with an area under the curve of 0.82, 95 â€‹% confidence interval (CI) 0.81-0.84, p â€‹< â€‹0.001. Patients in the highest FFS tertile had significantly higher rates of revascularization (61 â€‹% vs 5 â€‹%, p â€‹< â€‹0.001) and MACE (1.9 â€‹% vs 0.5 â€‹%, p â€‹= â€‹0.001) compared with the lowest FFS tertile. In the FORECAST cohort the FFS was an independent predictor of MACE at 9-month follow-up (hazard ratio 1.04, 95 â€‹% CI 1.01-1.08, p â€‹< â€‹0.01). CONCLUSION: The FFS is a quick-to-calculate and reproducible score, associated with revascularization and MACE in two distinct populations of stable symptomatic patients.

Dupilumab-induced psoriasiform dermatitis in two pediatric cardiac transplant patients.

Dupilumab is an interleukin-4 receptor antagonist important in the treatment of refractory atopic dermatitis (AD), particularly among pediatric patients. Two boys with a history of AD and cardiac transplant who developed psoriasiform dermatitis in response to dupilumab therapy are reported. These patients paradoxically developed an immune-mediated adverse drug reaction despite taking systemic immunosuppressive agents. While the literature suggests possible pathomechanisms for psoriasiform dermatitis despite immunosuppression, further research is necessary to better characterize this unique and unexpected phenomenon.

Atypical Pattern of Leukocytoclastic Vasculitis in Granulomatosis With Polyangiitis.

Granulomatosis with polyangiitis (GPA), formerly Wegener's granulomatosis, is a small- and medium-vessel vasculitis with characteristic cutaneous morphologic presentation and systemic involvement. Most patients have palpable purpura at some point in their disease course, but this is not always the presenting manifestation. This autoimmune disorder can affect a range of organs, with the upper and lower respiratory tract, kidneys, and nervous system being commonly implicated, while gastrointestinal and cardiac involvement is less frequent. This is a 44-year-old female presenting to the emergency department (ED) with polyarthralgia and palpable purpura. Palpable purpura was distributed on the oral palate, elbow, and lower back, and a punch biopsy revealed leukocytoclastic vasculitis (LCV). While this was an atypical distribution for leukocytoclastic vasculitis, the skin biopsy provided the necessary evidence to diagnose GPA. This case characterizes non-specific and atypical signs and symptoms of GPA that all providers should be aware of in order to diagnose the condition early in its disease course.

Impact of Coronary CT Angiography-derived Fractional Flow Reserve on Downstream Management and Clinical Outcomes in Individuals with and without Diabetes.

Purpose: To compare the clinical use of coronary CT angiography (CCTA)-derived fractional flow reserve (FFR) in individuals with and without diabetes mellitus (DM). Materials and Methods: This secondary analysis included participants (enrolled July 2015 to October 2017) from the prospective, multicenter, international The Assessing Diagnostic Value of Noninvasive CT-FFR in Coronary Care (ADVANCE) registry (ClinicalTrials.gov identifier, NCT02499679) who were evaluated for suspected coronary artery disease (CAD), with one or more coronary stenosis ≥30% on CCTA images, using CT-FFR. CCTA and CT-FFR findings, treatment strategies at 90 days, and clinical outcomes at 1-year follow-up were compared in participants with and without DM. Results: The study included 4290 participants (mean age, 66 years ± 10 [SD]; 66% male participants; 22% participants with DM). Participants with DM had more obstructive CAD (one or more coronary stenosis ≥50%; 78.8% vs 70.6%, P < .001), multivessel CAD (three-vessel obstructive CAD; 18.9% vs 11.2%, P < .001), and proportionally more vessels with CT-FFR ≤ 0.8 (74.3% vs 64.6%, P < .001). Treatment reclassification by CT-FFR occurred in two-thirds of participants which was consistent regardless of the presence of DM. There was a similar graded increase in coronary revascularization with declining CT-FFR in both groups. At 1 year, presence of DM was associated with higher rates of major adverse cardiovascular events (hazard ratio, 2.2; 95% CI: 1.2, 4.1; P = .01). However, no between group differences were observed when stratified by stenosis severity (<50% or ≥50%) or CT-FFR positivity. Conclusion: Both anatomic CCTA findings and CT-FFR demonstrated a more complex pattern of CAD in participants with versus without DM. Rates of treatment reclassification were similar regardless of the presence of DM, and DM was not an adverse prognostic indicator when adjusted for diameter stenosis and CT-FFR.Clinical trial registration no. NCT 02499679Keywords: Fractional Flow Reserve, CT Angiography, Diabetes Mellitus, Coronary Artery Disease Supplemental material is available for this article. See also the commentary by Ghoshhajra in this issue.© RSNA, 2023.

