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Objectives: To determine baseline prevalence of proteinuria and albuminuria among REPRIEVE participants and evaluate associated risk factors., Design: Cross sectional analysis of a baseline sample of participants from the REPRIEVE Trial., Methods: REPRIEVE is an international primary cardiovascular prevention RCT of pitavastatin calcium vs. placebo among PWH on antiretroviral therapy. A representative subset (2791 participants) had urine collected at study entry. Urine protein to creatinine ratios (uPCR) and albumin to creatinine ratios (uACR) were classified as normal, moderately increased and severely increased. These were dichotomized to Normal or Abnormal for log-binomial regression analysis. Demographic, cardiometabolic, and HIV-specific data were compared among those with normal versus abnormal results., Results: Overall, median age 49 years, 41% female sex, 47% black or African American race, 36% had eGFR <90 mL/min/1.73 mm2. For uPCR, 27% had moderately or severely increased values. For uACR, 9% had moderately or severely increased values. In the fully adjusted model for proteinuria, female sex, older age, residence in sub-Saharan Africa or East Asia, lower BMI, lower CD4 cell count, and use of TDF were associated with abnormal values. In the fully adjusted model for albuminuria, a diagnosis of HTN was associated with abnormal values., Conclusions: Abnormal proteinuria and albuminuria remain common (27% and 9%) despite controlled HIV. Lower current CD4 count and TDF use were strongly associated with proteinuria. Certain modifiable comorbidities, including HTN and smoking, were associated with abnormal values. In PWH with preserved eGFR, urine measures identify subclinical kidney disease and afford the opportunity for intervention., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The role of lipoprotein (a) (Lp[a]) in the development of obstructive coronary artery disease (CAD) and high-risk plaque (HRP) in primary prevention patients with stable chest pain is unknown. We sought to evaluate the relation of Lp(a), independent of low-density lipoprotein cholesterol (LDL-C), with the presence of obstructive CAD and HRP to improve understanding of the residual risk imparted by Lp(a) on CAD. We performed a secondary analysis in Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) Trial participants who had coronary computed tomographic angiography (CTA) performed and Lp(a) data available. Lp(a) concentration was analyzed as a binary variable, with elevated Lp(a) defined as ≥50 mg/100 ml. "Stenosis ≥50%" was defined as ≥50% coronary artery stenosis in any epicardial vessel, and "stenosis ≥70%" was defined as ≥70% coronary artery stenosis in any epicardial vessel and/or ≥50% left main coronary artery stenosis. HRP was defined as presence of plaque on CTA imaging with evidence of positive remodeling, low computed tomography attenuation, or napkin-ring sign. Multivariate logistic regression models were constructed to evaluate the association between Lp(a) and the outcomes of obstructive CAD and HRP stratified by LDL-C ≥100 versus <100 mg/100 ml. Of the 1,815 patients who underwent CTA and had Lp(a) data available, those with elevated Lp(a) were more commonly women and Black than those with lower Lp(a). Elevated Lp(a) was associated with stenosis ≥50% (odds ratio 1.57, 95% confidence interval 1.14 to 2.15, p = 0.005) and stenosis ≥70% (odds ratio 2.05, 95% confidence interval 1.34 to 3.11, p = 0.0008) in the multivariate models, and this relation was not modified by LDL-C ≥100 versus <100 mg/100 ml (interaction p >0.4). Elevated Lp(a) was not associated with HRP when adjusted for obstructive CAD. This study of patients without known CAD found that elevated Lp(a) ≥50 mg/100 ml was independently associated with the presence of obstructive CAD regardless of controlled versus uncontrolled LDL-C but was not independently associated with HRP when stenosis ≥50% or ≥70% was accounted for. Further research is warranted to delineate the role of Lp(a) in the residual risk for atherosclerotic cardiovascular disease that patients may have despite optimal LDL-C lowering., Competing Interests: Declaration of competing interest Dr. Shah reports research grants from Amgen, Janssen, Eli Lily, Novartis, and National Institutes of Health, and service as a consultant/advisor for Merck, Amgen, Norvartis, and New Amsterdam Pharma. Dr. Ferencik reports consulting fees from Cleerly, HeartFlow, Elucid, Siemens Healthineers, and BioMarin, and stock options from Elucid, and is a member of an advisory board for Cleerly. Dr. Lu reports research funding to his institution from the American Heart Association, AstraZeneca, Ionis, Johnson & Johnson Innovation, Kowa Pharmaceuticals America, MedImmune, National Academy of Medicine, National Heart, Lung, and Blood Institute, and Risk Management Foundation of the Harvard Medical Institutions outside the submitted work. Dr. Foldyna reports research grants from National Institutes of Health/National Heart, Lung, and Blood Institute (R01HL170877, 5P30DK040561), AstraZeneca, Cleerly Health, MedImmune, and MedTrace. Dr. Pagidipati reports research support from Alnylam, Amgen, Bayer, Boehringer Ingelheim (Ingelheim, Germany), Eggland's Best, Eli Lilly (Esperion), Novartis, Novo Nordisk, Merck; service on consultation/advisory panels for Amgen, Bayer, Boehringer Ingelheim, CRISPR Therapeutics, Eli Lilly, AstraZeneca, Merck, Novartis, and Novo Nordisk; service as an Executive Committee member for trials sponsored by Novo Nordisk and by Amgen and by AstraZeneca; service on a Data and Safety Monitoring Board for trials sponsored by Johnson & Johnson and Novartis; and service on a medical advisory board for Miga Health. The remaining authors have no competing interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Peptide drug discovery for the treatment of chronic kidney disease (CKD) has attracted much attention in recent years due to the urge to find novel drugs and mechanisms to delay the progression of the disease. In this study, we identified a novel short peptide (named YR-7, primary sequence 'YEVEDYR') from the natural Fibroin protein, and demonstrated that it significantly alleviated pathological renal changes in ADR-induced nephropathy. PANX1 was identified as the most notably upregulated component by RNA-sequencing. Further analysis showed that YR-7 alleviated the accumulation of lipid droplets via regulation of the lipid metabolism-related proteins PPAR α and PANK1. Using chemical proteomics, fluorescence polarization, microscale thermophoresis, surface plasmon resonance, and molecular docking, YR-7 was proven to directly bind to β-barrel domains of TGM2 protein to inhibit lipid accumulation. TGM2 knockdown in vivo increased the protein levels of PPAR α and PANK1 while decreased the levels of fibrotic-related proteins to alleviate nephropathy. In vitro, overexpression TGM2 reversed the protective effects of YR-7. Co-immunoprecipitation indicated that TGM2 interacted with PANX1 to promote lipid deposition, and pharmacological inhibition or knockdown of PANX1 decreased the levels of PPAR α and PANK1 induced by ADR. Taken together, our findings revealed that TGM2-PANX1 interaction in promoting lipid deposition may be a new signaling in promoting ADR-induced nephropathy. And a novel natural peptide could ameliorate renal fibrosis through TGM2-PANX1-PPAR α/PANK1 pathway, which highlight the potential of it in the treatment of CKD., (Copyright © 2024. Published by Elsevier Inc.)

In current clinical practice, qualitative or semi-quantitative measures are primarily used to report coronary artery disease on cardiac CT. With advancements in cardiac CT technology and automated post-processing tools, quantitative measures of coronary disease severity have become more broadly available. Quantitative coronary CT angiography has great potential value for clinical management of patients, but also for research. This document aims to provide definitions and standards for the performance and reporting of quantitative measures of coronary artery disease by cardiac CT., Competing Interests: Declaration of competing interest Héctor M. García-García reports the following Institutional grant support: Biotronik, Boston Scientific, Medtronic, Abbott, Neovasc, Shockwave, Phillips and Corflow; Consultancy fee from Boston Scientific, Abbott and Amgen. Koen Nieman acknowledges support from the NIH (NIH R01- HL141712; NIH R01 - HL146754), and reports unrestricted institutional research support from Siemens Healthineers, Bayer, HeartFlow Inc, Novartis unrelated to this work, consulting for Novartis and Siemens Medical Solutions USA, Artrya, Cleerly, Elucid, and equity in Lumen Therapeutics. Maksymilian P. Opolski reports institutional grant support from B. Braun; consulting for Boston Scientific and proctorship for Boston Scientific, Terumo and Biotronik. Michelle Williams has given talks for Canon Medical Systems, Siemens Healthineers and Novartis. Damini Dey has received software royalties from Cedars-Sinai Medical Center and is supported by grants from the NIH/NHLBI (1R01HL148787-01A1 and 1R01HL151266). Jonathon Leipsic is a consultant and holds stock options in HeartFlow Inc., is a consultant to Circle CVI and has received modest corelab personal fees from Arineta and has received modest speaking fees from GE Healthcare and Philips HealthCare. Michael T Lu reports institutional research support from the American Heart Association (18UNPG34030172; 810,966), AstraZeneca, Ionis, Johnson & Johnson Innovation, Kowa, the National Academy of Medicine, and the NIH (U01HL123339; U24HL164284; R33HL141047; R01HL164629). Maros Ferencik received grant support from the American Heart Association and National Institutes of Health. Maros Ferencik received consulting fees HeartFlow, Elucid, Siemens Healthineers., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose To assess the prognostic value of a deep learning-based chest radiographic age (hereafter, CXR-Age) model in a large external test cohort of Asian individuals. Materials and Methods This single-center, retrospective study included chest radiographs from consecutive, asymptomatic Asian individuals aged 50-80 years who underwent health checkups between January 2004 and June 2018. This study performed a dedicated external test of a previously developed CXR-Age model, which predicts an age adjusted based on the risk of all-cause mortality. Adjusted hazard ratios (HRs) of CXR-Age for all-cause, cardiovascular, lung cancer, and respiratory disease mortality were assessed using multivariable Cox or Fine-Gray models, and their added values were evaluated by likelihood ratio tests. Results A total of 36 924 individuals (mean chronological age, 58 years ± 7 [SD]; CXR-Age, 60 years ± 5; 22 352 male) were included. During a median follow-up of 11.0 years, 1250 individuals (3.4%) died, including 153 cardiovascular (0.4%), 166 lung cancer (0.4%), and 98 respiratory (0.3%) deaths. CXR-Age was a significant risk factor for all-cause (adjusted HR at chronological age of 50 years, 1.03; at 60 years, 1.05; at 70 years, 1.07), cardiovascular (adjusted HR, 1.11), lung cancer (adjusted HR for individuals who formerly smoked, 1.12; for those who currently smoke, 1.05), and respiratory disease (adjusted HR, 1.12) mortality ( P < .05 for all). The likelihood ratio test demonstrated added prognostic value of CXR-Age to clinical factors, including chronological age for all outcomes ( P < .001 for all). Conclusion Deep learning-based chest radiographic age was associated with various survival outcomes and had added value to clinical factors in asymptomatic Asian individuals, suggesting its generalizability. Keywords: Conventional Radiography, Thorax, Heart, Lung, Mediastinum, Outcomes Analysis, Quantification, Prognosis, Convolutional Neural Network (CNN) Supplemental material is available for this article. © RSNA, 2024 See also the commentary by Adams and Bressem in this issue.

Competing Interests: Declaration of competing interest Conflict of interest information will be provided by Stacy De La O, CAE, Consultant, SCCT Guidelines sdelao@scct.org.

