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High radiation exposure among male radiologists has been reported to result in a significantly higher proportion of female offspring. This study examined whether work-related radiation exposure was associated with a higher propensity for female offspring among male interventional cardiologists. On behalf of the interventional committee of the Society for Cardiovascular Angiography and Interventions, an Internet-based questionnaire was sent to the society's 2063 members. The 402 male respondents had a total of 518 biological offspring; 48.6% of them were female. Among the 172 high-volume male diagnostic operators (those who performed >300 cases annually), there were 218 biological offspring, of whom 46.8% were female. Among the 59 high-volume male interventional operators, there were 70 biological offspring, of whom 45.7% were female. P values were nonsignificant for all three groups. In conclusion, work-related radiation exposure of male invasive and interventional cardiologists was not associated with a statistically significant preponderance of female offspring. [ABSTRACT FROM AUTHOR]

Sixty-one patients with ST elevation acute myocardial infarction were randomized to receive open-label tirofiban in the emergency room before primary angioplasty versus glycoprotein IIb/IIIa inhibitors administered after initial coronary angiography. Early administration of tirofiban before primary angioplasty resulted in nonsignificant improvement in initial coronary flow (Thrombolysis In Myocardial Infarction trial grade 2 or 3 flow, 39% vs 27%, p >0.20). Patients receiving early tirofiban treatment were more likely to achieve complete (>70%) ST-segment resolution at 90 minutes (69% vs 44%, p = 0.07). [ABSTRACT FROM AUTHOR]

Background: The impact of tricuspid regurgitation (TR) on cardiac remodeling has not been thoroughly studied in a randomized controlled trial using advanced imaging., Objectives: The goal of this analysis was to provide comparative longitudinal changes in right heart remodeling using cardiac magnetic resonance and time-resolved functional computed tomography (4D-CT) in patients with symptomatic severe TR randomized to TriClip vs medical therapy (control)., Methods: TRILUMINATE Pivotal (Clinical Trial to Evaluate Cardiovascular Outcomes In Patients Treated With the Tricuspid Valve Repair System Pivotal) is an international randomized controlled trial in symptomatic patients with severe TR. A prospective imaging substudy was performed on TRILUMINATE Pivotal subjects at 10 sites. Cardiac magnetic resonance and 4D-CT were performed following dedicated imaging protocols at baseline and at 30 days, and a final 4D-CT at 1 year (all assessed by an imaging core lab)., Results: Sixty-nine randomized subjects (31 TriClip, 38 control) were enrolled. TR volume significantly decreased with TriClip at 30 days (P < 0.0001; 70% reduction). A strong association (r = 0.90; P < 0.0001) was observed between changes in TR volume and right ventricular end-diastolic volume at 30 days. Significant reductions in right ventricular end-diastolic volume (12% reduction; P < 0.001) and tricuspid annular area (11% reduction; P < 0.0001) were seen at 30 days and sustained through 1 year with TriClip. No meaningful changes were observed in the control group., Conclusions: Advanced imaging from the TRILUMINATE Pivotal imaging substudy demonstrated that TriClip effectively reduced TR. Significant cardiac remodeling was observed at 30 days and sustained at 1 year. With TriClip, the extent of cardiac remodeling was associated with the degree of TR reduction. (Clinical Trial to Evaluate Cardiovascular Outcomes In Patients Treated With the Tricuspid Valve Repair System Pivotal; NCT03904147)., Competing Interests: Funding Support and Author Disclosures This study was funded by Abbott. Dr Cavalcante has received consulting fees from 4C Medical, Abbott, Alleviant, Anteris, Boston Scientific, Circle Cardiovascular Imaging, Edwards Lifesciences, JenaValve, JC Medical, Medtronic, Novo Nordisk, Pie Medical, Siemens Healthineers, Shockwave, and Zoll; and has received research grant support Abbott Structural, Allina Health Foundation, JenaValve, and National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI). Dr Scherer has received consulting/speaker fees/honoraria from Abbott, Boston Scientific, Edwards Lifesciences, HeartFlow, Philips, and Siemens; and has received institutional grant/research support from Boston Scientific and HeartFlow. Dr Fukui has served as a consultant for Edwards Lifesciences and Anteris. Dr Harb has served as a speaker for Edwards Lifesciences; and has served as a consultant and speaker for Abbott, Boston Scientific, and TeraRecon. Dr Schwartz has served as a consultant for Abbott, Boston Scientific, Cordis, Edwards Lifesciences, Medtronic, and Phillips. Dr Ricciardi has received consultant and speaker fees from Abbott. Dr Khalique has received consulting fees from Siemens, Philips, Edwards, Croivalve, Triflo, and Restore Medical. Dr Kodali has received grant/research support from Boston Scientific, Edwards Lifesciences, and Medtronic; has received consulting fees/honoraria from Ancora Heart Inc, Aria CV Inc, Dura Biotech, Thubrikar Aortic Valve Inc, and Valfix Medical; and has owned equity from Admedus Regen Pty Ltd., Dura Biotech, Supira Medical, and Trisol Medical. Dr Whisenant has received consulting fees/honoraria from Abbott and Edwards Lifesciences. Dr Yadav is a consultant/speaker for Edwards Lifesciences, Abbott Vascular, Boston Scientific, and Medtronic; is on the Medical Advisory Board of Dasi Simulations, Trisol, and Opus; and has equity in Dasi Simulations and Opus. Dr Emaminia has received consultant fees from Abbott. Dr Batchelor has consulted for Abbott, Edwards, Boston Scientific, and Medtronic; and has received research support from Abbott and Boston Scientific. Dr Lin is an employee of Abbott. Dr Trusty is an employee of Abbott. Dr Hahn has served as a speaker for Abbott, Baylis Medical, Edwards Lifesciences, and Philips. Dr Adams has served as the national coprincipal investigator of Abbott TRILUMINATE Pivotal Trial, Medtronic APOLLO US Pivotal Trial, ReChord US Pivotal Trial, and Medtronic CoreValve US Pivotal Trial. Dr Sorajja has served as a consultant for Boston Scientific, Edwards Lifesciences, Evolution Medical, Medtronic, Shifamed, TriFlo, and WL Gore; has served as a member of the advisory board for VDyne and Anteris; and has served as the principal investigator of clinical trials for Abbott and HighLife. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Introduction: Spontaneous control of chronic-phase HIV/SIV viremia is often associated with the expression of specific MHC class I allotypes. HIV/SIV-specific CD8+ cytotoxic T lymphocytes (CTLs) restricted by these MHC class I allotypes appear to be critical for viremic control. Establishment of the elite controller (EC) phenotype is predictable in SIVmac239-infected Indian rhesus macaques (RMs), with approximately 50% of Mamu-B*08 + RMs and 20% of Mamu-B*17 + RMs becoming ECs. Despite extensive characterization of EC-associated CTLs in HIV/SIV-infected individuals, the precise mechanistic basis of elite control remains unknown. Because EC and non-EC viral load trajectories begin diverging by day 14 post-infection, we hypothesized that hyperacute innate immune responses may contribute to viremic control., Methods: To gain insight into the immunological factors involved in the determination of EC status, we vaccinated 16 Mamu-B*08 + RMs with Vif and Nef to elicit EC-associated CTLs, then subjected these 16 vaccinees and an additional 16 unvaccinated Mamu-B*08 + controls to repeated intrarectal SIVmac239 challenges. We then performed whole-blood transcriptomic analysis of all 32 SIVmac239-infected Mamu-B*08 + RMs and eight SIVmac239-infected Mamu-B*08 - RMs during the first 14 days of infection., Results: Vaccination did not provide protection against acquisition, but peak and setpoint viremia were significantly lower in vaccinees relative to controls. We did not identify any meaningful correlations between vaccine-induced CTL parameters and SIVmac239 acquisition rate or chronic-phase viral loads. Ultimately, 13 of 16 vaccinees (81%) and 7 of 16 controls (44%) became ECs (viremia ≤ 10,000 vRNA copies/mL plasma for ≥ 4 weeks). We identified subsets of immunomodulatory genes differentially expressed (DE) between RM groupings based on vaccination status, EC status, and MHC class I genotype. These DE genes function in multiple innate immune processes, including the complement system, cytokine/chemokine signaling, pattern recognition receptors, and interferon-mediated responses., Discussion: A striking difference in the kinetics of differential gene expression among our RM groups suggests that Mamu-B*08 -associated elite control is characterized by a robust, rapid innate immune response that quickly resolves. These findings indicate that, despite the association between MHC class I genotype and elite control, innate immune factors in hyperacute SIV infection preceding CTL response development may facilitate the establishment of the EC phenotype., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Rosen, Sawatzki, Ricciardi, Smith, Golez, Mauter, Pedreño-López, Yrizarry-Medina, Weisgrau, Vosler, Voigt, Louw, Tisoncik-Go, Whitmore, Panayiotou, Ghosh, Furlott, Parks, Desrosiers, Lifson, Rakasz, Watkins and Gale.)