Prognostic Value of Coronary CT Angiography-derived Fractional Flow Reserve on 3-year Outcomes in Patients with Stable Angina.

Background The prognostic value of coronary CT angiography (CTA)-derived fractional flow reserve (FFR) beyond 1-year outcomes and in patients with high levels of coronary artery calcium (CAC) is uncertain. Purpose To assess the prognostic value of coronary CTA-derived FFR test results on 3-year clinical outcomes in patients with coronary stenosis and among a subgroup of patients with high levels of CAC. Materials and Methods This study represents a 3-year follow-up of patients with new-onset stable angina pectoris who were consecutively enrolled in the Assessing Diagnostic Value of Noninvasive CT-FFR in Coronary Care, known as ADVANCE (ClinicalTrials.gov: NCT02499679) registry, between December 2015 and October 2017 at three Danish sites. A high CAC was defined as an Agatston score of at least 400. A lesion-specific coronary CTA-derived FFR value of 2 cm with distal-to-stenosis value at or below 0.80 represented an abnormal test result. The primary end point was a composite of all-cause death and nonfatal spontaneous myocardial infarction. Event rates were estimated using the one-sample binomial model, and relative risk was compared between participants stratified by results of coronary CTA-derived FFR. Results This study included 900 participants: 523 participants with normal results (mean age, 64 years ± 9.6 [SD]; 318 male participants) and 377 with abnormal results from coronary CTA-derived FFR (mean age, 65 years ± 9.6; 264 male participants). The primary end point occurred in 11 of 523 (2.1%) and 25 of 377 (6.6%) participants with normal and abnormal coronary CTA-derived FFR results, respectively (relative risk, 3.1; 95% CI: 1.6, 6.3; P < .001). In participants with high CAC, the primary end point occurred in four of 182 (2.2%) and 19 of 212 (9.0%) participants with normal and abnormal coronary CTA-derived FFR results, respectively (relative risk, 4.1; 95% CI: 1.4, 11.8; P = .001). Conclusion In individuals with stable angina, a normal coronary CTA-derived FFR test result identified participants with a low 3-year risk of all-cause death or nonfatal spontaneous myocardial infarction, both in the overall cohort and in participants with high CAC scores. Clinical trial registration no. NCT02499679 Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Sinitsyn in this issue.

Comparison of an Initial Risk-Based Testing Strategy vs Usual Testing in Stable Symptomatic Patients With Suspected Coronary Artery Disease: The PRECISE Randomized Clinical Trial.

Importance: Trials showing equivalent or better outcomes with initial evaluation using coronary computed tomography angiography (cCTA) compared with stress testing in patients with stable chest pain have informed guidelines but raise questions about overtesting and excess catheterization. Objective: To test a modified initial cCTA strategy designed to improve clinical efficiency vs usual testing (UT). Design, Setting, and Participants: This was a pragmatic randomized clinical trial enrolling participants from December 3, 2018, to May 18, 2021, with a median of 11.8 months of follow-up. Patients from 65 North American and European sites with stable symptoms of suspected coronary artery disease (CAD) and no prior testing were randomly assigned 1:1 to precision strategy (PS) or UT. Interventions: PS incorporated the Prospective Multicenter Imaging Study for the Evaluation of Chest Pain (PROMISE) minimal risk score to quantitatively select minimal-risk participants for deferred testing, assigning all others to cCTA with selective CT-derived fractional flow reserve (FFR-CT). UT included site-selected stress testing or catheterization. Site clinicians determined subsequent care. Main Outcomes and Measures: Outcomes were clinical efficiency (invasive catheterization without obstructive CAD) and safety (death or nonfatal myocardial infarction [MI]) combined into a composite primary end point. Secondary end points included safety components of the primary outcome and medication use. Results: A total of 2103 participants (mean [SD] age, 58.4 [11.5] years; 1056 male [50.2%]) were included in the study, and 422 [20.1%] were classified as minimal risk. The primary end point occurred in 44 of 1057 participants (4.2%) in the PS group and in 118 of 1046 participants (11.3%) in the UT group (hazard ratio [HR], 0.35; 95% CI, 0.25-0.50). Clinical efficiency was higher with PS, with lower rates of catheterization without obstructive disease (27 [2.6%]) vs UT participants (107 [10.2%]; HR, 0.24; 95% CI, 0.16-0.36). The safety composite of death/MI was similar (HR, 1.52; 95% CI, 0.73-3.15). Death occurred in 5 individuals (0.5%) in the PS group vs 7 (0.7%) in the UT group (HR, 0.71; 95% CI, 0.23-2.23), and nonfatal MI occurred in 13 individuals (1.2%) in the PS group vs 5 (0.5%) in the UT group (HR, 2.65; 95% CI, 0.96-7.36). Use of lipid-lowering (450 of 900 [50.0%] vs 365 of 873 [41.8%]) and antiplatelet (321 of 900 [35.7%] vs 237 of 873 [27.1%]) medications at 1 year was higher in the PS group compared with the UT group (both P < .001). Conclusions and Relevance: An initial diagnostic approach to stable chest pain starting with quantitative risk stratification and deferred testing for minimal-risk patients and cCTA with selective FFR-CT in all others increased clinical efficiency relative to UT at 1 year. Additional randomized clinical trials are needed to verify these findings, including safety. Trial Registration: ClinicalTrials.gov Identifier: NCT03702244.