Background: Coronary plaque is common among people with HIV (PWH) with low-to-moderate traditional atherosclerotic cardiovascular disease (ASCVD) risk., Objectives: The purpose of this study was to determine the association of high-sensitivity cardiac troponin T (hs-cTnT) levels with coronary plaque characteristics and evaluate if hs-cTnT improves identification of these features beyond traditional ASCVD risk factors among PWH., Methods: Among PWH receiving stable antiretroviral therapy with low-to-moderate ASCVD risk and no known history of ASCVD, hs-cTnT levels and measures of plaque by coronary computed tomography angiography were assessed. Primary outcomes included the association of hs-cTnT level with the presence of any plaque, vulnerable plaque, coronary artery calcium (CAC) score, and Leaman score. Assessment of model discrimination of hs-cTnT for plaque characteristics was also performed., Results: The cohort included 708 U.S. participants with a mean age of 51 ± 6 years, 119 (17%) females, a median ASCVD risk score of 4.4% (Q1-Q3: 2.5%-6.6%), and a median hs-cTnT level of 6.7 ng/L (detectable level ≥6 ng/L in 61%). Any plaque was present in 341 (48%), vulnerable plaque in 155 (22%), CAC>100 in 68 (10%), and a Leaman score >5 in 105 (15%). After adjustment for ASCVD risk score, participants with hs-cTnT >9.6 ng/L (highest category) versus an undetectable level (<6 ng/L) had a greater relative risk for any plaque (1.37, 95% CI: 1.12-1.67), vulnerable plaque (1.47, 95% CI: 1.16-1.87), CAC>100 (2.58, 95% CI: 1.37-4.83), and Leaman score >5 (2.13, 95% CI: 1.32-3.46). The addition of hs-cTnT level modestly improved the discrimination of ASCVD risk score to identify critical plaque features., Conclusions: In PWH without known ASCVD, hs-cTnT levels were strongly associated with and improved prediction of subclinical coronary plaque. (Evaluating the Use of Pitavastatin to Reduce the Risk of Cardiovascular Disease in HIV-Infected Adults [REPRIEVE]; NCT02344290)., Competing Interests: The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute or the National Institute of Allergy and Infectious Diseases; the National Institutes of Health; or the U.S. Department of Health and Human Services. This study is supported through NIH grants U01HL123336, to the Clinical Coordinating Center, and U01HL123339, to the Data Coordinating Center as well as funding from Kowa Pharmaceuticals America, Inc, Gilead Sciences, and ViiV Healthcare. The NIAID supported this study through grants UM1 AI068636, which supports the Advancing Clinical Therapeutics Globally (ACTG) Network Leadership and Operations Center; and UM1 AI106701, which supports the ACTG Laboratory Center. This work was also supported by the Nutrition Obesity Research Center at Harvard (P30DK040561 to SKG). Dr deFilippi has received grant support to his institution from Roche Diagnostics and consulting for Roche Diagnostics which manufacturers the troponin T assay; has received grants to his institution from Abbott Diagnostics, FujiRebio, Quidel/Ortho, Siemens Healthineers, and the NHLBI outside this submitted work; consulting for Abbott Diagnostics, FujiRebio, and Quidel/Ortho, and Siemens Healthineers; and serves as a member of the clinical endpoint committee for Siemens Healthineers. Dr Zanni is the principal investigator of research grants from 10.13039/100000002NIH (NIAID and NHLBI) and from 10.13039/100005564Gilead Sciences to her institution and participating in a DSMB for 10.13039/100000002NIH-funded studies involving no compensation. Dr Fichtenbaum has received grant support through his institution from 10.13039/100005564Gilead Sciences, 10.13039/100010877ViiV Healthcare, 10.13039/100004330GSK, 10.13039/100005565Janssen, 10.13039/100006483Abbvie, 10.13039/100004334Merck, 10.13039/100002429Amgen, and Cytodyn, outside the submitted work; and personal fees from Theratechnologies and ViiV for consulting and participation on Advisory Board unrelated to REPRIEVE with Theratechnologies and ViiV, and role as Chair on DSMB for Intrepid Study, outside the submitted work. Dr Aberg has received institutional research support for clinical trials from Emergent Biosolutions, Frontier Technologies, Gilead Sciences, GlaxoSmithKline, Janssen, MacroGenics, Merck, Pfizer, Regeneron, and ViiV Healthcare; and personal fees for advisory boards from Glaxo Smith Kline/Viiv and Merck and participation on DSMB for Kintor Pharmaceuticals, all outside the submitted work. Dr Malvestutto has received institutional research support by Lilly; and honoraria from 10.13039/100010877ViiV Healthcare and 10.13039/100005564Gilead Sciences for Advisory Board membership, outside the submitted work. Dr Pinto-Martinez has received honoraria from Gilead, Janssen, and ViiV Healthcare for presentations and educational events, outside the submitted work. Dr Stapleton has received institutional research support by 10.13039/100000002NIH. Dr Robbins has received grant support to his institution from Leonard-Meron Bioscience; consulting fees to his institution from Seed Inc and Teradyne Inc; payment for expert testimony from Tufts Medical Center, participation on a DSMB for an NIH trial, and unpaid membership on a review panel for DHHS OI Guidelines. Dr Taron has received support from 10.13039/501100001659Deutsche Forschungsgesellschaft (DFG, German Research Foundation) relevant to the present work; consulting fees from Universimed Cross Media Content GmbH, Core Lab Black Forrest GmbH; and payments or honoraria from Siemens Healthcare GmbH, Bayer AG, outside of the submitted work. Dr Foldyna has received institutional support from 10.13039/100004325AstraZeneca, 10.13039/501100004628MedImmune, and MedTrace, outside of the submitted work. Dr Lu has received grant support through his institution from Kowa Pharmaceuticals America, Inc, for the conduct of the study; grant support from 10.13039/501100004628MedImmune and 10.13039/100004325AstraZeneca; and personal fees from PQBypass, outside of the current work. Dr Ribaudo has received grants from 10.13039/100000002NIH/10.13039/100000050NHLBI and Kowa Pharmaceuticals during the conduct of the study as well as grants from 10.13039/100000002NIH/10.13039/100000060NIAID, and 10.13039/100000002NIH/10.13039/100000050NHLBI, 10.13039/100000002NIH/10.13039/100000062NIDDK, and 10.13039/100000002NIH/10.13039/100000049NIA outside the submitted work. Dr Grinspoon has received grant support through his institution from Kowa Pharmaceuticals America, Inc 10.13039/100005564Gilead Sciences, Inc; and 10.13039/100010877ViiV Healthcare for the conduct of the study, as well as grants from Theratechnologies and Navidea and personal fees from Theratechnologies and ViiV, all outside the submitted work; and is a member of the Scientific Advisory Board of Marathon Asset management. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: Long COVID, an emerging public health issue, is characterized by persistent symptoms following SARS-CoV-2 infection. This study aims to explore the relationship between post-COVID-19 symptomatology and patient distress employing Latent Class Analysis to uncover symptom co-occurrence patterns and their association with distress., Methods: A cross-sectional study was conducted using an online survey among 240 participants from a university and affiliated hospital of southern Taiwan. The survey quantified distress due to persistent symptoms and assessed the prevalence of Long COVID, symptom co-occurrence, and latent symptom classes. Latent Class Analysis (LCA) identified distinct symptom patterns, and multiple regression models evaluated associations between symptom patterns, distress, and demographic factors., Results: The study found that 80 % of participants experienced Long COVID, with symptoms persisting for over three months. Individuals with multiple COVID-19 infections showed a significant increase in general (β = 1.79), cardiovascular (β = 0.61), and neuropsychological symptoms (β = 2.18), and higher total distress scores (β = 6.35). Three distinct symptomatology classes were identified: "Diverse", "Mild", and "Severe" symptomatology. The "Mild Symptomatology" class was associated with lower distress (-10.61), while the "Severe Symptomatology" class showed a significantly higher distress due to symptoms (13.32)., Conclusion: The study highlights the significant impact of Long COVID on individuals, with distinct patterns of symptomatology and associated distress. It emphasizes the cumulative effect of multiple COVID-19 infections on symptom severity and the importance of tailored care strategies., Competing Interests: Declaration of Competing Interest The authors have no competing interest to declare., (Copyright © 2024. Published by Elsevier Ltd.)

People with human immunodeficiency virus (HIV, PWH) face an increased risk of cardiovascular disease (CVD) compared to the general population. We previously demonstrated that people with (versus without) HIV have higher macrophage-specific arterial infiltration in relation to systemic monocyte activation. We now show that select T lymphocyte subpopulations (naïve CD4+, effector memory CD4+, and central memory CD8+) are differentially associated with macrophage-specific arterial infiltration among participants with versus without HIV, with evidence of interaction by HIV status. Our results suggest that among PWH, circulating T lymphocytes associate with macrophage-specific arterial infiltration, of relevance to atherogenesis and CVD risk., Clinical Trials Registration: NCT02542371., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: To determine the relationship between lipoprotein particle size/number with hepatic steatosis (HS), given its association with traditional lipoproteins and coronary atherosclerosis., Methods: Individuals with available CT data and blood samples enrolled in the PROMISE trial were studied. HS was defined based on CT attenuation. Lipoprotein particle size/number were measured by nuclear magnetic resonance spectroscopy. Principal components analysis (PCA) was used for dimensionality reduction. The association of PCA factors and individual lipoprotein particle size/number with HS were assessed in multivariable regression models. Associations were validated in an independent cohort of 59 individuals with histopathology defined HS., Results: Individuals with HS (n=410/1,509) vs those without (n=1,099/1,509), were younger (59±8 vs 61±8 years) and less often females (47.6 % vs 55.9 %). All PCA factors were associated with HS: factor 1 (OR:1.36, 95 %CI:1.21-1.53), factor 3 (OR:1.75, 95 %CI:1.53-2.02) and factor 4 (OR:1.49; 95 %CI:1.32-1.68) were weighted heavily with small low density lipoprotein (LDL) and triglyceride-rich (TRL) particles, while factor 2 (OR:0.86, 95 %CI:0.77-0.97) and factor 5 (OR:0.74, 95 %CI:0.65-0.84) were heavily loaded with high density lipoprotein (HDL) and larger LDL particles. These observations were confirmed with the analysis of individual lipoprotein particles in PROMISE. In the validation cohort, association between HS and large TRL (OR: 8.16, 95 %CI:1.82-61.98), and mean sizes of TRL- (OR: 2.82, 95 %CI:1.14-9.29) and HDL (OR:0.35, 95 %CI:0.13-0.72) were confirmed., Conclusions: Large TRL, mean sizes of TRL-, and HDL were associated with radiographic and histopathologic HS. The use of lipoprotein particle size/number could improve cardiovascular risk assessment in HS., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier B.V.)

Background: People with HIV (PWH) have a high burden of coronary plaques; however, the comparison to people without known HIV (PwoH) needs clarification., Objectives: The purpose of this study was to determine coronary plaque burden/phenotype in PWH vs PwoH., Methods: Nonstatin using participants from 3 contemporary populations without known coronary plaques with coronary CT were compared: the REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) studying PWH without cardiovascular symptoms at low-to-moderate risk (n = 755); the SCAPIS (Swedish Cardiopulmonary Bioimage Study) of asymptomatic community PwoH at low-to-intermediate cardiovascular risk (n = 23,558); and the PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) of stable chest pain PwoH (n = 2,291). The coronary plaque prevalence on coronary CT was compared, and comparisons were stratified by 10-year atherosclerotic cardiovascular disease (ASCVD) risk, age, and coronary artery calcium (CAC) presence., Results: Compared to SCAPIS and PROMISE PwoH, REPRIEVE PWH were younger (50.8 ± 5.8 vs 57.3 ± 4.3 and 60.0 ± 8.0 years; P  < 0.001) and had lower ASCVD risk (5.0% ± 3.2% vs 6.0% ± 5.3% and 13.5% ± 11.0%; P  < 0.001). More PWH had plaque compared to the asymptomatic cohort (48.5% vs 40.3%; P  < 0.001). When stratified by ASCVD risk, PWH had more plaque compared to SCAPIS and a similar prevalence of plaque compared to PROMISE. CAC = 0 was more prevalent in PWH (REPRIEVE 65.2%; SCAPIS 61.6%; PROMISE 49.6%); among CAC = 0, plaque was more prevalent in PWH compared to the PwoH cohorts (REPRIEVE 20.8%; SCAPIS 5.4%; PROMISE 12.3%, P  < 0.001)., Conclusions: Asymptomatic PWH in REPRIEVE had more plaque than asymptomatic PwoH in SCAPIS but had similar prevalence to a higher-risk stable chest pain cohort in PROMISE. In PWH, CAC = 0 does not reliably exclude plaque., Competing Interests: 10.13039/100000002This paper received NIH grants U01HL123336 to the REPRIEVE Clinical Coordinating Center and U01HL123339 to the REPRIEVE Data Coordinating Center, as well as funding from Kowa Pharmaceuticals, Gilead Sciences, and ViiV Healthcare. The 10.13039/100000060National Institute of Allergy and Infectious Diseases (NIAID) supported this study through grants UM1 AI068636, which supports the AIDS Clinical Trials Group (ACTG) Leadership and Operations Center, and UM1 AI106701, which supports the ACTG Laboratory Center. The PROMISE trial was supported by the 10.13039/100000050National Heart, Lung, and Blood Institute (R01HL098237, R01HL098236, R01HL98305, and R01HL098235). The SCAPIS trial received funding from the Swedish Heart-Lung Foundation, Knut and Alice Wallenberg Foundation, Swedish Research Council and Vinnova (Sweden’s Innovation Agency), University of Gothenburg and Sahlgrenska University Hospital, Karolinska Institutet and Stockholm County Council, Linköping University and University Hospital, Lund University and Skåne University Hospital, Umeå University and University Hospital, and Uppsala University and University Hospital. The content of this manuscript is solely the responsibility of the authors and does not necessarily reflect the views of any of the funding agencies. Dr Lu has received funding to his institution from Kowa, AstraZeneca/MedImmune, Johnson & Johnson Innovation, Ionis, and the American Heart Association unrelated to this research. Dr Taron has received funding by Deutsche Forschungsgesellschaft (DFG, German Research Foundation) (TA 1438/1-2); is on Speakers Bureau for Siemens Healthcare GmbH and Bayer AG; and has received consulting fees from Universimed Cross Media Content GmbH and Core Lab Black Forrest GmbH, unrelated to this work. Dr Foldyna has received funding to his institution from AstraZeneca/MedImmune, MedTrace, and Eli Lilly unrelated to this research. Dr Currier served as an advisor to Merck. Dr Elvstam has received grants to his institution from Pfizer; and has received honoraria as a speaker from Gilead Sciences, unrelated to this research. Dr Dubé has received funding to his institution from Gilead Sciences unrelated to this research. Dr Fichtenbaum has received funding to the institution from ViiV Healthcare, Gilead Sciences, Merck, Cytodyn, and Moderna unrelated to this work and serves on the advisory board for ViiV Healthcare. Dr Malvestutto has received funding to his institution from Lilly; and has received consulting fees from Viiv Healthcare and Gilead Sciences unrelated to this work. Dr Zanni reports being PI on research grants from the NIH (NHLBI and NIAID) and Gilead Sciences to her institution. Dr Ribaudo has received grants from Kowa Pharmaceuticals during the conduct of the study, as well as grants from NIH/NIAID, NIH/NHLBI, NIH/NIDDK, and NIH/NIA, outside the submitted work. Dr Grinspoon reports being a part of the Scientific Advisory Board for Marathon Asset Management and consultant Theratechnologies is unrelated to this report; research funds come from Gilead, Viiv, and Kowa through his institution. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