The envelope (E) glycoprotein is the primary target of type-specific (TS) neutralizing antibodies (nAbs) after infection with any of the four distinct dengue virus serotypes (DENV1-4). nAbs can be elicited to distinct structural E domains (EDs) I, II, or III. However, the relative contribution of these domain-specific antibodies is unclear. To identify the primary DENV3 nAb targets in sera after natural infection or vaccination, chimeric DENV1 recombinant encoding DENV3 EDI, EDII, or EDIII were generated. DENV3 EDII is the principal target of TS polyclonal nAb responses and encodes two or more neutralizing epitopes. In contrast, some were individuals vaccinated with a DENV3 monovalent vaccine-elicited serum TS nAbs targeting each ED in a subject-dependent fashion, with an emphasis on EDI and EDIII. Vaccine responses were also sensitive to DENV3 genotypic variation. This DENV1/3 panel allows the measurement of serum ED TS nAbs, revealing differences in TS nAb immunity after natural infection or vaccination., Competing Interests: Declaration of interests R.S.B. and E.H. have served on the Scientific Advisory Boards for Takeda vaccines, VaxArt, and Invivyd Therapeutics and has collaborations with Gilead, Janssen Pharmaceuticals, Pardas Biosciences, and Chimerix. A.M.D. has served as an unpaid consultant for Moderna and Takeda vaccines and is an unpaid member of Merck’s dengue vaccine Scientific Advisory Board, and R.S.B. and A.M.D. are inventors on pending and approved flavivirus vaccine and diagnostic patents filed by the University of North Carolina at Chapel Hill. A.M.D. is co-directing a partnership program between UNC and Moderna to develop flavivirus vaccines. UNC has applied for a patent related to the chimeric viruses. J.E.C. has served as a consultant for Takeda vaccines, Sanofi Pasteur, Pfizer, and Novavax; is on the Scientific Advisory Boards of CompuVax and Meissa Vaccines; and is a Founder of IDBiologics, Inc., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The burden and prognostic significance of coronary artery disease (CAD) in adults with peripheral artery disease and chronic limb-threatening ischemia (CLTI) is unknown., Methods: Temporal trends in prevalence of significant CAD (history of myocardial infarction or coronary revascularizations) in hospitalizations for CLTI were determined using the 2000 to 2018 National Inpatient Sample (NIS) database. A multivariable regression analysis of outcomes was performed based on presence or absence of CAD., Results: Among 13 575 099 hospitalizations for CLTI (41% female, 69% white, mean age 69 years), 23% had concomitant CAD, of which 11% underwent lower extremity arterial revascularization (43.6% endovascular and 56.4% surgical). The prevalence of concomitant CAD with CLTI increased from 15.3% in 2000 to 23.1% in 2018. Furthermore, the frequency of endovascular revascularization in adults with CAD and CLTI increased from 15.1% to 48.3%, while there was a decreasing trend of surgical revascularization, from 84.9% to 51.7%. After multivariate adjustments, CLTI with CAD was associated with increased risk of in-hospital mortality (OR, 1.40; 95% CI, 1.32-1.47; P less than .0001) and bleeding requiring transfusion (OR, 1.10; 95% CI, 1.06-1.12; P less than .0001) compared with patients with CLTI without CAD. As compared with surgical revascularization, endovascular revascularization was associated with lower risk of in-hospital mortality in both patients with CLTI with CAD (OR, 0.69; 95% CI, 0.63-0.76; P less than .001) and CLTI without CAD (OR, 0.71; 95% CI, 0.67-0.76; P less than .001)., Conclusions: Prevalence of CAD has increased in adults presenting with CLTI and is associated with poor outcomes, warranting the need for effective interventions and secondary prevention in this high-risk population.

Background Prevention strategies targeting standard modifiable cardiovascular risk factors (SMuRFs; diabetes, hypertension, smoking, hypercholesterolemia) are critical to improving cardiovascular disease outcomes. However, acute myocardial infarction (AMI) among individuals who lack 1 or more SMuRFs is not uncommon. Moreover, the clinical characteristics and prognosis of SMuRFless individuals are not well characterized. Methods and Results We analyzed AMI hospitalizations from 2000 to 2014 captured by the ARIC (Atherosclerosis Risk in Community) study community surveillance. AMI was classified by physician review using a validated algorithm. Clinical data, medications, and procedures were abstracted from the medical record. Main study outcomes included short- and long-term mortality within 28 days and 1 year of AMI hospitalization. Between 2000 and 2014, a total of 742 (3.6%) of 20 569 patients with AMI were identified with no documented SMuRFs. Patients without SMuRFs were less likely to receive aspirin, nonaspirin antiplatelet therapy, or beta blockers and less often underwent angiography and revascularization. Compared with those with one or more SMuRFs, patients without SMuRFs had significantly higher 28-day (odds ratio, 3.23 [95% CI, 1.78-5.88]) and 1-year (hazard ratio, 2.09 [95% CI, 1.29-3.37]) adjusted mortality. When examined across 5-year intervals from 2000 to 2014, the incidence of 28-day mortality significantly increased for patients without SMuRFs (7% to 15% to 27%), whereas it declined for those with 1 or more SMuRFs (7% to 5% to 5%). Conclusions Individuals without SMuRFs presenting with AMI have an increased risk of all-cause mortality with an overall lower prescription rate for guideline-directed medical therapy. These findings highlight the need for evidence-based pharmacotherapy during hospitalization and the need to discover new markers and mechanisms for early risk identification in this population.

Background: Low- and middle-income countries account for most of the global burden of coronary artery disease. There is a paucity of data regarding epidemiology and outcomes for ST-segment elevation myocardial infarction (STEMI) patients in these regions., Objectives: The authors studied the contemporary characteristics, practice patterns, outcomes, and sex differences in patients with STEMI in India., Methods: NORIN-STEMI (North India ST-Segment Elevation Myocardial Infarction Registry) is an investigator-initiated prospective cohort study of patients presenting with STEMI at tertiary medical centers in North India., Results: Of 3,635 participants, 16% were female patients, one-third were <50 years of age, 53% had a history of smoking, 29% hypertension, and 24% diabetes. The median time from symptom onset to coronary angiography was 71 hours; the majority (93%) presented first to a non-percutaneous coronary intervention (PCI)-capable facility. Almost all received aspirin, statin, P2Y 12 inhibitors, and heparin on presentation; 66% were treated with PCI (98% femoral access) and 13% received fibrinolytics. The left ventricular ejection fraction was <40% in 46% of patients. The 30-day and 1-year mortality rates were 9% and 11%, respectively. Compared with male patients, female patients were less likely to receive PCI (62% vs 73%; P  < 0.0001) and had a more than 2-fold greater 1-year mortality (22% vs 9%; adjusted HR: 2.1; 95% CI: 1.7-2.7; P  < 0.001)., Conclusions: In this contemporary registry of patients with STEMI in India, female patients were less likely to receive PCI after STEMI and had a higher 1-year mortality compared with male patients. These findings have important public health implications, and further efforts are required to reduce these gaps., Competing Interests: Dr Qamar has received institutional grant support from Novo Nordisk, NorthShore Auxiliary Research Scholar Fund, and fees for educational activities from the American College of Cardiology, Society for Vascular Medicine, Society for Cardiovascular Angiography and Interventions, Janssen and Janssen, Pfizer, Medscape, and Clinical Exercise Physiology Association. Dr Bhatt is on the advisory board for AngioWave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys; is on board of directors for AngioWave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care, and TobeSoft; is chair and inaugural chair of the American Heart Association Quality Oversight Committee; is a consultant for Broadview Ventures; is on the Data Monitoring Committees for Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards Lifesciences), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute; and Rutgers University (for the NIH-funded MINT Trial); has received honoraria from American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; is on the RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; is on the AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor-in-Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor-in-Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees), and Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), and VA CART Research and Publications Committee (Chair); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither I nor Brigham and Women's Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio; Royalties: Elsevier (Editor, Braunwald’s Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; Trustee: American College of Cardiology; Unfunded Research: FlowCo and Takeda. Dr Gulati discloses the following relationships: K2P (Chair, prevention curriculum), WebMD (speaker); President-Elect and Executive Board of the American Society for Preventive Cardiology; Editorial Board of the Journal for Cardiac Failure, Associate Editor of Atherosclerosis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Yellow fever virus (YFV) is a reemerging global health threat, driven by several factors, including increased spread of the mosquito vector and rapid urbanization. Although a prophylactic vaccine exists, vaccine hesitancy, supply deficits, and distribution difficulties leave specific populations at risk of severe YFV disease, as evidenced by recent outbreaks in South America. To establish a treatment for patients with severe YFV infection, we tested 37 YFV-specific monoclonal antibodies isolated from vaccinated humans and identified two capable of potently neutralizing multiple pathogenic primary YFV isolates. Using both hamster and nonhuman primate models of lethal YFV infection, we demonstrate that a single administration of either of these two potently neutralizing antibodies during acute infection fully controlled viremia and prevented severe disease and death in treated animals. Given the potential severity of YFV-induced disease, our results show that these antibodies could be effective in saving lives and fill a much-needed void in managing YFV cases during outbreaks.