Deferred Testing in Stable Outpatients With Suspected Coronary Artery Disease: A Prespecified Secondary Analysis of the PRECISE Randomized Clinical Trial.

Importance: Guidelines recommend deferral of testing for symptomatic people with suspected coronary artery disease (CAD) and low pretest probability. To our knowledge, no randomized trial has prospectively evaluated such a strategy. Objective: To assess process of care and health outcomes in people identified as minimal risk for CAD when testing is deferred. Design, Setting, and Participants: This randomized, pragmatic effectiveness trial included prespecified subgroup analysis of the PRECISE trial at 65 North American and European sites. Participants identified as minimal risk by the validated PROMISE minimal risk score (PMRS) were included. Intervention: Randomization to a precision strategy using the PMRS to assign those with minimal risk to deferred testing and others to coronary computed tomography angiography with selective computed tomography-derived fractional flow reserve, or to usual testing (stress testing or catheterization with PMRS masked). Randomization was stratified by PMRS risk. Main Outcome: Composite of all-cause death, nonfatal myocardial infarction (MI), or catheterization without obstructive CAD through 12 months. Results: Among 2103 participants, 422 were identified as minimal risk (20%) and randomized to deferred testing (n = 214) or usual testing (n = 208). Mean age (SD) was 46 (8.6) years; 304 were women (72%). During follow-up, 138 of those randomized to deferred testing never had testing (64%), whereas 76 had a downstream test (36%) (at median [IQR] 48 [15-78] days) for worsening (30%), uncontrolled (10%), or new symptoms (6%), or changing clinician preference (19%) or participant preference (10%). Results were normal for 96% of these tests. The primary end point occurred in 2 deferred testing (0.9%) and 13 usual testing participants (6.3%) (hazard ratio, 0.15; 95% CI, 0.03-0.66; P = .01). No death or MI was observed in the deferred testing participants, while 1 noncardiovascular death and 1 MI occurred in the usual testing group. Two participants (0.9%) had catheterizations without obstructive CAD in the deferred testing group and 12 (5.8%) with usual testing (P = .02). At baseline, 70% of participants had frequent angina and there was similar reduction of frequent angina to less than 20% at 12 months in both groups. Conclusion and Relevance: In symptomatic participants with suspected CAD, identification of minimal risk by the PMRS guided a strategy of initially deferred testing. The strategy was safe with no observed adverse outcome events, fewer catheterizations without obstructive CAD, and similar symptom relief compared with usual testing. Trial Registration: ClinicalTrials.gov Identifier: NCT03702244.

Influence of Obesity on Coronary Artery Disease and Clinical Outcomes in the ADVANCE Registry.