The biphenyl scaffold represents a prominent privileged structure within the realms of organic chemistry and drug development. Biphenyl derivatives have demonstrated notable biological activities, including antimicrobial, anti-inflammatory, anti-HIV, and the treatment of neuropathic pain. Importantly, their anticancer abilities should not be underestimated. In this context, the present study involves the design and synthesis of a series of biphenyl derivatives featuring an additional privileged structure, namely the quinoline core. We have also diversified the substituents attached to the benzyloxy group at either the meta or para position of the biphenyl ring categorized into two distinct groups: [4,3']biphenylaminoquinoline-substituted and [3,3']biphenylaminoquinoline-substituted compounds. We embarked on an assessment of the cytotoxic activities of these derivatives in colorectal cancer cell line SW480 and prostate cancer cell line DU145 for exploring the structure-activity relationship. Furthermore, we determined the IC 50 values of selected compounds that exhibited superior inhibitory effects on cell viability against SW480, DU145 cells, as well as MDA-MB-231 and MiaPaCa-2 cells. Notably, [3,3']biphenylaminoquinoline derivative 7j displayed the most potent cytotoxicity against these four cancer cell lines, SW480, DU145, MDA-MB-231, and MiaPaCa-2, with IC 50 values of 1.05 μM, 0.98 μM, 0.38 μM, and 0.17 μM, respectively. This highly promising outcome underscores the potential of [3,3']biphenylaminoquinoline 7j for further investigation as a prospective anticancer agent in future research endeavors., (© 2024 John Wiley & Sons Ltd.)

A 74-year-old man presented with symptoms and noninvasive diagnostic studies suggestive of myocardial infarction. Coronary angiography revealed total occlusion of the distal right coronary artery with a unique accessory coronary ring that provided retrograde collateral flow to the left ventricle, demonstrating the importance of considering non-native vessels when identifying target lesions., Competing Interests: Dr Drachman has received consulting fees for Boston Scientific, Broadview Ventures, Cardiovascular Systems Inc, and Cordis not relevant to the current submission. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: Cytomegalovirus (CMV) seropositivity is associated with poor outcomes, including physical function impairment, in people without HIV. We examined associations between CMV IgG titer and physical function in virologically suppressed people with HIV (PWH)., Methods: REPRIEVE is a double-blind randomized trial evaluating pitavastatin for primary prevention of atherosclerotic cardiovascular disease in PWH. This analysis focused on participants enrolled in a substudy with additional biomarker testing, imaging [coronary CT angiography], and physical function measures at entry. CMV IgG was measured using quantitative enzyme immunoassay, physical function by Short Physical Performance Battery, and muscle density and area by CT. Associations between CMV IgG (risk factor) and outcomes were evaluated using the partial Spearman correlation and linear and log-binomial regression., Results: Among 717 participants, 82% male, the median CMV IgG was 2716 (Q1, Q3: 807, 6672) IU/mL, all above the limit of quantification. Among 631 participants with imaging, there was no association between CMV IgG and CT-based muscle density or area, controlling for age (r = -0.03 and r = -0.01, respectively; P ≥ 0.38). Among 161 participants with physical function data, higher CMV IgG was associated with poorer overall modified Short Physical Performance Battery score ( P = 0.02), adjusted for age, nadir CD4, and high-sensitivity C-reactive protein., Conclusions: Higher CMV IgG titer was associated with poorer physical function, not explained by previous immune compromise, inflammation, or muscle density or area. Further mechanistic studies are needed to understand this association and whether CMV-specific therapy can affect physical function in PWH., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Coronary artery disease (CAD) is a leading cause of death among the 38.4 million people with HIV globally. The extent to which cardiovascular polygenic risk scores (PRSs) derived in non-HIV populations generalize to people with HIV is not well understood., Methods and Results: PRSs for CAD (GPS Mult ) and lipid traits were calculated in a global cohort of people with HIV treated with antiretroviral therapy with low-to-moderate atherosclerotic cardiovascular disease risk enrolled in REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV). The PRSs were associated with baseline lipid traits in 4495 genotyped participants, and with subclinical CAD in a subset of 662 who underwent coronary computed tomography angiography. Among participants who underwent coronary computed tomography angiography (mean age, 50.9 [SD, 5.8] years; 16.1% women; 41.8% African, 57.3% European, 1.1% Asian), GPS Mult was associated with plaque presence with odds ratio (OR) per SD in GPS Mult of 1.42 (95% CI, 1.20-1.68; P =3.8×10 -5 ), stenosis >50% (OR, 2.39 [95% CI, 1.48-3.85]; P =3.4×10 -4 ), and noncalcified/vulnerable plaque (OR, 1.45 [95% CI, 1.23-1.72]; P =9.6×10 -6 ). Effects were consistent in subgroups of age, sex, 10-year atherosclerotic cardiovascular disease risk, ancestry, and CD4 count. Adding GPS Mult to established risk factors increased the C-statistic for predicting plaque presence from 0.718 to 0.734 ( P =0.02). Furthermore, a PRS for low-density lipoprotein cholesterol was associated with plaque presence with OR of 1.21 (95% CI, 1.01-1.44; P =0.04), and partially calcified plaque with OR of 1.21 (95% CI, 1.01-1.45; P =0.04) per SD., Conclusions: Among people with HIV treated with antiretroviral therapy without documented atherosclerotic cardiovascular disease and at low-to-moderate calculated risk in REPRIEVE, an externally developed CAD PRS was predictive of subclinical atherosclerosis. PRS for low-density lipoprotein cholesterol was also associated with subclinical atherosclerosis, supporting a role for low-density lipoprotein cholesterol in HIV-associated CAD., Registration: URL: https://www.reprievetrial.org; Unique identifier: NCT02344290.

Background: Guidelines for primary prevention of atherosclerotic cardiovascular disease (ASCVD) recommend a risk calculator (ASCVD risk score) to estimate 10-year risk for major adverse cardiovascular events (MACE). Because the necessary inputs are often missing, complementary approaches for opportunistic risk assessment are desirable., Objective: To develop and test a deep-learning model (CXR CVD-Risk) that estimates 10-year risk for MACE from a routine chest radiograph (CXR) and compare its performance with that of the traditional ASCVD risk score for implications for statin eligibility., Design: Risk prediction study., Setting: Outpatients potentially eligible for primary cardiovascular prevention., Participants: The CXR CVD-Risk model was developed using data from a cancer screening trial. It was externally validated in 8869 outpatients with unknown ASCVD risk because of missing inputs to calculate the ASCVD risk score and in 2132 outpatients with known risk whose ASCVD risk score could be calculated., Measurements: 10-year MACE predicted by CXR CVD-Risk versus the ASCVD risk score., Results: Among 8869 outpatients with unknown ASCVD risk, those with a risk of 7.5% or higher as predicted by CXR CVD-Risk had higher 10-year risk for MACE after adjustment for risk factors (adjusted hazard ratio [HR], 1.73 [95% CI, 1.47 to 2.03]). In the additional 2132 outpatients with known ASCVD risk, CXR CVD-Risk predicted MACE beyond the traditional ASCVD risk score (adjusted HR, 1.88 [CI, 1.24 to 2.85])., Limitation: Retrospective study design using electronic medical records., Conclusion: On the basis of a single CXR, CXR CVD-Risk predicts 10-year MACE beyond the clinical standard and may help identify individuals at high risk whose ASCVD risk score cannot be calculated because of missing data., Primary Funding Source: None., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-1898.

Purpose This special report outlines a retrospective observational study of CT fractional flow reserve (CT-FFR) analysis using dual-source coronary CT angiography (CTA) scans performed without heart rate control and its impact on clinical outcomes. Materials and Methods All patients who underwent clinically indicated coronary CTA between August 2020 and August 2021 were included in this retrospective observational study. Scans were performed in the late systolic to early diastolic period without heart rate control and analyzed at the interpreting physician's discretion. Demographics, coronary CTA features, and rates of invasive coronary angiography (ICA), percutaneous coronary intervention (PCI), myocardial infarction, and all-cause death at 3 months were assessed by chart review. Results During the study period, 3098 patients underwent coronary CTA, of whom 113 with coronary bypass grafting were excluded. Of the remaining 2985 patients, 292 (9.7%) were referred for CT-FFR analysis. Two studies (0.7%) were rejected from CT-FFR analysis, and six (2.1%) analyses did not evaluate the lesion of concern. A total of 160 patients (56.3%) had CT-FFR greater than 0.80. Among patients with significant stenosis at coronary CTA, patients who underwent CT-FFR analysis presented with lower rates of ICA (74.5% vs 25.5%, P = .04) and PCI (78.9% vs 21.1%, P = .05). Conclusion CT-FFR was implemented in patients not requiring heart rate control by using dual-source coronary CTA acquisition and showed the potential to decrease rates of ICA and PCI without compromising safety in patients with significant stenosis and an average heart rate of 65 beats per minute. Keywords: Angiography, CT, CT-Angiography, Fractional Flow Reserve, Cardiac, Heart, Arteriosclerosis Supplemental material is available for this article. © RSNA, 2024.