Background Mechanical circulatory support devices, such as the intra-aortic balloon pump (IABP) and Impella, are often used in patients on veno-arterial extracorporeal life support (VA-ECLS) with cardiogenic shock despite limited supporting clinical trial data. Methods and Results Hospitalizations for cardiogenic shock from 2016 to 2018 were identified from the National Inpatient Sample. Trends in the use of VA-ECLS with and without an IABP or Impella were assessed semiannually. Multivariable logistic regression and general linear regression evaluated the association of Impella and IABP use with in-hospital outcomes. Overall, 12 035 hospitalizations with cardiogenic shock and VA-ECLS were identified, of which 3115 (26%) also received an IABP and 1880 (16%) an Impella. Use of an Impella with VA-ECLS substantially increased from 10% to 18% over this period ( P <0.001), whereas an IABP modestly increased from 25% to 26% ( P <0.001). In-hospital mortality decreased 54% to 48% for VA-ECLS only, 61% to 58% for VA-ECLS with an Impella, and 54% to 49% for VA-ECLS with an IABP ( P <0.001 each). Most (57%) IABPs or Impellas were placed on the same day as VA-ECLS. After adjustment, there were no differences in in-hospital mortality or length of stay with the addition of an IABP or Impella compared with VA-ECLS alone. Conclusions From 2016 to 2018 in the United States, use of an Impella and IABP with VA-ECLS significantly increased. More than half of Impellas and IABPs were placed on the same day as VA-ECLS, and the use of a second mechanical circulatory support device did not impact in-hospital mortality. Further studies are needed to decipher the optimal timing and patient selection for this growing practice.

The rapid spread of SARS-CoV-2 variants poses a constant threat of escape from monoclonal antibody and vaccine countermeasures. Mutations in the ACE2 receptor binding site on the surface S protein have been shown to disrupt antibody binding and prevent viral neutralization. Here, we used a directed evolution-based approach to engineer three neutralizing antibodies for enhanced binding to S protein. The engineered antibodies showed increased in vitro functional activity in terms of neutralization potency and/or breadth of neutralization against viral variants. Deep mutational scanning revealed that higher binding affinity reduces the total number of viral escape mutations. Studies in the Syrian hamster model showed two examples where the affinity-matured antibody provided superior protection compared to the parental antibody. These data suggest that monoclonal antibodies for antiviral indications would benefit from affinity maturation to reduce viral escape pathways and appropriate affinity maturation in vaccine immunization could help resist viral variation., Competing Interests: J.G.J., D.R.B., and F.Z. are listed as inventors on pending patent applications describing the engineered SARS-CoV-2 neutralizing antibodies., (© 2022 The Authors.)

An effective vaccine against the dengue virus (DENV) should induce a balanced, long-lasting antibody (Ab) response against all four viral serotypes. The burst of plasmablasts in the peripheral blood after vaccination may reflect enriched vaccine-specific Ab secreting cells. Here we characterize the acute plasmablast responses from naïve and DENV-exposed individuals following immunization with the live attenuated tetravalent (LAT) Butantan DENV vaccine (Butantan-DV). The frequency of circulating plasmablasts was determined by flow cytometric analysis of fresh whole blood specimens collected from 40 participants enrolled in the Phase II Butantan-DV clinical trial (NCT01696422) before and after (days 6, 12, 15 and 22) vaccination. We observed a peak in the number of circulating plasmablast at day 15 after vaccination in both the DENV naïve and the DENV-exposed vaccinees. DENV-exposed vaccinees experienced a significantly higher plasmablast expansion. In the DENV-naïve vaccinees, plasmablasts persisted for approximately three weeks longer than among DENV-exposed volunteers. Our findings indicate that the Butantan-DV can induce plasmablast responses in both DENV-naïve and DENV-exposed individuals and demonstrate the influence of pre-existing DENV immunity on Butantan DV-induced B-cell responses., Competing Interests: JK and RP are former employees of the Butantan Institute. AP is an employee of the Butantan Institute. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer (CP) declared a shared affiliation with the author (MT) to the handling editor at the time of review., (Copyright © 2022 Silveira, Magnani, Costa, Avelino-Silva, Ricciardi, Timenetsky, Goulart, Correia, Marmorato, Ferrari, Nakagawa, Tomiyama, Tomiyama, Kalil, Palacios, Precioso, Watkins and Kallás.)

Aim: To compare the efficacy and safety of P2Y 12 inhibitor or aspirin monotherapy for secondary prevention in patients with atherosclerotic cardiovascular disease (ASCVD)., Methods and Results: Medline, Embase, and Cochrane Central databases were searched to identify randomized trials comparing monotherapy with a P2Y 12 inhibitor versus aspirin for secondary prevention in patients with ASCVD (cardiovascular, cerebrovascular, or peripheral artery disease). The primary outcome was major adverse cardiac events (MACE). Secondary outcomes were myocardial infarction (MI), stroke, all-cause mortality, and major bleeding. A random-effects model was used to calculate risk ratios (RR) and the corresponding 95% confidence interval (CI) and heterogeneity among studies was assessed using the Higgins I 2 value. A total of 9 eligible trials (5 with clopidogrel and 4 with ticagrelor) with 61 623 patients were included in our analyses. Monotherapy with P2Y 12 inhibitors significantly reduced the risk of MACE by 11% (0.89, 95% CI 0.84-0.95, I 2 = 0%) and MI by 19% (0.81, 95% CI 0.71-0.92, I2 = 0%) compared with aspirin monotherapy. There was no significant difference in the risk of stroke (0.85, 95% CI 0.73-1.01), or all-cause mortality (1.01, 95% CI 0.92-1.11). There was also no significant difference in the risk of major bleeding with P2Y 12 inhibitor monotherapy compared with aspirin (0.94, 95% CI 0.72-1.22, I 2 = 42.6%). Results were consistent irrespective of the P2Y 12 inhibitor used., Conclusion: P2Y 12 inhibitor monotherapy for secondary prevention is associated with a significant reduction in atherothrombotic events compared with aspirin alone without an increased risk of major bleeding., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

Background: Placement of an interatrial shunt device reduces pulmonary capillary wedge pressure during exercise in patients with heart failure and preserved or mildly reduced ejection fraction. We aimed to investigate whether an interatrial shunt can reduce heart failure events or improve health status in these patients., Methods: In this randomised, international, blinded, sham-controlled trial performed at 89 health-care centres, we included patients (aged ≥40 years) with symptomatic heart failure, an ejection fraction of at least 40%, and pulmonary capillary wedge pressure during exercise of at least 25 mm Hg while exceeding right atrial pressure by at least 5 mm Hg. Patients were randomly assigned (1:1) to receive either a shunt device or sham procedure. Patients and outcome assessors were masked to randomisation. The primary endpoint was a hierarchical composite of cardiovascular death or non-fatal ischemic stroke at 12 months, rate of total heart failure events up to 24 months, and change in Kansas City Cardiomyopathy Questionnaire overall summary score at 12 months. Pre-specified subgroup analyses were conducted for the heart failure event endpoint. Analysis of the primary endpoint, all other efficacy endpoints, and safety endpoints was conducted in the modified intention-to-treat population, defined as all patients randomly allocated to receive treatment, excluding those found to be ineligible after randomisation and therefore not treated. This study is registered with ClinicalTrials.gov, NCT03088033., Findings: Between May 25, 2017, and July 24, 2020, 1072 participants were enrolled, of whom 626 were randomly assigned to either the atrial shunt device (n=314) or sham procedure (n=312). There were no differences between groups in the primary composite endpoint (win ratio 1·0 [95% CI 0·8-1·2]; p=0·85) or in the individual components of the primary endpoint. The prespecified subgroups demonstrating a differential effect of atrial shunt device treatment on heart failure events were pulmonary artery systolic pressure at 20W of exercise (p interaction =0·002 [>70 mm Hg associated with worse outcomes]), right atrial volume index (p interaction =0·012 [≥29·7 mL/m 2 , worse outcomes]), and sex (p interaction =0·02 [men, worse outcomes]). There were no differences in the composite safety endpoint between the two groups (n=116 [38%] for shunt device vs n=97 [31%] for sham procedure; p=0·11)., Interpretation: Placement of an atrial shunt device did not reduce the total rate of heart failure events or improve health status in the overall population of patients with heart failure and ejection fraction of greater than or equal to 40%., Funding: Corvia Medical., Competing Interests: Declaration of interests SJS reports research grants from the National Institutes of Health (NIH; U54 HL160273, R01 HL107577, R01 HL127028, R01 HL140731, and R01 HL149423), Actelion, AstraZeneca, Corvia, Novartis, and Pfizer; and personal fees from Abbott, Actelion, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer-Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiora, Coridea, CVRx, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Eisai, Imara, Impulse Dynamics, Intellia, Ionis, Ironwood, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sanofi, Shifamed, Tenax, Tenaya, and United Therapeutics. BAB reports research funding from the National Institutes of Health, Axon, AstraZeneca, Corvia, Medtronic, GlaxoSmithKline, Mesoblast, Novartis, and Tenax Therapeutics; and personal fees from Actelion, Amgen, Aria, Boehringer Ingelheim, Edwards, Eli Lilly, Imbria, Janssen, Merck, Novo Nordisk, and VADovations. ESC reports personal fees from Abbott, EBR systems, Medtronic, Intershunt, LivaNova, CVRx, and Cardionomics. GH reports personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Impulse Dynamics, Novartis, Pfizer, Servier, and Vifor Pharma. RK reports personal fees from Medtronic, Impulse Dynamics, and Cardionomic. SEL reports personal fees from Axon Therapies and CVRx. PL reports research grants from Abbott Vascular, Edwards Lifesciences, and ReCor. JMM reports personal fees from Corvia. RCM reports personal fees from Pfizer, Akcea, Eidos, Alnylam, and CareDx. SDS reports research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myer Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, NIH, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and personal fees from Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, PureHealth. ALS reports research grants from the National Heart Foundation of Australia Future Leader Fellowships (#101918 & 106025), NSW Health (Australia), Biotronik, RACE Oncology, Bristol Myer Squibb, Roche Diagnostics, and Vifor; and personal fees from Novartis, Bayer, Bristol Myer Squibb, AstraZeneca, and Boehringer Ingelheim. VS reports personal fees from Abbott Laboratories and Boston Scientific. SW reports personal fees from Novartis, AstraZeneca, and Bayer. MBL reports institutional research grants from Abbott, Boston Scientific, Edwards LifeSciences, and Medtronic. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