BACKGROUND: The relationship between body size and cardiovascular events is complex. This study utilized the ADVANCE (Assessing Diagnostic Value of Noninvasive FFRCT in Coronary Care) Registry to investigate the association between body mass index (BMI), coronary artery disease (CAD), and clinical outcomes. METHODS: The ADVANCE registry enrolled patients undergoing evaluation for clinically suspected CAD who had >30% stenosis on cardiac computed tomography angiography. Patients were stratified by BMI: normal <25 kg/m2, overweight 25-29.9 kg/m2, and obese ≥30 kg/m2. Baseline characteristics, cardiac computed tomography angiography and computed tomography fractional flow reserve (FFRCT), were compared across BMI groups. Adjusted Cox proportional hazards models assessed the association between BMI and outcomes. RESULTS: Among 5014 patients, 2166 (43.2%) had a normal BMI, 1883 (37.6%) were overweight, and 965 (19.2%) were obese. Patients with obesity were younger and more likely to have comorbidities, including diabetes and hypertension (all P<0.001), but were less likely to have obstructive coronary stenosis (65.2% obese, 72.2% overweight, and 73.2% normal BMI; P<0.001). However, the rate of hemodynamic significance, as indicated by a positive FFRCT, was similar across BMI categories (63.4% obese, 66.1% overweight, and 67.8% normal BMI; P=0.07). Additionally, patients with obesity had a lower coronary volume-to-myocardial mass ratio compared with patients who were overweight or had normal BMI (obese BMI, 23.7; overweight BMI, 24.8; and normal BMI, 26.3; P<0.001). After adjustment, the risk of major adverse cardiovascular events was similar regardless of BMI (all P>0.05). CONCLUSIONS: Patients with obesity in the ADVANCE registry were less likely to have anatomically obstructive CAD by cardiac computed tomography angiography but had a similar degree of physiologically significant CAD by FFRCT and similar rates of adverse events. An exclusively anatomic assessment of CAD in patients with obesity may underestimate the burden of physiologically significant disease that is potentially due to a significantly lower volume-to-myocardial mass ratio.

DRAK2 contributes to type 1 diabetes by negatively regulating IL-2 sensitivity to alter regulatory T cell development.

Drak2-deficient (Drak2-/-) mice are resistant to multiple models of autoimmunity yet effectively eliminate pathogens and tumors. Thus, DRAK2 represents a potential target to treat autoimmune diseases. However, the mechanisms by which DRAK2 contributes to autoimmunity, particularly type 1 diabetes (T1D), remain unresolved. Here, we demonstrate that resistance to T1D in non-obese diabetic (NOD) mice is due to the absence of Drak2 in T cells and requires the presence of regulatory T cells (Tregs). Contrary to previous hypotheses, we show that DRAK2 does not limit TCR signaling. Rather, DRAK2 regulates IL-2 signaling by inhibiting STAT5A phosphorylation. We further demonstrate that enhanced sensitivity to IL-2 in the absence of Drak2 augments thymic Treg development. Overall, our data indicate that DRAK2 contributes to autoimmunity in multiple ways by regulating thymic Treg development and by impacting the sensitivity of conventional T cells to Treg-mediated suppression.

Artificial Intelligence-based Coronary Stenosis Quantification at Coronary CT Angiography versus Quantitative Coronary Angiography.

Purpose To evaluate the performance of a new artificial intelligence (AI)-based tool by comparing the quantified stenosis severity at coronary CT angiography (CCTA) with a reference standard derived from invasive quantitative coronary angiography (QCA). Materials and Methods This secondary, post hoc analysis included 120 participants (mean age, 59.7 years ± 10.8 [SD]; 73 [60.8%] men, 47 [39.2%] women) from three large clinical trials (AFFECTS, P3, REFINE) who underwent CCTA and invasive coronary angiography with QCA. Quantitative analysis of coronary stenosis severity at CCTA was performed using an AI-based coronary stenosis quantification (AI-CSQ) software service. Blinded comparison between QCA and AI-CSQ was measured on a per-vessel and per-patient basis. Results The per-vessel AI-CSQ diagnostic sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were 80%, 88%, 86%, 65%, and 94%, respectively, for diameter stenosis (DS) 50% or greater; and 78%, 92%, 91%, 47%, and 98%, respectively, for DS 70% or greater. The areas under the receiver operating characteristic curve (AUCs) to predict DS of 50% or greater and 70% or greater on a per-vessel basis were 0.92 (95% CI: 0.88, 0.95; P < .001) and 0.93 (95% CI: 0.89, 0.97; P < .001), respectively. The AUCs to predict DS of 50% or greater and 70% or greater on a per-patient basis were 0.93 (95% CI: 0.88, 0.97; P < .001) and 0.88 (95% CI: 0.81, 0.94; P < .001), respectively. Conclusion AI-CSQ at CCTA demonstrated a high diagnostic performance compared with QCA both on a per-patient and per-vessel basis, with high sensitivity for stenosis detection. Keywords: CT Angiography, Cardiac, Coronary Arteries Supplemental material is available for this article. Published under a CC BY 4.0 license.