Importance: Cardiovascular disease (CVD) is increased in people with HIV (PWH) and is characterized by premature noncalcified coronary plaque. In the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE), pitavastatin reduced major adverse cardiovascular events (MACE) by 35% over a median of 5.1 years., Objective: To investigate the effects of pitavastatin on noncalcified coronary artery plaque by coronary computed tomography angiography (CTA) and on inflammatory biomarkers as potential mechanisms for MACE prevention., Design, Setting, and Participants: This double-blind, placebo-controlled randomized clinical trial enrolled participants from April 2015 to February 2018 at 31 US clinical research sites. PWH without known CVD who were taking antiretroviral therapy and had low to moderate 10-year CVD risk were included. Data were analyzed from April to November 2023., Intervention: Oral pitavastatin calcium, 4 mg per day., Main Outcomes and Measures: Coronary CTA and inflammatory biomarkers at baseline and 24 months. The primary outcomes were change in noncalcified coronary plaque volume and progression of noncalcified plaque., Results: Of 804 enrolled persons, 774 had at least 1 evaluable CTA. Plaque changes were assessed in 611 who completed both CT scans. Of 611 analyzed participants, 513 (84.0%) were male, the mean (SD) age was 51 (6) years, and the median (IQR) 10-year CVD risk was 4.5% (2.6-7.0). A total of 302 were included in the pitavastatin arm and 309 in the placebo arm. The mean noncalcified plaque volume decreased with pitavastatin compared with placebo (mean [SD] change, -1.7 [25.2] mm3 vs 2.6 [27.1] mm3; baseline adjusted difference, -4.3 mm3; 95% CI, -8.6 to -0.1; P = .04; 7% [95% CI, 1-12] greater reduction relative to placebo). A larger effect size was seen among the subgroup with plaque at baseline (-8.8 mm3 [95% CI, -17.9 to 0.4]). Progression of noncalcified plaque was 33% less likely with pitavastatin compared with placebo (relative risk, 0.67; 95% CI, 0.52-0.88; P = .003). Compared with placebo, the mean low-density lipoprotein cholesterol decreased with pitavastatin (mean change: pitavastatin, -28.5 mg/dL; 95% CI, -31.9 to -25.1; placebo, -0.8; 95% CI, -3.8 to 2.2). The pitavastatin arm had a reduction in both oxidized low-density lipoprotein (-29% [95% CI, -32 to -26] vs -13% [95% CI, -17 to -9]; P < .001) and lipoprotein-associated phospholipase A2 (-7% [95% CI, -11 to -4] vs 14% [95% CI, 10-18]; P < .001) compared with placebo at 24 months., Conclusions and Relevance: In PWH at low to moderate CVD risk, 24 months of pitavastatin reduced noncalcified plaque volume and progression as well as markers of lipid oxidation and arterial inflammation. These changes may contribute to the observed MACE reduction in REPRIEVE., Trial Registration: ClinicalTrials.gov Identifier: NCT02344290.

Background: Heavy smokers are at increased risk for cardiovascular disease and may benefit from individualized risk quantification using routine lung cancer screening chest computed tomography. We investigated the prognostic value of deep learning-based automated epicardial adipose tissue quantification and compared it to established cardiovascular risk factors and coronary artery calcium., Methods: We investigated the prognostic value of automated epicardial adipose tissue quantification in heavy smokers enrolled in the National Lung Screening Trial and followed for 12.3 (11.9-12.8) years. The epicardial adipose tissue was segmented and quantified on non-ECG-synchronized, non-contrast low-dose chest computed tomography scans using a validated deep-learning algorithm. Multivariable survival regression analyses were then utilized to determine the associations of epicardial adipose tissue volume and density with all-cause and cardiovascular mortality (myocardial infarction and stroke)., Results: Here we show in 24,090 adult heavy smokers (59% men; 61 ± 5 years) that epicardial adipose tissue volume and density are independently associated with all-cause (adjusted hazard ratios: 1.10 and 1.38; P < 0.001) and cardiovascular mortality (adjusted hazard ratios: 1.14 and 1.78; P < 0.001) beyond demographics, clinical risk factors, body habitus, level of education, and coronary artery calcium score., Conclusions: Our findings suggest that automated assessment of epicardial adipose tissue from low-dose lung cancer screening images offers prognostic value in heavy smokers, with potential implications for cardiovascular risk stratification in this high-risk population., (© 2024. The Author(s).)

Shortcomings of fixation have been reported as a source of graft failure in anterior cruciate ligament (ACL) reconstruction. While interference screws have long been used as fixation devices for ACL reconstruction, they are not without complications. Previous studies have highlighted the use of bone void filler as a fixation method; however, no biomechanical comparisons using soft tissue grafts with interference screws exist to our knowledge. The purpose of this study is to evaluate the fixation strength of a calcium phosphate cement bone void filler compared with screw fixation in an ACL reconstruction bone replica model with human soft tissue grafts. In total, 10 ACL grafts were constructed using semitendinosus and gracilis tendons harvested from 10 donors. Grafts were affixed with either an 8-10 mm × 23 mm polyether ether ketone interference screw ( n  = 5) or with approximately 8 mL of calcium phosphate cement ( n  = 5) into open cell polyurethane blocks. Graft constructs were tested to failure in cyclic loading under displacement control at a rate of 1 mm per second. When compared with screw construct, the cement construct showed a 978% higher load at yield, 228% higher load at failure, 181% higher displacement at yield, 233% higher work at failure, and a 545% higher stiffness. Normalized data for the screw constructs relative to the cement constructs from the same donor showed 14 ± 11% load at yield, 54 ± 38% load at failure, and 172 ± 14% graft elongation. The results of this study indicate that cement fixation of ACL grafts may result in a stronger construct compared with the current standard of fixation with interference screws. This method could potentially reduce the incidence of complications associated with interface screw placement such as bone tunnel widening, screw migration, and screw breakage., Competing Interests: All grafts used in this study were donated by the Musculoskeletal Transplant Foundation and all fixation methods were donated by Arthrex., (Thieme. All rights reserved.)

Abstract: Clonal hematopoiesis of indeterminate potential (CHIP), the clonal expansion of myeloid cells with leukemogenic mutations, results in increased coronary artery disease (CAD) risk. CHIP is more prevalent among people with HIV (PWH), but the risk factors are unknown. CHIP was identified among PWH in REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) using whole-exome sequencing. Logistic regression was used to associate sociodemographic factors and HIV-specific factors with CHIP adjusting for age, sex, and smoking status. In the studied global cohort of 4486 PWH, mean age was 49.9 (standard deviation [SD], 6.4) years; 1650 (36.8%) were female; and 3418 (76.2%) were non-White. CHIP was identified in 223 of 4486 (4.97%) and in 38 of 373 (10.2%) among those aged ≥60 years. Age (odds ratio [OR], 1.07; 95% confidence interval [CI], 1.05-1.09; P < .0001) and smoking (OR, 1.37; 95% CI, 1.14-1.66; P < .001) associated with increased odds of CHIP. Globally, participants outside of North America had lower odds of CHIP including sub-Saharan Africa (OR, 0.57; 95% CI, 0.4-0.81; P = .0019), South Asia (OR, 0.45; 95% CI, 0.23-0.80; P = .01), and Latin America/Caribbean (OR, 0.56; 95% CI, 0.34-0.87; P = .014). Hispanic/Latino ethnicity (OR, 0.38; 95% CI, 0.23-0.54; P = .002) associated with significantly lower odds of CHIP. Among HIV-specific factors, CD4 nadir <50 cells/mm3 associated with a 1.9-fold (95%CI, 1.21-3.05; P = .006) increased odds of CHIP, with the effect being significantly stronger among individuals with short duration of antiretroviral therapy (ART; OR, 4.15; 95% CI, 1.51-11.1; P = .005) (Pinteraction= .0492). Among PWH at low-to-moderate CAD risk on stable ART, smoking, CD4 nadir, North American origin, and non-Hispanic ethnicity associated with increased odds of CHIP. This trial was registered at www.ClinicalTrials.gov as NCT02344290., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Aims: Quality-of-care and safety of patients with suspected acute coronary syndrome (ACS) would benefit if management was independent of which high-sensitivity cardiac troponin (hs-cTn) assay was used for risk stratification. We aimed to determine the concordance of hs-cTn assays to risk-stratify patients with suspected ACS according to the European Society of Cardiology (ESC) 2020 Guidelines., Methods and Results: Blood samples were obtained at arrival and at 2 h from patients with suspected ACS using four hs-cTn assays. The patients were classified into rule-out/observe/rule-in strata based on the ESC 2020 Guidelines. Concordance was determined among the assays for rule-out/observe/rule-in strata. The prevalences of significant underlying disease (≥50% stenosis on coronary computed tomography or inducible myocardial ischaemia on stress testing) and adjudicated ACS, plus quality-of-care outcomes, were compared. Among 238 patients (52.7 ± 8.0 years; 40.3% female), the overall concordance across assays to classify patients into rule-out/observe/rule-in strata was 74.0% (176/238). Platforms significantly differed for rule-out (89.9 vs. 76.5 vs. 78.6 vs. 86.6%, P < 0.001) and observe strata (6.7 vs. 20.6 vs. 17.7 vs. 9.2%, P < 0.001), but not for rule-in strata (3.4 vs. 2.9 vs. 3.8 vs. 4.2%, P = 0.62). Among patients in ruled-out strata, 19.1-21.6% had significant underlying disease and 3.3-4.2% had ACS. The predicted disposition of patients and cost-of-care differed across the assays (all P < 0.001). When compared with observed strata, conventional troponin-based management and predicted quality-of-care outcomes significantly improved with hs-cTn-based strategies (direct discharge: 21.0 vs. 80.3-90.8%; cost-of-care: $3889 ± 4833 vs. $2578 ± 2896-2894 ± 4371, all P < 0.001)., Conclusion: Among individuals with suspected ACS, patient management may differ depending on which hs-cTn assay is utilized. More data are needed regarding the implications of inter-assay differences., Trail Registration: NCT01084239., Competing Interests: Conflict of interest: J.T.N. has received research funds from Roche Diagnostics, Ortho Diagnostics, and Alere/Biosite to the Massachusetts General Hospital unrelated to this research. W.F.P. has received grant support from Abbott, Boehringer Ingelheim, Braincheck, CSL Behring, Daiichi-Sankyo, ImmunArray, Janssen, Ortho Clinical Diagnostics, Portola, Relypsa, Roche, Salix, and Siemens; consulting income from Abbott, Astra-Zeneca, Bayer, Beckman, Boehringer Ingelheim, Ischemia Care, Dx, ImmunArray, Instrument Labs, Janssen, Nabriva, Ortho Clinical Diagnostics, Relypsa, Roche, Quidel, Salix, and Siemens; expert testimony from Johnson and Johnson; and reports stock/ownership interest for AseptiScope Inc., Brainbox Inc., Comprehensive Research Associates LLC, Emergencies in Medicine LLC, and Ischemia DX LLC unrelated to this research. M.T.L. reports funding to his institution from Astra-Zeneca/MedImmune and Kowa and consulting fees from PQBypass unrelated to this research. B.M. reports personal fees from Biotronik, Abbott, Astra-Zeneca, Boehringer Ingelheim, and Novartis and institutional grants from Medtronic and Boston Scientific unrelated to this research. J.L.J. is a Trustee of the American College of Cardiology; is a Board member of Imbria Pharmaceuticals; has received grant support from Abbott, Applied Therapeutics, Innolife, HeartFlow, Janssen, Novartis Pharmaceuticals, and Roche Diagnostics; has received consulting income from Abbott, Janssen, Novartis, Pfizer, Merck, and Roche Diagnostics; and participates in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Boehringer Ingelheim, CVRx, Intercept, Eidos, Janssen, and Takeda unrelated to this research. W.K. reports personal fees from AstraZeneca, Novartis, Pfizer, The Medicines Company, DalCor, Kowa, Amgen, Corvidia, Genentech, Esperion, Amarin, Daiichi-Sanky, OMEICOS, Novo Nordisk, and Sanofi and grants and non-financial support from Beckmann, Singulex, Abbott, and Roche Diagnostics unrelated to this research. M.F. was supported by the grant from the American Heart Association (Fellow to Faculty Award #13FTF16450001) and has received consulting income from Biograph, Inc., Siemens Healthineers, and Elucid unrelated to this research. U.H. reported receiving research support from Duke University (Abbott), HeartFlow, Kowa Company Limited, and MedImmune/Astrazeneca and receiving consulting fees from Duke University (NIH), Recor Medical, Clinical Cardiovascular Sciences, and MedTrace unrelated to this research. The remaining authors have reported nothing to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The skin of Arachis hypogaea L. (peanut or groundnut) is a rich source of polyphenols, which have been shown to exhibit a wider spectrum of noteworthy biological activities, including anticancer effects. However, the anticancer activity of peanut skin extracts against melanoma and colorectal cancer (CRC) cells remains elusive. In this study, we systematically investigated the cytotoxic, antiproliferative, pro-apoptotic, and anti-migration effects of peanut skin ethanolic extract and its fractions on melanoma and CRC cells. Cell viability results showed that the ethyl acetate fraction (AHE) of peanut skin ethanolic crude extract and one of the methanolic fractions (AHE-2) from ethyl acetate extraction exhibited the highest cytotoxicity against melanoma and CRC cells but not in nonmalignant human skin fibroblasts. AHE and AHE-2 effectively modulated the cell cycle-related proteins, including the suppression of cyclin-dependent kinase 4 (CDK4), cyclin-dependent kinase 6 (CDK6), phosphorylation of Retinoblastoma (p-Rb), E2F1, Cyclin A, and activation of tumor suppressor p53, which was associated with cell cycle arrest and paralleled their antiproliferative efficacies. AHE and AHE-2 could also induce caspase-dependent apoptosis and inhibit migration activities in melanoma and CRC cells. Moreover, it is noteworthy that autophagy, manifested by microtubule-associated protein light chain 3B (LC3B) conversion and the aggregation of GFP-LC3, was detected after AHE and AHE-2 treatment and provided protective responses in cancer cells. Significantly, inhibition of autophagy enhanced AHE- and AHE-2-induced cytotoxicity and apoptosis. Together, these findings not only elucidate the anticancer potential of peanut skin extracts against melanoma and CRC cells but also provide a new insight into autophagy implicated in peanut skin extracts-induced cancer cell death.