A prophylactic vaccine that confers durable protection against human immunodeficiency virus (HIV) would provide a valuable tool to prevent new HIV/AIDS cases. As herpesviruses establish lifelong infections that remain largely subclinical, the use of persistent herpesvirus vectors to deliver HIV antigens may facilitate the induction of long-term anti-HIV immunity. We previously developed recombinant (r) forms of the gamma-herpesvirus rhesus monkey rhadinovirus (rRRV) expressing a replication-incompetent, near-full-length simian immunodeficiency virus (SIVnfl) genome. We recently showed that 8/16 rhesus macaques (RMs) vaccinated with a rDNA/rRRV-SIVnfl regimen were significantly protected against intrarectal (i.r.) challenge with SIVmac239. Here we investigated the longevity of this vaccine-mediated protection. Despite receiving no additional booster immunizations, the protected rDNA/rRRV-SIVnfl vaccinees maintained detectable cellular and humoral anti-SIV immune responses for more than 1.5 years after the rRRV boost. To assess if these responses were still protective, the rDNA/rRRV-SIVnfl vaccinees were subjected to a second round of marginal-dose i.r. SIVmac239 challenges, with eight SIV-naive RMs serving as concurrent controls. After three SIV exposures, 8/8 control animals became infected, compared to 3/8 vaccinees. This difference in SIV acquisition was statistically significant ( P =  0.0035). The three vaccinated monkeys that became infected exhibited significantly lower viral loads than those in unvaccinated controls. Collectively, these data illustrate the ability of rDNA/rRRV-SIVnfl vaccination to provide long-term immunity against stringent mucosal challenges with SIVmac239. Future work is needed to identify the critical components of this vaccine-mediated protection and the extent to which it can tolerate sequence mismatches in the challenge virus. IMPORTANCE We report on the long-term follow-up of a group of rhesus macaques (RMs) that received an AIDS vaccine regimen and were subsequently protected against rectal acquisition of simian immunodeficiency virus (SIV) infection. The vaccination regimen employed included a live recombinant herpesvirus vector that establishes persistent infection in RMs. Consistent with the recurrent SIV antigen expression afforded by this herpesvirus vector, vaccinees maintained detectable SIV-specific immune responses for more than 1.5 years after the last vaccination. Importantly, these vaccinated RMs were significantly protected against a second round of rectal SIV exposures performed 1 year after the first SIV challenge phase. These results are relevant for HIV vaccine development because they show the potential of herpesvirus-based vectors to maintain functional antiretroviral immunity without the need for repeated boosting.

Postinfarction ventricular septal rupture is a rare and devastating complication of myocardial infarction. Despite attempts at acute surgical and percutaneous defect closure, morbidity and mortality remain high. Herein, we describe a hybrid surgical and catheter-based approach to defect closure in a 63-year-old woman with postinfarction ventricular septal rupture and cardiogenic shock., (© 2020 Wiley Periodicals LLC.)

As the prevalence of asymptomatic COVID-19 continues to increase, there is an increasing possibility that patients with COVID-19 may presen with ST-segment elevation myocardial infarction (STEMI). With social distancing and restricted access to preventive healthcare and emergency services, the management of acute cardiac emergencies such as myocardial infarction has suffered collateral damage. Thus far, global trends suggest a decrease in STEMI activations with possible worse outcomes due to delayed presentation and management. In this review, we discuss the challenges to STEMI management in the COVID-19 era and provide potential solutions for adherence to evidence-based therapies as the pandemic progresses into the year 2021., (Copyright © 2020. Published by Elsevier Inc.)

The antiviral properties of broadly neutralizing antibodies against HIV are well-documented but no vaccine is currently able to elicit protective titers of these responses in primates. While current vaccine modalities can readily induce non-neutralizing antibodies against simian immunodeficiency virus (SIV) and HIV, the ability of these responses to restrict lentivirus transmission and replication remains controversial. Here, we investigated the antiviral properties of non-neutralizing antibodies in a group of Indian rhesus macaques (RMs) that were vaccinated with vif , rev, tat, nef , and env , as part of a previous study conducted by our group. These animals manifested rapid and durable control of viral replication to below detection limits shortly after SIVmac239 infection. Although these animals had no serological neutralizing activity against SIVmac239 prior to infection, their pre-challenge titers of Env-binding antibodies correlated with control of viral replication. To assess the contribution of anti-Env humoral immune responses to virologic control in two of these animals, we transiently depleted their circulating antibodies via extracorporeal plasma immunoadsorption and inhibition of IgG recycling through antibody-mediated blockade of the neonatal Fc receptor. These procedures reduced Ig serum concentrations by up to 80% and temporarily induced SIVmac239 replication in these animals. Next, we transferred purified total Ig from the rapid controllers into six vaccinated RMs one day before intrarectal challenge with SIVmac239. Although recipients of the hyperimmune anti-SIV Ig fraction were not protected from infection, their peak and chronic phase viral loads were significantly lower than those in concurrent unvaccinated control animals. Together, our results suggest that non-neutralizing Abs may play a role in the suppression of SIVmac239 viremia., Competing Interests: JL was employed by Leidos Biomedical Research Inc. MM has a consulting financial interest in Emmune, Inc., a company that is developing HIV immunotherapies based on the immunoadhesin eCD4-Ig. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pedreño-Lopez, Rosen, Flores, Gorman, Voigt, Ricciardi, Crosno, Weisgrau, Parks, Lifson, Alter, Rakasz, Magnani, Martins and Watkins.)

To evaluate k-t accelerated 3D cine b-SSFP (balanced steady state free precession) as magnetic resonance imaging (MRI) technique for aortic annular area measurement in transcatheter aortic valve replacement (TAVR) planning compared to computed tomography angiography (CTA) and other non-contrast MRI sequences with reduced imaging time and without contrast administration. 6 volunteers and 7 TAVR candidates were prospectively enrolled. The volunteers underwent an MRI while TAVR candidates underwent an MRI and CTA. The following non-contrast MRI sequences were obtained at the level of the aortic root: 2D cine b-SSFP [GRAPPA (GeneRalized Autocalibrating Partially Parallel Acquisitions), R = 2], 3D cine b-SSFP [GRAPPA R = 2], navigator triggered 3D b-SSFP MRA [GRAPPA, R = 2] and k-t accelerated 3D cine b-SSFP [PEAK GRAPPA, R = 5]. Qualitative analysis and aortic annular area measurements in systole and diastole were obtained. k-t accelerated 3D cine b-SSFP provided image quality that is acceptable for confident diagnosis with very good interrater agreement. There was no statistically significant difference in aortic annular measurements between k-t accelerated 3D cine b-SSFP and CTA or other MRI sequences (p > 0.05). Bland-Altman analysis showed no systemic difference of annular area measurements between k-t accelerated 3D cine b-SSFP and each of the other techniques. There was excellent inter-rater agreement on aortic annular area measurements during systolic (ICC = 0.976, p < 0.001) and diastolic (ICC = 0.971, p < 0.001) phases using k-t accelerated 3D cine b-SSFP. K-t accelerated 3D cine b-SSFP is a promising alternative for the assessment of annular sizing in pre-TAVR evaluation while offering a reasonable combination of imaging parameters during one breath-hold.

Given the complex biology of human immunodeficiency virus (HIV) and its remarkable capacity to evade host immune responses, HIV vaccine efficacy may benefit from the induction of both humoral and cellular immune responses of maximal breadth, potency, and longevity. Guided by this rationale, we set out to develop an immunization protocol aimed at maximizing the induction of anti-Envelope (anti-Env) antibodies and CD8 + T cells targeting non-Env epitopes in rhesus macaques (RMs). Our approach was to deliver the entire simian immunodeficiency virus (SIV) proteome by serial vaccinations. To that end, 12 RMs were vaccinated over 81 weeks with DNA, modified vaccinia Ankara (MVA), vesicular stomatitis virus (VSV), adenovirus type 5 (Ad5), rhesus monkey rhadinovirus (RRV), and DNA again. Both the RRV and the final DNA boosters delivered a near-full-length SIVmac239 genome capable of assembling noninfectious SIV particles and inducing T-cell responses against all nine SIV proteins. Compared to previous SIV vaccine trials, the present DNA-MVA-VSV-Ad5-RRV-DNA regimen resulted in comparable levels of Env-binding antibodies and SIV-specific CD8 + T-cells. Interestingly, one vaccinee developed low titers of neutralizing antibodies (NAbs) against SIVmac239, a tier 3 virus. Following repeated intrarectal marginal-dose challenges with SIVmac239, vaccinees were not protected from SIV acquisition but manifested partial control of viremia. Strikingly, the animal with the low-titer vaccine-induced anti-SIVmac239 NAb response acquired infection after the first SIVmac239 exposure. Collectively, these results highlight the difficulties in eliciting protective immunity against immunodeficiency virus infection. IMPORTANCE Our results are relevant to HIV vaccine development efforts because they suggest that increasing the number of booster immunizations or delivering additional viral antigens may not necessarily improve vaccine efficacy against immunodeficiency virus infection., (Copyright © 2020 American Society for Microbiology.)

Consensus regarding a reasonable strategy to manage cardiac conduction disturbances after transcatheter aortic valve replacement (TAVR) has been elusive. This is due to the absence of adequately powered, randomized controlled trials; the often transient nature of the conduction disturbances; evolving technologies; and the interplay of cardiology subspecialties involved. In the absence of high-quality trials, numerous practice styles have been developed, and prolonged observation, electrophysiological testing, and pre-emptive pacemaker implantation have been described. Although the 2013 European Society of Cardiology guidelines address pacing post-TAVR, they do not provide in-depth discussion of this topic. Furthermore, a summary and proposed strategy for this problem have not been published by cardiovascular societies in the United States, despite an interest in establishing best practices in TAVR, valvular heart disease, and cardiovascular implantable electrical devices. This document reviews existing data and experience regarding the management of conduction disturbances after TAVR and proposes an evidence-based expert consensus decision pathway for their management. Where evidence is lacking or insufficient, the recommendations herein are based on expert opinion., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this registry was to evaluate the feasibility and safety of transcatheter tricuspid valve implantation (TTVI) in patients with extreme surgical risk., Background: Isolated tricuspid regurgitation (TR) surgery is associated with high in-hospital mortality., Methods: Thirty consecutive patients (mean age 75 ± 10 years; 56% women) from 10 institutions, with symptomatic functional TR, had institutional and notified body approval for compassionate use of the GATE TTVI system. Baseline, discharge, and 30-day follow-up echocardiographic data and procedural, in-hospital, and follow-up clinical outcomes were collected., Results: At baseline, all patients had multiple comorbidities, severe or greater TR, and reduced baseline right ventricular function. Technical success was achieved in 26 of 30 patients (87%). Device malpositioning occurred in 4 patients, with conversion to open heart surgery in 2 (5%). Of those who received the device, 100% had reductions in TR of ≥1, and 75% experienced reductions of ≥2 grades, resulting in 18 of 24 of patients (76%) with mild or less TR at discharge. All patients had mild or less central TR. There was continued improvement in TR grade between discharge and 30 days in 15 of 19 patients (79%). In-hospital mortality was 10%. At mean follow-up of 127 ± 82 days, 4 patients (13%) had died. Of patients alive at follow-up, 62% were in New York Heart Association functional class I or II, with no late device-related adverse events., Conclusions: Compassionate treatment of severe, symptomatic functional TR using a first-generation TTVI device is associated with significant reduction in TR and improvement in functional status with acceptable in-hospital mortality. Further studies are needed to determine the appropriate patient population and long-term outcomes with TTVI therapy., Competing Interests: Author Relationship With Industry Drs. Bartus and Rodés-Cabau are consultants for NaviGate Cardiac Structures. Dr. Hahn has received speaking fees from Boston Scientific, Baylis Medical, Edwards Lifesciences, and Medtronic; is an advisory board member for Abbott Structural, Edwards Lifesciences, Medtronic, NaviGate Cardiac Structures, and Philips Healthcare; holds equity in NaviGate Cardiac Structures; has received nonfinancial support from 3mensio; and is the chief scientific officer for the Echocardiography Core Laboratory at the Cardiovascular Research Foundation for multiple industry-sponsored trials, for which she receives no direct industry compensation. Dr. Latib is a consultant for Medtronic, Edwards Lifesciences, Abbott, and NeoChord. Dr. Navia is a consultant for NaviGate Cardiac Structures, with equity and royalties for inventor patents of the device. Dr. Sievert is a consultant for 4tech Cardio, Abbott, Ablative Solutions, Ancora Heart, Append Medical, Bavaria Medizin Technologie, BioVentrix, Boston Scientific, Carag, Cardiac Dimensions, Cardimed, CeloNova Biosciences, Comed, Contego, CVRx, Dinova, Edwards Lifesciences, Endologix, Hemoteq, Hangzhou Nuomao Medtech, Holistick Medical, Lifetech Scientific, Maquet Getinge Group, Medtronic, Mokita, Occlutech, ReCor Medical, Renal Guard, Terumo, Vascular Dynamics, Vectorious Medtech, Venock, Venus, and Vivasure Medical. All other authors have reported that they have no relationships relevant to the content of this paper to disclose., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: Chronic total occlusion (CTO) has been linked to worse survival. While controversial and limited to observational data, successful CTO percutaneous coronary intervention (PCI) has been associated with improved left ventricular (LV) function and mortality. However, the role of CTO PCI prior to transcatheter aortic valve replacement (TAVR) is not clear. We sought to explore the prognostic impact of a pre-TAVR CTO on post-TAVR outcomes., Methods and Results: We retrospectively reviewed 783 consecutive TAVR cases performed at a single tertiary care medical center. Pre-TAVR angiograms were analyzed for the presence of a CTO. At the time of TAVR, 12.6% (n = 99) patients had a CTO. At one-year post-TAVR, there was no significant association between the presence of a CTO and death (14.2% vs 13.1%, p = 0.75), functional status, quality of life, or adverse events. There was also no difference in long-term survival (4.1 years vs 4.1 years, p = 0.55). LV ejection fraction was lower in the CTO group at baseline and one year (p < 0.01)., Conclusions: The presence of a CTO did not have any prognostic impact on mortality, change in LV function, or improvement in functional status and angina scores following TAVR in our cohort of elderly, high-risk patients. CTO before TAVR was associated with decreased ejection fraction at baseline and at one year., Competing Interests: Declaration of competing interest Dr. Malaisrie is a consultant for Edwards Lifesciences and Medtronic., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The use of LDT may signify significant hemodynamic changes and left ventricular remodeling in severe aortic stenosis (AS). Therefore, we sought to determine whether loop diuretic therapy (LDT) is associated with adverse outcomes following transcatheter aortic valve implantation (TAVI) in patients with severe symptomatic AS. Subjects undergoing TAVI at a single institution from June 2008 to December 2017 were analyzed. LDT doses were normalized to oral furosemide daily equivalents. All outcomes were adjudicated using VARC2 criteria. Descriptive statistics, multivariate logistic regression, and propensity score matching were used. Of the 804 subjects studied, 48.3% were on pre-TAVI LDT with a mean dose of 51.1 mg furosemide dose-equivalents. Subjects on LDT were higher risk, frail patients with more co-morbidities including chronic kidney disease, coronary artery disease requiring prior bypass grafting, peripheral arterial disease, atrial fibrillation or flutter, and diabetes with more severe heart failure symptoms. Those on LDT also had worse left ventricular systolic function, lower transvalvular gradients, and markers of adverse left ventricular remodeling, including increased left ventricular mass index and higher rates of concentric and eccentric hypertrophy. On propensity-score matching, death within one year post-TAVI was borderline significantly higher in the pre-LDT as compared with no-LDT group (16.9% vs 10.4 %, p = 0.068). In conclusion, use of pre-TAVI LDT for severe symptomatic AS is associated with a trend towards worse 1-year mortality and is a marker of high-risk, frail individuals with advanced left ventricular remodeling., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Countermeasures to prevent and treat coronavirus disease 2019 (COVID-19) are a global health priority. We enrolled a cohort of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-recovered participants, developed neutralization assays to investigate antibody responses, adapted our high-throughput antibody generation pipeline to rapidly screen more than 1800 antibodies, and established an animal model to test protection. We isolated potent neutralizing antibodies (nAbs) to two epitopes on the receptor binding domain (RBD) and to distinct non-RBD epitopes on the spike (S) protein. As indicated by maintained weight and low lung viral titers in treated animals, the passive transfer of a nAb provides protection against disease in high-dose SARS-CoV-2 challenge in Syrian hamsters. The study suggests a role for nAbs in prophylaxis, and potentially therapy, of COVID-19. The nAbs also define protective epitopes to guide vaccine design., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