Perilla (Perilla frutescens) is a potential specific oilseed crop with an extremely high α-linolenic acid (ALA) content in its seeds. AP2/ERF transcription factors (TFs) play important roles in multiple biological processes. However, limited information is known about the regulatory mechanism of the AP2/ERF family in perilla's oil accumulation. In this research, we identified 212 AP2/ERF family members in the genome of perilla, and their domain characteristics, collinearity, and sub-genome differentiation were comprehensively analyzed. Transcriptome sequencing revealed that genes encoding key enzymes involved in oil biosynthesis (e.g., ACCs, KASII, GPAT, PDAT and LPAAT) were up-regulated in the high-oil variety. Moreover, the endoplasmic reticulum-localized FAD2 and FAD3 were significantly up-regulated in the high-ALA variety. To investigate the roles of AP2/ERFs in lipid biosynthesis, we conducted a correlation analysis between non-redundant AP2/ERFs and key lipid metabolism genes using WGCNA. A significant correlation was found between 36 AP2/ERFs and 90 lipid metabolism genes. Among them, 12 AP2/ERFs were identified as hub genes and showed significant correlation with lipid synthase genes (e.g., FADs, GPAT and ACSL) and key regulatory TFs (e.g., LEC2, IAA, MYB, UPL3). Furthermore, gene expression analysis identified three AP2/ERFs (WRI, ABI4, and RAVI) potentially playing an important role in the regulation of oil accumulation in perilla. Our study suggests that PfAP2/ERFs are important regulatory TFs in the lipid biosynthesis pathway, providing a foundation for the molecular understanding of oil accumulation in perilla and other oilseed crops., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Background: Pericoronary adipose tissue (PCAT) may influence plaque development through inflammatory mechanisms. We assessed PCAT density, as a measure of pericoronary inflammation, in relationship to coronary plaque among people with human immunodeficiency virus (HIV [PWH]) and to a matched control population., Methods: In this baseline analysis of 727 participants of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) Mechanistic Substudy, we related computed tomography-derived PCAT density to presence and extent (Leaman score) of coronary artery disease (CAD), noncalcified plaque, coronary artery calcium (CAC), and vulnerable plaque features using multivariable logistic regression analyses. We further compared the PCAT density between PWH and age, sex, body mass index, CAC score, and statin use-matched controls from the community-based Framingham Heart Study (N = 464), adjusting for relevant clinical covariates., Results: Among 727 REPRIEVE participants (age 50.8 ± 5.8 years; 83.6% [608/727] male), PCAT density was higher in those with (vs without) coronary plaque, noncalcified plaque, CAC >0, vulnerable plaque, and high CAD burden (Leaman score >5) (P < .001 for each comparison). PCAT density related to prevalent coronary plaque (adjusted odds ratio [per 10 HU]: 1.44; 95% confidence interval, 1.22-1.70; P < .001), adjusted for clinical cardiovascular risk factors, body mass index, and systemic immune/inflammatory biomarkers. Similarly, PCAT density related to CAC >0, noncalcified plaque, vulnerable plaque, and Leaman score >5 (all P ≤ .002). PCAT density was greater among REPRIEVE participants versus Framingham Heart Study (-88.2 ± 0.5 HU versus -90.6 ± 0.4 HU; P < .001)., Conclusions: Among PWH in REPRIEVE, a large primary cardiovascular disease prevention cohort, increased PCAT density independently associated with prevalence and severity of coronary plaque, linking increased coronary inflammation to CAD in PWH., Competing Interests: Potential conflicts of interest. B. F. reports institutional research support from AstraZeneca, MedImmune, and MedTrace, all outside of the submitted work. M. V. Z. reports grant support through her institution from NIH/NIAID and Gilead Sciences, Inc., relevant to the conduct of the study, as well as grants from NIH/NIAID and NIH/NHLBI (RO1AI123001 PI, R01 HL137562 PI, R01HL146267 PI, K24AI157882 PI, U01HL123336 Co-I, U01HL123336-06S2 Co-I, R01HL151283 Co-I) outside the submitted work; travel support from conference organizing committees for CROI and International Workshop for HIV and Women; and unpaid participation in DSMB for NIH-funded studies. A. L. reports institutional research support from NIH/NIA, outside of the submitted work. T. H. B. reports equity in Excision Bio Therapeutics and serves on its Scientific Advisory Board, outside the submitted work. G. S. B. reports research grants (R01HL157531, U01HL146382, R56HL152803, R01MD013493) and royalties from UpToDate.com. C. D. M. reports institutional research support by Lilly and personal fees from ViiV Healthcare, Pfizer, and Gilead Sciences for participation in advisory board meetings outside the submitted work. C. J. F. reports grant support through his institution from Gilead Sciences, ViiV Healthcare, GSK, Janssen, Abbvie, Merck, Amgen, and Cytodyn, outside the submitted work; and personal fees from Theratechnologies and ViiV for consulting and participation on Advisory Board unrelated to REPRIEVE with Theratechnologies and ViiV, and role as Chair on DSMB for Intrepid Study, outside the submitted work. J. A. A. reports institutional research support for clinical trials from Atea, Emergent Biosolutions, Frontier Technologies, Gilead Sciences, Glaxo Smith Kline, Janssen, Merck, Pfizer, Regeneron, and ViiV Healthcare and personal fees for data safety monitoring or advisory boards from Kintor Pharmaceuticals, Glaxo Smith Kline, and Merck; all outside the submitted work. J. S. C. reports consulting fees from Merck and Company. H. J. R. reports grants from NIH/NHLBI and Kowa Pharmaceuticals during the conduct of the study as well as grants from NIH/NIAID, and NIH/NHLBI, NIH/NIDDK, and NIH/NIA outside the submitted work. U. H. reports institutional research support from Kowa, AstraZeneca, MedImmune, and HeartFlow; consulting fees from Recor Medical, Stanford University, Clinical Cardiovascular Sciences, MedTrace Inc., and Rapid AI; stock or stock options in Cleerly Inc. as Chief Scientific Officer; and personal fees from Duke University, all outside of the submitted work. M. T. L. reports grant support through his institution from NIH/NHLIBI and Kowa Pharmaceuticals America, Inc., for the conduct of the study; institutional grant support from MedImmune, CRICO, Ionis, Johnson & Johnson Innovation, National Academy of Medicine, and Astrazeneca; and personal fees from PQBypass, outside of the current work. P. S. D. reports consulting fees from Foresite Labs; receipt of equipment or drugs from Kowa and Caption Health; and an institutional grant for HeartFlow (outside of the current work). S. K. G. reports grants from NIH, KOWA Pharmaceuticals, Gilead Sciences, and ViiV Healthcare during the conduct of the study as well as personal consulting fees from TheraTechnologies, Navidea, and ViiV Healthcare, and Marathon Asset Management outside the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Competing Interests: Disclosures of conflicts of interest: V.K.R. Grants from American Heart Association and Norn Group; stock or stock options in Alphabet, Apple, and NVIDIA. M.T.L. No relevant relationships.

Background: Hepatic steatosis, including nonalcoholic fatty liver disease (NAFLD), is common among people with HIV (PWH). We present baseline steatosis prevalence and cardiometabolic characteristics among REPRIEVE substudy participants., Methods: REPRIEVE is an international, primary cardiovascular disease prevention, randomized, controlled trial of pitavastatin calcium vs. placebo among 7769 PWH ages 40-75 years on antiretroviral therapy (ART) and with low-to-moderate cardiovascular risk. A subset of participants underwent noncontrast computed tomography, with hepatic steatosis defined as mean hepatic attenuation less than 40 HU or liver/spleen ratio less than 1.0, and NAFLD defined as steatosis in the absence of frequent alcohol use or viral hepatitis., Results: Of 687 evaluable persons, median age was 51 years, BMI 27 kg/m 2 , CD4 + T-cell count 607 cells/μl; 17% natal female sex, 36% Black, 24% Hispanic, and 98% HIV-1 RNA less than 400 copies/ml. Hepatic steatosis prevalence was 22% (149/687), and NAFLD 21% (96/466). Steatosis/NAFLD prevalence was higher in men and with older age, non-Black race, and higher BMI and waist circumference. Both were associated with BMI greater than 30 kg/m 2 , metabolic syndrome components, higher atherosclerotic cardiovascular disease (ASCVD) risk score, HOMA-IR, LpPLA-2 and hs-CRP, and lower high-density lipoprotein cholesterol. Of HIV-specific/ART-specific characteristics, only history of an AIDS-defining illness was more common among persons with steatosis/NAFLD. After adjusting for age, sex and race/ethnicity, BMI greater than 30 kg/m 2 , HOMA-IR greater than 2.0, Metabolic syndrome and each of its components were associated with NAFLD prevalence., Conclusion: In this cohort with controlled HIV and low-to-moderate cardiovascular risk, hepatic steatosis and NAFLD were common and associated with clinically relevant metabolic and inflammatory disturbances but not current HIV-related or ART-related factors., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To investigate the diagnostic value of liver imaging reporting and data system (LI-RADS) v2018 and other imaging features in dual-phenotype hepatocellular carcinoma (DPHCC), establish a prediagnostic model based on gadoxetic acid-enhanced MRI, and explore the prognostic significance after surgery of the DPHCC., Materials and Methods: Preoperative enhanced MRI findings and the clinical and pathological data of patients with surgically confirmed HCC were analysed retrospectively. Image analysis was based on LI-RADS v2018 and other image features. Univariate analysis was used to screen for predictive factors of DPHCC, and multivariate logistic regression analysis was used to determine the predictive factors. A regression diagnostic model was established. Receiver operating characteristic (ROC) curve analysis was used to determine the critical value, area under curve (AUC), and the corresponding 95% confidence interval (95% CI). The diagnostic performance was verified by fivefold cross-validation. Cox regression analysis was used to determine the prognostic factors associated with early recurrence after surgical resection., Results: In total, 158 patients were included, of whom 79 had DPHCC and 79 had non-DPHCC. Multivariate analysis showed that rim arterial phase hyperenhancement (Rim APHE) and targetoid restriction were independent risk factors for DPHCC (P < 0.05). The AUC (95% CI) of the model was 0.862 (0.807-0.918), sensitivity was 81.01%, and specificity was 89.874%. Cox regression analysis showed that DPHCC, microvascular invasion, tumour diameter, and an increase of alpha-fetoprotein were independent factors for recurrence., Conclusion: Rim APHE and targetoid restriction were sensitive imaging features of DPHCC before surgery, and the identification of DPHCC has important prognostic significance for early recurrence., (© 2023. Italian Society of Medical Radiology.)