CD8 + cytotoxic T lymphocytes (CTLs) exert potent antiviral activity after HIV/SIV infection. However, efforts to harness the antiviral efficacy of CTLs for HIV/SIV prophylaxis and therapy have been severely hindered by two major problems: viral escape and exhaustion. By contrast, CTLs directed against human cytomegalovirus (HCMV), a ubiquitous chronic herpesvirus, seldom select for escape mutations and remain functional and refractory to exhaustion during chronic HCMV and HIV infection. Recently, attempts have been made to retarget HCMV-specific CTLs for cancer immunotherapy. We speculate that such a strategy may also be beneficial in the context of HIV/SIV infection, facilitating CTL-mediated control of HIV/SIV replication. As a preliminary assessment of the validity of this approach, we investigated the phenotypes and functionality of rhesus CMV (RhCMV)-specific CTLs in SIVmac239-infected Indian rhesus macaques (RMs), a crucial HIV animal model system. We recently identified two immunodominant, Mamu-A ∗ 02 -restricted CTL epitopes derived from RhCMV proteins and sought to evaluate the phenotypic and functional characteristics of these CTL populations in chronic SIVmac239 infection. We analyzed and directly compared RhCMV- and SIVmac239-specific CTLs during SIVmac239 infection in a cohort of Mamu-A ∗ 01 + and Mamu-A ∗ 02 + RMs. CTL populations specific for at least one of the RhCMV-derived CTL epitopes were detected in ten of eleven Mamu-A ∗ 02 + animals tested, and both populations were detected in five of these animals. Neither RhCMV-specific CTL population exhibited significant changes in frequency, memory phenotype, granzyme B expression, exhaustion marker (PD-1 and CTLA-4) expression, or polyfunctionality between pre- and chronic SIVmac239 infection timepoints. In chronic SIVmac239 infection, RhCMV-specific CTLs exhibited higher levels of granzyme B expression and polyfunctionality, and lower levels of exhaustion marker expression, than SIVmac239-specific CTLs. Additionally, compared to SIVmac239-specific CTLs, greater proportions of RhCMV-specific CTLs were of the terminally differentiated effector memory phenotype (CD28 - CCR7 - ) during chronic SIVmac239 infection. These results suggest that, in contrast to SIVmac239-specific CTLs, RhCMV-specific CTLs maintain their phenotypes and cytolytic effector functions during chronic SIVmac239 infection, and that retargeting RhCMV-specific CTLs might be a promising SIV immunotherapeutic strategy., (Copyright © 2020 Rosen, Pedreño-Lopez, Ricciardi, Reed, Sacha, Rakasz and Watkins.)

Simian immunodeficiency virus (SIV) infection of Indian rhesus macaques (RMs) is one of the best-characterized animal models for human immunodeficiency virus (HIV) infection. Monoclonal antibodies (mAbs) have shown promise for prevention and treatment of HIV infection. However, it has been difficult to isolate mAbs that potently neutralize the highly pathogenic SIVmac239 strain. This has been largely due to the low frequency of circulating B cells encoding neutralizing Abs. Here we describe a novel technique to isolate mAbs directly from bone marrow-derived, Ab-secreting plasma cells. We employed an automated micromanipulator to isolate single SIVmac239 SOSIP.664-specific plasma cells from the bone marrow of a SIVmac239-infected RM with serum neutralization titers against SIVmac239. After picking plasma cells, we obtained 44 paired Ab sequences. Ten of these mAbs were SIV specific. Although none of these mAbs neutralized SIVmac239, three mAbs completely neutralized the related SIVmac316 strain. The majority of these mAbs bound to primary rhesus CD4+ T cells infected with SIVmac239 and induced Ab-dependent cellular cytotoxicity. This method is a first step in successful isolation of antigen-specific bone marrow-derived plasma cells from RMs., (© 2020 The Author(s).)

Tricuspid valve (TV) degeneration after surgical repair with an annuloplasty ring is problematic as redo operation carries high mortality. This can be addressed with transcatheter therapies to implant a valve within in prior ring (tricuspid valve-in-ring). When an incomplete ring is present, paravalvular leak is commonly encountered after tricuspid valve-in-ring (TViR) implant; however, this can be addressed with paravalvular leak closure devices. Multimodality imaging including cardiac computed tomography and three-dimensional (3D) transesophageal echocardiography (TEE) are important for successful TViR implant. We report a case of tricuspid regurgitation after tricuspid repair with an incomplete annuloplasty ring and subsequent paravalvular leak closure., (© 2020 Wiley Periodicals LLC.)

Structural characterization of the HIV-1 Envelope (Env) glycoprotein has facilitated the development of Env probes to isolate HIV-specific monoclonal antibodies (mAbs). However, preclinical studies have largely evaluated these virus-specific mAbs against chimeric viruses, which do not naturally infect non-human primates, in contrast to the unconstrained simian immunodeficiency virus (SIV)mac239 clone. Given the paucity of native-like reagents for the isolation of SIV-specific B cells, we examined a method to isolate SIVmac239-specific mAbs without using Env probes. We first activated virus-specific B cells by inducing viral replication after the infusion of a CD8β-depleting mAb or withdrawal of antiretroviral therapy in SIVmac239-infected rhesus macaques. Following the rise in viremia, we observed 2- to 4-fold increases in the number of SIVmac239 Env-reactive plasmablasts in circulation. We then sorted these activated B cells and obtained 206 paired Ab sequences. After expressing 122 mAbs, we identified 14 Env-specific mAbs. While these Env-specific mAbs bound to both the SIVmac239 SOSIP.664 trimer and to infected primary rhesus CD4 + T cells, five also neutralized SIVmac316. Unfortunately, none of these mAbs neutralized SIVmac239. Our data show that this method can be used to isolate virus-specific mAbs without antigenic probes by inducing bursts of contemporary replicating viruses in vivo ., (© 2020 The Author(s).)

Objective: Transcatheter aortic valve replacement is a safe, minimally invasive treatment for severe aortic stenosis in patients with moderate-to-high surgical risk. Monitored anesthesia is administered by an anesthesiologist. This study compares transcatheter aortic valve outcomes under monitored anesthesia vs general anesthesia., Methods: Data were prospectively collected for 286 patients undergoing transcatheter aortic valve replacement at a single academic hospital from March 2012 to August 2016. The patients were grouped by type of anesthesia: monitored vs general. A propensity score match was performed to compare intraoperative and post-operative outcomes between groups., Results: General anesthesia was used in 102 patients and moderate sedation in 184. Propensity score matching produced 80 pairs. Compared to procedures under general anesthesia, patients receiving monitored anesthesia had shorter procedure (1.6 [1.4, 2.0] vs 2.0 [1.6, 2.5] hours; P < 0.001) and fluoroscopy times (17 [14.5, 22.5] vs 25 [17.9, 30.3] minutes; P < 0.001) and shorter hospital length-of-stay (3 [2.0, 4.0] vs 5 [3.0, 7.0] days; P < 0.001) but no difference in intensive care unit length-of-stay. Blood transfusion was more common in patients undergoing general anesthesia, but there was no difference in stroke, renal failure, postoperative atrial fibrillation, or need for permanent pacemaker. More patients were discharged to home after monitored anesthesia (90% vs 64%; P < 0.001). There was no difference in 30-day mortality (0% vs 3%; P = 0.15)., Conclusions: Transcatheter aortic valve replacement under monitored anesthesia provides the safety of anesthesia-led sedation without intubation and general anesthetic. We found no compromise in patient safety or clinical outcomes.

A prophylactic vaccine against human immunodeficiency virus (HIV) remains a top priority in biomedical research. Given the failure of conventional immunization protocols to confer robust protection against HIV, new and unconventional approaches may be needed to generate protective anti-HIV immunity. Here we vaccinated rhesus macaques (RMs) with a recombinant (r)DNA prime (without any exogenous adjuvant), followed by a booster with rhesus monkey rhadinovirus (RRV)-a herpesvirus that establishes persistent infection in RMs (Group 1). Both the rDNA and rRRV vectors encoded a near-full-length simian immunodeficiency virus (SIVnfl) genome that assembles noninfectious SIV particles and expresses all nine SIV gene products. This rDNA/rRRV-SIVnfl vaccine regimen induced persistent anti-Env antibodies and CD8+ T-cell responses against the entire SIV proteome. Vaccine efficacy was assessed by repeated, marginal-dose, intrarectal challenges with SIVmac239. Encouragingly, vaccinees in Group 1 acquired SIVmac239 infection at a significantly delayed rate compared to unvaccinated controls (Group 3). In an attempt to improve upon this outcome, a separate group of rDNA/rRRV-SIVnfl-vaccinated RMs (Group 2) was treated with a cytotoxic T-lymphocyte antigen-4 (CTLA-4)-blocking monoclonal antibody during the vaccine phase and then challenged in parallel with Groups 1 and 3. Surprisingly, Group 2 was not significantly protected against SIVmac239 infection. In sum, SIVnfl vaccination can protect RMs against rigorous mucosal challenges with SIVmac239, a feat that until now had only been accomplished by live-attenuated strains of SIV. Further work is needed to identify the minimal requirements for this protection and whether SIVnfl vaccine efficacy can be improved by means other than anti-CTLA-4 adjuvant therapy., Competing Interests: The authors have declared that no competing interests exist.

The Zika epidemic in the Americas has challenged surveillance and control. As the epidemic appears to be waning, it is unclear whether transmission is still ongoing, which is exacerbated by discrepancies in reporting. To uncover locations with lingering outbreaks, we investigated travel-associated Zika cases to identify transmission not captured by reporting. We uncovered an unreported outbreak in Cuba during 2017, a year after peak transmission in neighboring islands. By sequencing Zika virus, we show that the establishment of the virus was delayed by a year and that the ensuing outbreak was sparked by long-lived lineages of Zika virus from other Caribbean islands. Our data suggest that, although mosquito control in Cuba may initially have been effective at mitigating Zika virus transmission, such measures need to be maintained to be effective. Our study highlights how Zika virus may still be "silently" spreading and provides a framework for understanding outbreak dynamics. VIDEO ABSTRACT., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Preexisting immunity against dengue virus or West Nile virus was previously reported to mediate antibody-dependent enhancement (ADE) of Zika virus (ZIKV) infection in a mouse model. We show here that ZIKV-immune plasma samples from both symptomatic and asymptomatic individuals mediated ZIKV ADE of infection in vitro and in mice. In a lethal infection model with a viral inoculum 10 times higher, both ADE and protection were observed, depending on the amount of infused immune plasma. In a vertical-transmission model, ZIKV-immune plasma infused to timed pregnant mice increased fetal demise and decreased the body weight of surviving fetuses. Depletion of IgG from an immune plasma abolished ADE of infection, and the presence of purified IgG alone mediated ADE of infection. Higher viral loads and proinflammatory cytokines were detected in mice treated with ZIKV-immune plasma samples compared to those receiving control plasma. Together, these data show that passive immunization with homotypic ZIKV antibodies, depending on the concentration, could either worsen or limit a subsequent ZIKV infection. IMPORTANCE Antibody-dependent enhancement (ADE) of virus infection is common to many viruses and is problematic when plasma antibody levels decline to subneutralizing concentrations. ADE of infection is especially important among flaviviruses, many of which are the cause of global health problems. Recently, human plasma samples immune to heterologous flaviviruses were shown to promote Zika virus (ZIKV) infection. Here we showed in immunocompromised mouse models that homologous immune plasma samples protect mice from subsequent infection at high antibody concentrations but that they mediate ADE of infection and increase ZIKV pathogenesis in adult mice and fetal demise during pregnancy at low concentrations., (Copyright © 2019 Shim et al.)

Transcatheter aortic valve implantation (TAVI) is a recognized treatment method for high-risk patients with aortic stenosis. TAVI is also recommended for structural valve degeneration of a biological valve prosthesis. TAVI-specific complications, such as prosthesis embolization and aortic dissection, are uncommon but potential concerns. A 73-year-old woman presented with structural valve degeneration 14 years after aortic root replacement with a bioprosthetic valved conduit. The patient underwent TAVI valve-in-valve under monitored anaesthesia care. Intraoperatively, the self-expandable prosthesis was difficult to deploy within the valved conduit and ultimately migrated distally. During the technically difficult passage of the prosthesis delivery system through the tortuous aorta, the patient started reporting symptoms suggestive of aortic dissection. An emergency computed tomography scan confirmed type B dissection. Thoracic endovascular aortic repair followed by deployment of a balloon-expandable prosthesis below the self-expandable implant was performed. Careful prosthesis selection in valve-in-valve patients after aortic root replacement is crucial for procedural success., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Zika virus (ZIKV) is an arbovirus that caused widespread panic beginning in 2015 in northeastern Brazil due to the threatening link between infection and fetal abnormalities such as microcephaly, spontaneous abortions, and stillbirths. Since the epidemic began, the virus has been further investigated, unveiling that the long-term dangers of ZIKV infection go beyond fetal neurological impairment. Characterization of the active infection has proven difficult as only 20% of infected individuals are symptomatic. Additionally, ZIKV is often misdiagnosed due to serological cross-reactivity with similar flaviviruses such as dengue, yellow fever, and West Nile. To date, there is no approved vaccine or therapy against ZIKV, highlighting the urgent need to accurately identify active infection to help minimize the spread of the virus. Herein, we describe a highly specific and sensitive enzyme-linked immunosorbent assay to detect early active ZIKV using neutralizing human monoclonal antibodies isolated from infected patients in Brazil that do not cross-react with dengue viruses 1-4 and bind directly to a ZIKV immunodominant epitope. The calculated limits of detection of active ZIKV fall within the physiological ranges of the virus in human bodily fluids. This selective immunoassay creates the platform required for future translation toward a point-of-care assay for ZIKV, a necessity to diagnose active ZIKV in the remote regions of which it thrives., Competing Interests: The authors declare no competing financial interest.

Approximately 50% of rhesus macaques (RMs) expressing the major histocompatibility complex class I (MHC-I) allele Mamu-B*08 spontaneously control chronic-phase viremia after infection with the pathogenic simian immunodeficiency virus mac239 (SIVmac239) clone. CD8 + T-cell responses in these animals are focused on immunodominant Mamu-B*08-restricted SIV epitopes in Vif and Nef, and prophylactic vaccination with these epitopes increases the incidence of elite control in SIVmac239-infected Mamu-B*08 -positive ( Mamu-B*08 + ) RMs. Here we evaluated if robust vaccine-elicited CD8 + T-cell responses against Vif and Nef can prevent systemic infection in Mamu-B*08 + RMs following mucosal SIV challenges. Ten Mamu-B*08 + RMs were vaccinated with a heterologous prime/boost/boost regimen encoding Vif and Nef, while six sham-vaccinated MHC-I-matched RMs served as the controls for this experiment. Vaccine-induced CD8 + T cells against Mamu-B*08-restricted SIV epitopes reached high frequencies in blood but were present at lower levels in lymph node and gut biopsy specimens. Following repeated intrarectal challenges with SIVmac239, all control RMs became infected by the sixth SIV exposure. By comparison, four vaccinees were still uninfected after six challenges, and three of them remained aviremic after 3 or 4 additional challenges. The rate of SIV acquisition in the vaccinees was numerically lower (albeit not statistically significantly) than that in the controls. However, peak viremia was significantly reduced in infected vaccinees compared to control animals. We found no T-cell markers that distinguished vaccinees that acquired SIV infection from those that did not. Additional studies will be needed to validate these findings and determine if cellular immunity can be harnessed to prevent the establishment of productive immunodeficiency virus infection. IMPORTANCE It is generally accepted that the antiviral effects of vaccine-induced classical CD8 + T-cell responses against human immunodeficiency virus (HIV) are limited to partial reductions in viremia after the establishment of productive infection. Here we show that rhesus macaques (RMs) vaccinated with Vif and Nef acquired simian immunodeficiency virus (SIV) infection at a lower (albeit not statistically significant) rate than control RMs following repeated intrarectal challenges with a pathogenic SIV clone. All animals in the present experiment expressed the elite control-associated major histocompatibility complex class I (MHC-I) molecule Mamu-B*08 that binds immunodominant epitopes in Vif and Nef. Though preliminary, these results provide tantalizing evidence that the protective efficacy of vaccine-elicited CD8 + T cells may be greater than previously thought. Future studies should examine if vaccine-induced cellular immunity can prevent systemic viral replication in RMs that do not express MHC-I alleles associated with elite control of SIV infection., (Copyright © 2019 American Society for Microbiology.)