Background: Increased renin angiotensin aldosterone system (RAAS) activity may contribute to excess cardiovascular disease in people with HIV (PWH). We investigated how RAAS blockade may improve myocardial perfusion, injury, and function among well-treated PWH., Methods: Forty PWH, on stable ART, without known heart disease were randomized to eplerenone 50 mg PO BID (n = 20) or identical placebo (n = 20) for 12 months. The primary endpoints were (1) myocardial perfusion assessed by coronary flow reserve (CFR) on cardiac PET or stress myocardial blood flow (sMBF) on cardiac MRI or (2) myocardial inflammation by extracellular mass index (ECMi) on cardiac MRI., Results: Beneficial effects on myocardial perfusion were seen for sMBF by cardiac MRI (mean [SD]: 0.09 [0.56] vs -0.53 [0.68] mL/min/g; P = .03) but not CFR by cardiac PET (0.01 [0.64] vs -0.07 [0.48]; P = .72, eplerenone vs placebo). Eplerenone improved parameters of myocardial function on cardiac MRI including left ventricular end diastolic volume (-13 [28] vs 10 [26] mL; P = .03) and global circumferential strain (GCS; median [interquartile range 25th-75th]: -1.3% [-2.9%-1.0%] vs 2.3% [-0.4%-4.1%]; P = .03), eplerenone versus placebo respectively. On cardiac MRI, improvement in sMBF related to improvement in global circumferential strain (ρ = -0.65, P = .057) among those treated with eplerenone. Selecting for those with impaired myocardial perfusion (CFR <2.5 and/or sMBF <1.8), there was a treatment effect of eplerenone versus placebo to improve CFR (0.28 [0.27] vs -0.05 [0.36]; P = .04). Eplerenone prevented a small increase in troponin (0.00 [-0.13-0.00] vs 0.00 [0.00-0.74] ng/L; P = .03) without effects on ECMi (0.9 [-2.3-4.3] vs -0.7 [-2.2--0.1] g/m2; P = .38). CD4+ T-cell count (127 [-38-286] vs -6 [-168-53] cells/μL; P = .02) increased in the eplerenone- versus placebo-treated groups., Conclusions: RAAS blockade with eplerenone benefitted key indices and prevented worsening of myocardial perfusion, injury, and function among PWH with subclinical cardiac disease when compared with placebo., Clinical Trials Registration: NCT02740179 (https://clinicaltrials.gov/ct2/show/NCT02740179?term=NCT02740179&draw=2&rank=1)., Competing Interests: Potential conflicts of interest. S. S. was the recipient of a Gilead Sciences Research Scholars award. M. T. L. has received research funding from KOWA, MedImmune, AstraZeneca, Ionis, and Johnson & Johnson Innovation. T. H. B. is a paid member of the Scientific Advisory Board and has equity in Excision BioTherapeutics, Inc. C. R. d. receives consulting fees from Abbott Diagnostics, Quidel/Ortho, Roche Diagnostics, and Siemens Diagnostics. G. K. R. has received trials support from Leonard Meron Biosciences and consulting fees from Teradyne for clinical trial design and from SEED for COVID consulting. He is also an unpaid panel member of the Department of Health and Human Services (DHHS) Opportunistic Infections guidelines review committee and has provided expert medical review testimony for Tufts Medical Center. G. K. R. also reports unpaid participation on a Data Safety Monitoring Board or Advisory Board for Arterial Inflammation and Coronary Microvascular Dysfunction among Women with HIV: Missing Pieces to the MI Risk Puzzle (grant number R01HL146267). S. K. G. has received research funding from KOWA, Gilead, ViiV, and Theratechnologies and received consulting fees from Theratechnologies and ViiV. He is a member of the Scientific Advisory Board of Marathon Asset Management. M. D. reports grants or contracts paid to institutions from Gilead Sciences and Spectrum Dynamics; consulting fees from Sanofi and MedTrace Pharma; and receipt of equipment, materials, drugs, medical writing, gifts, or other services from Amgen. All disclosures are unrelated to this manuscript. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Skeletal muscle quality and mass are important for maintaining physical function during advancing age. We leveraged baseline data from Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) to evaluate whether paraspinal muscle density and muscle area are associated with cardiac or physical function outcomes in people with HIV (PWH)., Methods: REPRIEVE is a double-blind randomized trial evaluating the effect of pitavastatin for primary prevention of major adverse cardiovascular events in PWH. This cross-sectional analysis focuses on participants who underwent coronary computed tomography at baseline. Lower thoracic paraspinal muscle density (Hounsfield units [HU]) and area (cm 2 ) were assessed on noncontrast computed tomography., Results: Of 805 PWH, 708 had paraspinal muscle measurements. The median age was 51 years and 17% were natal female patients. The median muscle density was 41 HU (male) and 30 HU (female); area 13.2 cm 2 /m (male) and 9.9 cm 2 /m (female). In adjusted analyses, greater density (less fat) was associated with a lower prevalence of any coronary artery plaque, coronary artery calcium score >0, and high plaque burden ( P = 0.06); area was not associated with plaque measures. Among 139 patients with physical function measures, greater area (but not density) was associated with better performance on a short physical performance battery and grip strength., Conclusions: Among PWH, greater paraspinal muscle density was associated with a lower prevalence of coronary artery disease while greater area was associated with better physical performance. Whether changes in density or area are associated with changes in CAD or physical performance will be evaluated through longitudinal analyses in REPRIEVE., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Plasma vascular endothelial growth factor (VEGF) coreceptor neuropilin-1 (NRP-1) had the largest association with coronary plaque in the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) proteomics analysis. With little known about NRP-1 in people with human immunodeficiency virus (PWH), we explored its relation to other proteins in REPRIEVE and validated our findings through a Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) case-cohort study by assessing its relation to host factors and incident cardiovascular disease and cancer. Within REPRIEVE, NRP-1 was associated with proteins involved in angiogenesis, signal transduction, immunoregulation, and cell migration/adhesion. Within CNICS, NRP-1 was associated with key host factors, including older age and male sex. NRP-1 was associated with an increased hazard of multiple cancers but a decreased prostate cancer risk. Finally, NRP-1 was most strongly associated with mortality and type 2 myocardial infarction. These data suggest that NRP-1 is part of a clinically relevant immunoregulatory pathway related to multiple comorbidities in PWH. Clinical Trials Registration . NCT02344290., Competing Interests: Potential conflicts of interest. S. R. S. reports grant support through his institution from NIH/NIAID. M. V. Z. reports grant support through her institution from NIH/NIAID and Gilead Sciences, relevant to the conduct of the study, and grants from NIH/NIAID and NIH/NHLBI, outside the submitted work. M. T. reports grant support from NIH/NHLBI, American Heart Association, and Robert Wood Johnson Foundation, outside the submitted work. C. J. F. reports grant support through his institution from Gilead Sciences, ViiV Healthcare, GSK, Janssen, AbbVie, Merck, Amgen, and Cytodyn, outside the submitted work. J. J. E. reports grant support through his institution from Gilead Sciences, ViiV Healthcare, and Janssen and personal fees from ViiV Healthcare, Merck, and Gilead Sciences, outside the submitted work. J. M. J. reports grant support through his institution from NIH/NIAID. K. H. M. reports unrestricted research grants to his institution from Gilead Sciences, Merck, and ViiV Healthcare and has served on scientific advisory boards for Gilead and Merck, outside the submitted work. C. M. reports institutional research support by Lilly and honoraria from ViiV Healthcare and Gilead Sciences for advisory board membership, outside the submitted work. R. D. M. reports grant support to his institution from NIH/NIAID and NIH/National Institute on Drug Abuse (NIDA) relevant to the conduct of the study. T. U. reports grant support from NIH/NHLBI and Kowa Pharmaceuticals during the conduct of the study and grants from NIH/NIAID and NIH/National Institute on Aging (NIA), outside the submitted work. M. S. S. reports grant support from NIH/NIAID relevant to the conduct of the study. J. A. A. reports institutional research support for clinical trials from Emergent Biosolutions, Frontier Technologies, Gilead Sciences, GlaxoSmithKline, Janssen, Macrogenics, Merck, Pfizer, Regeneron, and ViiV Healthcare; personal fees for advisory boards from GlaxoSmithKline and Merck; and data and safety monitoring board membership for Kintor Pharmaceuticals, outside the submitted work. J. S. C. reports consulting fees from Merck and Co and Resvirlogix. J. A. C. D. reports through to his institution from NIH/NHLBI, outside the submitted work. H. J. R. reports grants from NIH/NIAID and NIH/NHLBI during the conduct of the study, as well as grants from NIH/NIAID, NIH/NHLBI, NIH/National Institute of Diabetes and Digestive and Kidney Diseases, and NIH/NIA, outside the submitted work. H. M. C. reports grants from NIH/NHLBI during the conduct of this study; grants through her institution from NIH/NIDA, the Agency for Healthcare Research and Quality, and ViiV Healthcare; and advisory board membership for Gilead, outside the submitted work. P. W. H. reports grant support through his institution from Gilead Sciences; drug donation for an NIH-sponsored clinical trial he is leading from Merck; and personal fees from ViiV Healthcare, Gilead Sciences, and Merck. S. K. G. reports grant support through his institution from Kowa Pharmaceuticals America, Gilead Sciences, and ViiV Healthcare for the conduct of the study; and grants from Theratechnologies and Navidea, personal fees from Theratechnologies and ViiV, and service on the scientific advisory board of Marathon Asset Management, all outside the submitted work. All other authors report no potential conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: The aminoquinoline core exhibits versatile pharmacological properties, particularly in the area of anticancer activity. This study was designed to investigate the potential of the 4-aminoquinoline scaffold in the development of anticancer agents by targeting the HIF-1α signaling pathway. Methodology: The authors synthesized multiple derivatives of 4-aminoquinoline containing heterocyclic rings by a microwave reactor and assessed the cytotoxicity and inhibitory effects of these derivatives on the HIF-1α signaling pathway. Conclusion: Compound 3s was identified as the most promising HIF-1α inhibitor due to its exceptional antiproliferative effects, with IC 50 values of 0.6 and 53.3 nM observed in MiaPaCa-2 and MDA-MB-231 cells, respectively. Furthermore, compound 3s was found to inhibit HIF-1α expression by decreasing the level of HIF-1α mRNA.

Background: The risk of cardiovascular disease is increased among persons with human immunodeficiency virus (HIV) infection, so data regarding primary prevention strategies in this population are needed., Methods: In this phase 3 trial, we randomly assigned 7769 participants with HIV infection with a low-to-moderate risk of cardiovascular disease who were receiving antiretroviral therapy to receive daily pitavastatin calcium (at a dose of 4 mg) or placebo. The primary outcome was the occurrence of a major adverse cardiovascular event, which was defined as a composite of cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke, transient ischemic attack, peripheral arterial ischemia, revascularization, or death from an undetermined cause., Results: The median age of the participants was 50 years (interquartile range, 45 to 55); the median CD4 count was 621 cells per cubic millimeter (interquartile range, 448 to 827), and the HIV RNA value was below quantification in 5250 of 5997 participants (87.5%) with available data. The trial was stopped early for efficacy after a median follow-up of 5.1 years (interquartile range, 4.3 to 5.9). The incidence of a major adverse cardiovascular event was 4.81 per 1000 person-years in the pitavastatin group and 7.32 per 1000 person-years in the placebo group (hazard ratio, 0.65; 95% confidence interval [CI], 0.48 to 0.90; P = 0.002). Muscle-related symptoms occurred in 91 participants (2.3%) in the pitavastatin group and in 53 (1.4%) in the placebo group; diabetes mellitus occurred in 206 participants (5.3%) and in 155 (4.0%), respectively., Conclusions: Participants with HIV infection who received pitavastatin had a lower risk of a major adverse cardiovascular event than those who received placebo over a median follow-up of 5.1 years. (Funded by the National Institutes of Health and others; REPRIEVE ClinicalTrials.gov number, NCT02344290.)., (Copyright © 2023 Massachusetts Medical Society.)

Grape ripe rot, which is predominantly caused by the Colletotrichum species, presents a growing threat to global grape cultivation. This threat is amplified by the increasing populations of the Colletotrichum species in response to warmer climates. In this review, we investigate the wide-ranging spectrum of grape ripe rot, specifically highlighting the role and characteristics of the C. gloeosporioides species complex (CGSC). We incorporate this understanding as we explore the diverse symptoms that lead to infected grapevines, their intricate life cycle and epidemiology, and the escalating prevalence of C. viniferum in Asia and globally. Furthermore, we delve into numerous disease management strategies, both conventional and emerging, such as prevention and mitigation measures. These strategies include the examination of host resistances, beneficial cultivation practices, sanitation measures, microbiome health maintenance, fungicide choice and resistance, as well as integrated management approaches. This review seeks to enhance our understanding of this globally significant disease, aspiring to assist in the development and improvement of effective prevention and control strategies.

Background: Persons with well-treated human immunodeficiency virus (HIV) demonstrate a 2-fold higher risk of cardiovascular disease (CVD), which may be related to excess visceral adipose tissue (VAT). The visceral adiposity index (VAI) is a score to approximate VAT by combining biochemical measures with anthropometrics without quantification by imaging. We evaluated VAI in association with cardiometabolic factors among persons with HIV (PWH)., Methods: Forty-five PWH on antiretroviral therapy and virologically controlled with increased abdominal VAT (VAT area >110 cm 2 on CT) and no known CVD were included. VAI was calculated using standard sex-specific formulas. Coronary plaque was assessed using coronary CT angiography., Results: Participants were predominantly male (73%), white (53%), and non-Hispanic (84%), with a mean age of 55 (standard deviation, 7) years. Among PWH, median VAI was calculated to be 4.9 (interquartile range [IQR], 2.8-7.3). Log VAI correlated with log VAT ( r = 0.59, P < .0001) and anthropometric measures (body mass index: r = 0.36, P = .02; waist circumference: r = 0.43, P = .004; waist-to-hip ratio: r = 0.33, P = .03). Participants with coronary plaque had a higher VAI compared to those without coronary plaque (median, 5.3 [IQR, 3.4-10.5] vs 2.8 [IQR, 1.8-5.0]; P = .004). VAI (area under the curve = 0.760, P = .008) performed better than the atherosclerotic CVD risk score to predict the presence of plaque in receiver operating characteristic analyses., Conclusions: VAI may be a useful biomarker of metabolic dysfunction and increased CVD risk that may occur with VAT accumulation in PWH., Clinical Trials Registration: NCT02740179., Competing Interests: Potential conflicts of interest. S. S. was the recipient of a Gilead Sciences Research Scholars award. M. T. L. has received research funding from KOWA, MedImmune, AstraZeneca, Ionis, and Johnson & Johnson Innovation. S. K. G. has received research funding from KOWA, Gilead, ViiV, and Theratechnologies; has received consulting fees from Theratechnologies and ViiV; and is a member of the scientific advisory board of Marathon Asset Management, all unrelated to the present work. All other authors report no potential conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objectives: To compare the prognostic value of individual CT-derived coronary artery disease (CAD) characteristics across categories of clinical cardiovascular risk., Methods: The central core laboratory assessed coronary artery calcium (CAC), obstructive CAD (stenosis ≥ 50%), and high-risk plaque (HRP) in stable outpatients with suspected CAD enrolled in the PROMISE trial. Multivariable Cox regression models (endpoint: unstable angina, nonfatal myocardial infarction, or all-cause mortality; median follow-up: 2 years) were used to compare hazard ratios (HR) of the CT measures between low-borderline (< 7.5%) and moderate-high (≥ 7.5%) atherosclerotic cardiovascular disease (ASCVD) risk based on the pooled cohort equation., Results: Among 4356 included patients (aged 61 ± 8 years, 52% women), 67% had ASCVD risk ≥ 7.5%. Stratified by ASCVD risk, CAD ≥ 50% had nearly threefold greater HR in individuals with ASCVD < 7.5% (aHR, 6.85; 95% CI, 2.33-20.15; p < 0.001) vs. ASCVD ≥ 7.5% (aHR: 2.66, 95% CI: 1.67-4.25, p < 0.001; interaction p = 0.041). CAC predicted events solely in ASCVD ≥ 7.5% patients (aHR: 1.92, 95% CI: 1.01-3.63, p = 0.045; interaction p = 0.571), while HRP predicted events only in ASCVD < 7.5% (aHR: 3.11, 95% CI: 1.09-8.85, p = 0.034; interaction p = 0.034)., Conclusions: Prognostic values of CT-derived CAD characteristics differ by ASCVD risk categories. While CAD ≥ 50% has the highest prognostic value regardless of ASCVD risk, CAC is prognostic in high and HRP in low ASCVD risk. These findings suggest that CAD ≥ 50% and HRP detection rather than CAC scoring may better risk-stratify symptomatic low-risk patients and thus potentially improve downstream care., Key Points: • Prognostic value of individual CT-derived CAD characteristics differs by categories of cardiovascular risk. • Presence of obstructive coronary artery stenosis ≥ 50% has the highest prognostic value regardless of cardiovascular risk. • Coronary artery calcium is independently prognostic in high and high-risk plaque features in low cardiovascular risk., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Prevention and management of chronic lung diseases (asthma, lung cancer, etc.) are of great importance. While tests are available for reliable diagnosis, accurate identification of those who will develop severe morbidity/mortality is currently limited. Here, we developed a deep learning model, CXR Lung-Risk, to predict the risk of lung disease mortality from a chest x-ray. The model was trained using 147,497 x-ray images of 40,643 individuals and tested in three independent cohorts comprising 15,976 individuals. We found that CXR Lung-Risk showed a graded association with lung disease mortality after adjustment for risk factors, including age, smoking, and radiologic findings (Hazard ratios up to 11.86 [8.64-16.27]; p < 0.001). Adding CXR Lung-Risk to a multivariable model improved estimates of lung disease mortality in all cohorts. Our results demonstrate that deep learning can identify individuals at risk of lung disease mortality on easily obtainable x-rays, which may improve personalized prevention and treatment strategies., (© 2023. The Author(s).)

Objective: To investigate relationships between Life's Simple 7 (LS7), an assessment of cardiovascular health (CVH), and coronary plaque among people with HIV (PWH)., Design: Cross-sectional., Methods: Coronary computed tomography angiography, immune/inflammatory biomarkers, and characterization of LS7 were collected among a subset of ART-treated PWH enrolled in REPRIEVE, a primary prevention trial. Analyses adjusted for cardiovascular disease risk (ASCVD score)., Results: Median age of the 735 participants was 51(±6) years, 16% female, and median (Q1-Q3) CVD risk was 4.5% (2.6-6.9). Forty percent had poor (≤2 ideal components), 51% had intermediate (three or four ideal components), and only 9% had ideal CVH (≥5). Coronary plaque was present in 357 (49%); 167 (23%) had one or more vulnerable plaque features, 293 (40%) had noncalcified plaque, and 242 (35%) had a coronary artery calcium score >0. All three phenotypes were increasingly more prevalent with poorer CVH and these relationships remained after adjusting for ASCVD risk. Poor CVH was associated with higher high-sensitivity C-reactive protein, oxidized low-density cholesterol, and interleukin-6. The relationship of LS7 to plaque remained after adjusting for these biomarkers., Conclusions: Among PWH, poor CVH as measured by LS7 was associated with coronary plaque presence, vulnerable features, and calcification. LS7 was also associated with selected biomarkers; adjustment for these and ASCVD score reduced but did not eliminate LS7's association with plaque, suggesting the possibility of additional protective mechanisms against atherogenesis and plaque remodeling. Clinical use of LS7 and further exploration of its relationships with coronary artery disease may enhance efforts to reduce cardiovascular morbidity and mortality in PWH., Clinical Trials Registration: NCT02344290., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Inflammasome activation is increased in people with human immunodeficiency virus (PWH), but its relationship with coronary plaque is poorly understood in this setting., Methods: In a large human immunodeficiency virus cardiovascular prevention cohort, relationships between caspase-1, interleukin (IL)-1β, and IL-18 and coronary plaque indices were assessed by multivariate logistic regression., Results: Higher IL-18 and IL-1β were associated with Leaman score, an integrative measure of plaque burden and composition., Conclusions: As Leaman score >5 is associated with cardiovascular events in the general population, future work is needed to determine how the inflammasome relates to events and whether strategies to reduce its activation affect events or plaque progression among PWH., Competing Interests: Potential conflicts of interest. SRS reports grant support through his institution from NIH/NIAID. THS reports grant support through her institution from NIH/NIAID and NIH/National Institute of Allergy and Infectious Diseases outside the submitted work. THB reports equity in Excision BioTherapeutics and serves on their Scientific Advisory Board, outside the submitted work. JTS reports grant support through his institution from NIH/NIAID, the US Department of Veterans Affairs, HRSA (Ryan White HIV/AIDS Program), and Abbvie, DSMB service for Transposon Therapeutics, Inc., and honoraria for lectures at Iowa State University, all outside the submitted work. JLC reports honoraria for presentations for Gilead, MSD, and Janssen and advisory board membership for ViiV Healthcare and Gilead Sciences, all outside the submitted work. JT reports funding by Deutsche Forschungsgesellschaft ([DFG], German Research Foundation), speakers bureau for Siemens Healthcare GmbH and Bayer AG, reviewer for Universimed Cross Media Content GmbH, and consultant for Core Lab Black Forrest GmbH, all outside the submitted work. JSC reports consulting fees from Merck, outside the submitted work. MVZ reports grant support through her institution from NIH/NIAID and Gilead Sciences, Inc. relevant to the conduct of the study, as well as grants from NIH/NIAID and NIH/National Heart, Lung, and Blood Institute (NHLBI) outside the submitted work. CM reports institutional research support by Lilly and honoraria from ViiV Healthcare and Gilead Sciences for advisory board membership, all outside the submitted work. CJF reports grant support through his institution from Gilead Sciences, ViiV Healthcare, GSK, Janssen, Abbvie, Merck, Amgen, and Cytodyn; personal fees from Theratechnologies and ViiV for consulting and participation on Advisory Board unrelated to REPRIEVE; and DSMB Chair for Intrepid Study, all outside the submitted work. JAA reports institutional research support for clinical trials from Atea, Emergent Biosolutions, Frontier Technologies, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Pfizer, Regeneron, and ViiV Healthcare and personal fees for advisory boards from GlaxoSmithKline/ViiV and Merck; and participation on DSMB for Kintor Pharmaceuticals, all outside the submitted work. HJR reports grants from NIH/NHLBI and Kowa Pharmaceuticals during the conduct of the study, as well as grants from NIH/NIAID, NIH/NHLBI, NIH/National Institute of Diabetes and Digestive and Kidney Diseases, and NIH/National Institute on Aging, outside the submitted work. MTL reports grant support through his institution from Kowa Pharmaceuticals America, Inc., for the conduct of the study. He also reports grant support from MedImmune/AstraZeneca and personal fees from PQBypass, outside of the current work. SKG reports grant support through his institution from NIH, Kowa Pharmaceuticals America, Inc., Gilead Sciences, Inc., and ViiV Healthcare for the conduct of the study; personal fees from Theratechnologies and ViiV; and service on the Scientific Advisory Board of Marathon Asset Management, all outside the submitted work. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Cytomegalovirus (CMV) infection is thought to result in increased immune activation in people with human immunodeficiency virus (HIV, PWH). Although some data have linked asymptomatic CMV infection to cardiovascular disease among PWH, it remains unknown whether CMV is associated with increased or high-risk coronary plaque., Methods: The Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) enrolled PWH aged 40-75 years on stable antiretroviral therapy (ART) with low-to-moderate atherosclerotic cardiovascular disease (ASCVD) risk. Among a subset of US REPRIEVE participants, coronary plaque was assessed by coronary computed tomography angiography. Here, we assessed the relationship between CMV immunoglobulin G (IgG) titer and (1) levels of immune activation, (2) inflammatory biomarkers, and (3) coronary plaque phenotypes at study entry., Results: Of 672 participants, mean age was 51 years, 83% were men, median ASCVD risk score was 4.5%, and 66% had current CD4+ T-cell count ≥500 cells/mm3. Higher CMV IgG quartile group was associated with older age and lower current and nadir CD4+ T-cell counts. CMV IgG titer was associated with specific inflammatory biomarkers (sCD163, MCP-1, interleukin [IL]-6, hsCRP) in univariate analysis, but not after controlling for HIV-specific factors. In contrast, CMV IgG titer was not associated with coronary artery disease indexes, including presence of plaque, coronary artery calcium (CAC) score >0, vulnerable plaque presence, or Leaman score >5., Conclusions: No meaningful association was seen between CMV IgG titer and coronary artery disease indexes among ART-treated PWH at study enrollment. Longitudinal assessments in REPRIEVE will determine the relationship of CMV IgG titer to plaque progression and cardiovascular events., Clinical Trials Registration: NCT02344290., Competing Interests: Potential conflicts of interest. The views expressed in this article are those of the authors and do not necessarily represent the views of the NHLBI, the NIAID, the NIH, or the US Department of Health and Human Services. S. R. S. reports grant support through his institution from NIH/NIAID. M. T. L. reports grant support through his institution from Kowa Pharmaceuticals America, Inc, for the conduct of the study. He also reports grant support from MedImmune/Astrazeneca and personal fees from PQBypass outside of the current work. T. H. B. reports equity in Excision BioTherapeutics and serves on their Scientific Advisory Board, outside the submitted work. M. V. Z. reports grant support through her institution from NIH/NIAID and Gilead Sciences, Inc, relevant to the conduct of the study, as well as grants from NIH/NIAID and NIH/NHLBI outside the submitted work: RO1AI123001 PI, U01HL123336 Co-I, R01 HL137562 PI, U01HL123336-06S2 Co-I, R01HL146267 PI, R01HL151283 Co-I, K24AI157882 PI. M. V. Z. also reports support for attending meetings and/or travel from CROI and International Workshop for HIV and Women from conference organizing committee when abstract reviewer and/or speaker; unpaid participation on DSMB for NIH funded studies. B. F. reports unrelated grant support paid to institution from NIH/NHLBI, MedImmune/Astrazeneca, and MedTrace. C. M. reports grants to institution from Gilead Sciences, unrelated to this work, participation on Advisory Boards for ViiV Healthcare and Gilead Sciences, and no other disclosures. C. J. F. reports grant support through his institution from Gilead Sciences, ViiV Healthcare, GSK, Janssen, Abbvie, Merck, Amgen, and Cytodyn, outside the submitted work, and participation as Chair of DSMB for Intrepid Study. J. A. A. reports institutional research support for clinical trials from Atea, Emergent Biosolutions, Frontier Technologies, Gilead Sciences, Glaxo Smith Kline, Janssen, Merck, Pfizer, Regeneron, and ViiV Healthcare and personal fees for advisory boards from Glaxo Smith Kline/ViiV and Merck, and participation on a DSMB for Kintor; all outside the submitted work. E. T. O. reports grant support through his institution from NIH, Gilead, ViiV, and GSK, personal fees from Merck, ViiV Healthcare, and Theratechnologies, outside the submitted work, and roles as chair of Comorbidity Transformational Science Group for NIH-funded ACTG and as member of Scientific Review Committee for NIH-funded HVTN. J. C. reports consulting fees from Merck and Company (11/2021) and Resvirlogix. B. E. S. reports grant support through her institution from ViiV Healthcare and Gilead (Focus grant) outside the submitted work. H. J. R. reports grants from NIH/NIAID and NIH/NHLBI during the conduct of the study, as well as grants from NIH/NIAID, NIH/NHLBI, NIH/NIDDK, and NIH/NIA, outside the submitted work. K. M. E. reports grant support from Gilead Sciences, Inc., and consulting fees from Gilead Sciences, Inc, ViiV Pharmaceuticals America, Inc., and Janssen Therapeutics (all paid to the University of Colorado), and participation on DSMB for NIH study (paid to institution), outside the submitted work. S. K. G. reports grant support through his institution from Kowa Pharmaceuticals America, Inc, Gilead Sciences, Inc, and ViiV Healthcare for the conduct of the study, as well as grants from Theratechnologies and Navidea and personal fees from Theratechnologies Consulting and ViiV Consulting and Navidea, all outside the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background Patients presenting to the emergency department (ED) with acute chest pain (ACP) syndrome undergo additional testing to exclude acute coronary syndrome (ACS), pulmonary embolism (PE), or aortic dissection (AD), often yielding negative results. Purpose To assess whether deep learning (DL) analysis of the initial chest radiograph may help triage patients with ACP syndrome more efficiently. Materials and Methods This retrospective study used electronic health records of patients with ACP syndrome at presentation who underwent a combination of chest radiography and additional cardiovascular or pulmonary imaging or stress tests at two hospitals (Massachusetts General Hospital [MGH], Brigham and Women's Hospital [BWH]) between January 2005 and December 2015. A DL model was trained on 23 005 patients from MGH to predict a 30-day composite end point of ACS, PE, AD, and all-cause mortality based on chest radiographs. Area under the receiver operating characteristic curve (AUC) was used to compare performance between models (model 1: age + sex; model 2: model 1 + conventional troponin or d-dimer positivity; model 3: model 2 + DL predictions) in internal and external test sets from MGH and BWH, respectively. Results At MGH, 5750 patients (mean age, 59 years ± 17 [SD]; 3329 men, 2421 women) were evaluated. Model 3, which included DL predictions, significantly improved discrimination of those with the composite outcome compared with models 2 and 1 (AUC, 0.85 [95% CI: 0.84, 0.86] vs 0.76 [95% CI: 0.74, 0.77] vs 0.62 [95% CI: 0.60 0.64], respectively; P < .001 for all). When using a sensitivity threshold of 99%, 14% (813 of 5750) of patients could be deferred from cardiovascular or pulmonary testing for differential diagnosis of ACP syndrome using model 3 compared with 2% (98 of 5750) of patients using model 2 ( P < .001). Model 3 maintained its diagnostic performance in different age, sex, race, and ethnicity groups. In external validation at BWH (22 764 patients; mean age, 57 years ± 17; 11 470 women), trends were similar and improved after fine tuning. Conclusion Deep learning analysis of chest radiographs may facilitate more efficient triage of patients with acute chest pain syndrome in the emergency department. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Goo in this issue.