Background: Transcatheter aortic valve replacement (TAVR) is increasingly used to treat severe aortic stenosis. A frequent complication of TAVR is high-grade or complete atrioventricular (AV) block requiring a permanent pacemaker (PPM). There are little data on the long-term dependency on pacing after TAVR. The objective of this study was to determine the proportion of patients receiving a PPM for high-grade or complete AV block after TAVR who remain dependent on the PPM in follow-up and to determine any risk factors for, particularly the effect of postballoon dilation (PBD) on, pacemaker dependency., Methods: Of 594 consecutive patients without prior PPM undergoing TAVR (81.9% balloon-expandable, 18.1% self-expandable valve), 67 (13.1%) received a PPM after TAVR. PPM dependency was defined as AV block with a ventricular escape rate of ≤ 40 beats/min. Patient and procedural characteristics were examined according to PPM dependency status., Results: Of the 67 patients who received a PPM within 10 days after TAVR, 27/67 (40.3%) were dependent at first follow-up and only 9/41 (21.9%) at 1 year. PPM dependency was more common after a self-expanding valve (76.9% vs 31.5%, P < 0.01), in those who underwent PBD (66.7% vs 24.4%, P < 0.01), and in patients in persistent complete AV block at PPM implantation (62.5% vs 7.4%, P < 0.01)., Conclusions: Fewer than half of patients who receive a new PPM following TAVR are pacemaker dependent at early follow-up (< 30 days). The use of self-expanding valves and PBD are associated with a markedly increased risk of PPM dependency., (© 2018 Wiley Periodicals, Inc.)

Zika virus (ZIKV) constitutes an increasing public health problem. Previous studies have shown that CD8 + T cells play an important role in ZIKV-specific protective immunity. We have previously defined antigenic targets of the ZIKV-specific CD8 + T cell response in humans. In this study, we characterized the quality and phenotypes of these responses by a combined use of flow cytometry and transcriptomic methods, using PBMCs from donors deriving from different geographical locations collected in the convalescent phase of infection. We show that ZIKV-specific CD8 + T cells are characterized by a polyfunctional IFN-γ signature with upregulation of TNF-α, TNF receptors, and related activation markers, such as CD69, as well as a cytotoxic signature characterized by strong upregulation of GZMB and CRTAM. The signature is stable and not influenced by previous dengue virus exposure, geographical location, or time of sample collection postinfection. To our knowledge, this work elucidates the first in-depth characterization of human CD8 + T cells responding to ZIKV infection., (Copyright © 2018 by The American Association of Immunologists, Inc.)

Importance: In patients with heart failure (HF) and left ventricular ejection fraction (LVEF) equal to or greater than 40%, a transcatheter interatrial shunt device (IASD; Corvia Medical) reduces exercise pulmonary capillary wedge pressure (PCWP) and is safe compared with sham control treatment at 1 month of follow-up. The longer-term safety and patency of the IASD has not yet been demonstrated in the setting of a randomized clinical trial (RCT)., Objective: To evaluate the 1-year safety and clinical outcomes of the IASD compared with a sham control treatment., Design, Setting, and Participants: This phase 2, double-blind, 1-to-1 sham-controlled multicenter RCT of IASD implantation vs a sham procedure (femoral venous access and imaging of the interatrial septum without IASD) was conducted in 22 centers in the United States, Europe, and Australia on patients with New York Heart Association (NYHA) class III or ambulatory class IV HF, LVEF equal to or greater than 40%, exercise PCWP equal to or greater than 25 mm Hg, and PCWP-right atrial pressure gradient equal to or greater than 5 mm Hg., Main Outcomes and Measures: Safety was assessed by major adverse cardiac, cerebrovascular, or renal events (MACCRE). Exploratory outcomes evaluated at 1 year were hospitalizations for HF, NYHA class, quality of life, a 6-minute walk test, and device patency., Results: After 1 year, shunts were patent in all IASD-treated patients; MACCRE did not differ significantly in the IASD arm (2 of 21 [9.5%]) vs the control arm (5 of 22 [22.7%]; P = .41), and no strokes occurred. The yearly rate of hospitalizations for HF was 0.22 in the IASD arm and 0.63 in the control arm (P = .06). Median improvement in NYHA class was 1 class in the IASD arm (IQR, -1 to 0) vs 0 in the control arm (IQR, -1 to 0; P = .08). Quality of life and 6-minute walk test distance were similar in both groups. At 6 months, there was an increase in right ventricular size in the IASD arm (mean [SD], 7.9 [8.0] mL/m2) vs the control arm (-1.8 [9.6] mL/m2; P = .002), consistent with left-to-right shunting through the device; no further increase occurred in the IASD arm at 12 months., Conclusions and Relevance: The REDUCE LAP-HF I phase 2, sham-controlled RCT confirms the longer-term patency of the IASD. Through 1 year of follow-up, IASD treatment appears safe, with no significant differences in MACCRE in patients receiving IASD compared with those who received sham control treatment., Trial Registration: ClinicalTrials.gov identifier: NCT02600234.

Functional mitral regurgitation (FMR) is common in patients with heart failure and portends a poor prognosis. The etiology is secondary to nonischemic or ischemic (postmyocardial infarction) adverse remodeling. Treatment includes guideline-directed medical therapy, cardiac resynchronization therapy, and in some cases, surgical repair or replacement. Transcatheter mitral valve (MV) repair with the MitraClip device is approved in patients with degenerative MR and is currently under investigation for use in FMR, as are several transcatheter MV replacement devices. This review discusses the basis of FMR pathophysiology, classification, and prognosis; provides an overview of current therapeutic approaches; examines the available literature on the use of MitraClip in patients with FMR; and provides insight into ongoing clinical trials and new investigational devices for the treatment of FMR.

Certain major histocompatibility complex class I (MHC-I) alleles are associated with spontaneous control of viral replication in human immunodeficiency virus (HIV)-infected people and simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs). These cases of "elite" control of HIV/SIV replication are often immune-mediated, thereby providing a framework for studying anti-lentiviral immunity. In this study, we examined how vaccination impacts SIV replication in RMs expressing the MHC-I allele Mamu-B*17 Approximately 21% of Mamu-B*17 + and 50% of Mamu-B*08 + RMs control chronic-phase viremia after SIVmac239 infection. Because CD8 + T cells targeting Mamu-B*08-restricted SIV epitopes have been implicated in virologic suppression in Mamu-B*08 + RMs, we investigated whether this might also be true for Mamu-B*17 + RMs. Two groups of Mamu-B*17 + RMs were vaccinated with genes encoding Mamu-B*17-restricted epitopes in Vif and Nef. These genes were delivered by themselves (group 1) or together with env (group 2). Group 3 included MHC-I-matched RMs and served as the control group. Surprisingly, the group 1 vaccine regimen had little effect on viral replication compared to group 3, suggesting that unlike Mamu-B*08 + RMs, preexisting SIV-specific CD8 + T cells alone do not facilitate long-term virologic suppression in Mamu-B*17 + RMs. Remarkably, however, 5/8 group 2 vaccinees controlled viremia to <15 viral RNA copies/ml soon after infection. No serological neutralizing activity against SIVmac239 was detected in group 2, although vaccine-elicited gp140-binding antibodies correlated inversely with nadir viral loads. Collectively, these data shed new light on the unique mechanism of elite control in Mamu-B*17 + RMs and implicate vaccine-induced, nonneutralizing anti-Env antibodies in the containment of immunodeficiency virus infection. IMPORTANCE A better understanding of the immune correlates of protection against HIV might facilitate the development of a prophylactic vaccine. Therefore, we investigated simian immunodeficiency virus (SIV) infection outcomes in rhesus macaques expressing the major histocompatibility complex class I allele Mamu-B*17 Approximately 21% of Mamu-B*17 + macaques spontaneously controlled chronic phase viremia after SIV infection, an effect that may involve CD8 + T cells targeting Mamu-B*17-restricted SIV epitopes. We vaccinated Mamu-B*17 + macaques with genes encoding immunodominant epitopes in Vif and Nef alone (group 1) or together with env (group 2). Although neither vaccine regimen prevented SIV infection, 5/8 group 2 vaccinees controlled viremia to below detection limits shortly after infection. This outcome, which was not observed in group 1, was associated with vaccine-induced, nonneutralizing Env-binding antibodies. Together, these findings suggest a limited contribution of Vif- and Nef-specific CD8 + T cells for virologic control in Mamu-B*17 + macaques and implicate anti-Env antibodies in containment of SIV infection., (Copyright © 2018 American Society for Microbiology.)

Zika virus (ZIKV) infection of pregnant women is associated with pathologic complications of fetal development. Here, we infect pregnant rhesus macaques (Macaca mulatta) with a minimally passaged ZIKV isolate from Rio de Janeiro, where a high rate of fetal development complications was observed. The infection of pregnant macaques with this virus results in maternal viremia, virus crossing into the amniotic fluid (AF), and in utero fetal deaths. We also treated three additional ZIKV-infected pregnant macaques with a cocktail of ZIKV-neutralizing human monoclonal antibodies (nmAbs) at peak viremia. While the nmAbs can be effective in clearing the virus from the maternal sera of treated monkeys, it is not sufficient to clear ZIKV from AF. Our report suggests that ZIKV from Brazil causes fetal demise in non-human primates (NHPs) without additional mutations or confounding co-factors. Treatment with a neutralizing anti-ZIKV nmAb cocktail is insufficient to fully stop vertical transmission.