Background: Among people with HIV (PWH), sex differences in presentations of atherosclerotic cardiovascular disease (ASCVD) may be influenced by differences in coronary plaque parameters, immune/inflammatory biomarkers, or relationships therein., Methods: REPRIEVE, a primary ASCVD prevention trial, enrolled antiretroviral therapy (ART)-treated PWH. At entry, a subset of US participants underwent coronary computed tomography angiography (CTA) and immune phenotyping (n = 755 CTA; n = 725 CTA + immune). We characterized sex differences in coronary plaque and immune/inflammatory biomarkers and compared immune-plaque relationships by sex. Unless noted otherwise, analyses adjust for ASCVD risk score., Results: The primary analysis cohort included 631 males and 124 females. ASCVD risk was higher among males (median: 4.9% vs 2.1%), while obesity rates were higher among females (48% vs 21%). Prevalence of any plaque and of plaque with either ≥1 visible noncalcified portion or vulnerable features (NC/V-P) was lower among females overall and controlling for relevant risk factors (RR [95% CI] for any plaque: .67 [.50, .92]; RR for NC/V-P: .71 [.51, 1.00] [adjusted for ASCVD risk score and body mass index]). Females showed higher levels of IL-6, hs-CRP, and D-dimer and lower levels of Lp-PLA2 (P < .001 for all). Higher levels of Lp-PLA2, MCP-1, and oxLDL were associated with higher plaque (P < .02) and NC/V-P prevalence, with no differences by sex. Among females but not males, D-dimer was associated with higher prevalence of NC/V-P (interaction P = .055)., Conclusions: Among US PWH, females had a lower prevalence of plaque and NC/V-P, as well as differences in key immune/inflammatory biomarkers. Immune-plaque relationships differed by sex for D-dimer but not other tested parameters. Clinical Trial Registration. ClinicalTrials.gov; identifier: NCT0234429 (date of initial registration: 22 January 2015)., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: The Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) estimates mortality risk only for certain common procedures (eg, coronary artery bypass or valve surgery) and is cumbersome, requiring greater than 60 inputs. We hypothesized that deep learning can estimate postoperative mortality risk based on a preoperative chest radiograph for cardiac surgeries in which STS-PROM scores were available (STS index procedures) or unavailable (non-STS index procedures)., Methods: We developed a deep learning model (CXR-CTSurgery) to predict postoperative mortality based on preoperative chest radiographs in 9283 patients at Massachusetts General Hospital (MGH) having cardiac surgery before April 8, 2014. CXR-CTSurgery was tested on 3615 different MGH patients and externally tested on 2840 patients from Brigham and Women's Hospital (BWH) having surgery after April 8, 2014. Discrimination for mortality was compared with the STS-PROM using the C-statistic. Calibration was assessed using the observed-to-expected ratio (O/E ratio)., Results: For STS index procedures, CXR-CTSurgery had a C-statistic similar to STS-PROM at MGH (CXR-CTSurgery: 0.83 vs STS-PROM: 0.88; P = .20) and BWH (0.74 vs 0.80; P = .14) testing cohorts. The CXR-CTSurgery C-statistic for non-STS index procedures was similar to STS index procedures in the MGH (0.87 vs 0.83) and BWH (0.73 vs 0.74) testing cohorts. For STS index procedures, CXR-CTSurgery had better calibration than the STS-PROM in the MGH (O/E ratio: 0.74 vs 0.52) and BWH (O/E ratio: 0.91 vs 0.73) testing cohorts., Conclusions: CXR-CTSurgery predicts postoperative mortality based on a preoperative CXR with similar discrimination and better calibration than the STS-PROM. This may be useful when the STS-PROM cannot be calculated or for non-STS index procedures., (Copyright © 2023 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: REPRIEVE, the Randomized Trial to Prevent Vascular Events in HIV, is a multicenter, primary prevention trial evaluating whether a statin can prevent major cardiovascular events in people with HIV. REPRIEVE is conducted at >100 clinical research sites (CRSs) globally. Detailed, comprehensive, and novel methods for evaluating and communicating CRS performance are required to ensure trial integrity and data quality. In this analysis we describe a comprehensive multidimensional methodology for evaluating CRS performance., Methods: The REPRIEVE Data Coordinating and Clinical Coordinating Centers developed a robust system for evaluation of and communication with CRSs, designed to identify potential issues and obstacles to performance, provide real-time technical support, and make recommendations for process improvements to facilitate efficient trial execution. We describe these systems and evaluate their impact on participant retention, data management, and specimen management from 2019 to 2022, corresponding to the period from end of recruitment to present. This evaluation was based on pre-defined metrics, regular reviews, and bidirectional communication., Results: Participant retention, data management, and specimen management all remained steady over the three-year period, although metrics varied by country of enrollment. Targeted messaging relating to certain performance metrics was effective., Conclusion: Site performance is vital to ensure trial integrity and achievement of key trial goals. This analysis demonstrates that utilization of a comprehensive approach allows for a thorough evaluation of CRS performance, facilitates data and specimen management, and enhances participant retention. Our approach may serve as a guidepost for maximizing future large-scale clinical trials' operational success and scientific rigor., Clinicaltrials: gov Identifier: NCT02344290., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Cardiovascular disease (CVD) is the leading cause of mortality in adults with hepatic steatosis (HS). However, risk factors for CVD in HS are unknown. We aimed to identify factors associated with coronary artery disease (CAD) and incident major adverse cardiovascular events (MACE) in individuals with HS. We performed a nested cohort study of adults with HS detected on coronary computed tomography in the PROspective Multicenter Imaging Study for Evaluation of chest pain (PROMISE) trial. Obstructive CAD was defined as ≥50% coronary stenosis. MACE included hospitalization for unstable angina, nonfatal myocardial infarction, or all-cause death. Multivariate modeling, adjusted for age, sex, atherosclerotic CVD (ASCVD) risk score and body mass index, identified factors associated with obstructive CAD. Cox regression, adjusted for ASCVD risk score, determined the predictors of MACE. A total of 959 of 3,756 (mean age 59.4 years, 55.0% men) had HS. Obstructive CAD was present in 15.2% (145 of 959). Male sex (adjusted odds ratio [aOR] = 1.83, 95% confidence interval [CI] 1.18-1.2.84; p = 0.007), ASCVD risk score (aOR = 1.05, 95% CI 1.03-1.07; p < 0.001), and n-terminal pro-b-type natriuretic peptide (NT-proBNP; aOR = 1.90, 95% CI 1.38-2.62; p < 0.001) were independently associated with obstructive CAD. In the 25-months median follow-up, MACE occurred in 4.4% (42 of 959). Sedentary lifestyle (adjusted hazard ratio [aHR] = 2.53, 95% CI 1.27-5.03; p = 0.008) and NT-proBNP (aOR = 1.50, 95% CI 1.01-2.25; p = 0.046) independently predicted MACE. Furthermore, the risk of MACE increased by 3% for every 1% increase in ASCVD risk score (aHR = 1.03, 95% CI 1.01-1.05; p = 0.02). Conclusion: In individuals with HS, male sex, NT-pro-BNP, and ASCVD risk score are associated with obstructive CAD. Furthermore, ASCVD, NT-proBNP, and sedentary lifestyle are independent predictors of MACE. These factors, with further validation, may help risk-stratify adults with HS for incident CAD and MACE., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)