Increasing Adoption of Left Atrial Appendage Occlusion in Isolated Coronary Artery Bypass Grafting.

BACKGROUND: Recent randomized trial data showed fewer strokes with left atrial appendage occlusion (LAAO) following cardiac surgery in patients with atrial fibrillation. We developed a quality initiative to increase LAAO adoption. METHODS: Among 11,099 patients undergoing isolated CABG between January 2019-March 2021 at 33 hospitals in Michigan, those with atrial fibrillation undergoing first-time, on-pump CABG were eligible (n=1,241). A goal LAAO rate of 75% was selected as a quality improvement target through a statewide collaborative. An interrupted time series analysis evaluated the change in LAAO rate before (January-December 2019) versus after (January 2020-March 2021) implementation. RESULTS: Implementation of the quality metric improved LAAO rate from 61% (357/581) before to 79% (520/660) after implementation (p<0.001). Compared to patients not undergoing concomitant LAAO, LAAO patients (71%, 877/1,241) were older, more frequently male, and had a lower STS-PROM (2.9±3.5% vs. 3.7±5.7%, p=0.003), while other baseline characteristics including CHA2DS2-VASc scores were similar. Mean bypass and cross-clamp times were 7 and 6 minutes longer, respectively, in the LAAO group among those who did not undergo concomitant ablation. Operative mortality, major morbidity, blood product administration, and thromboembolic events were similar between groups. Interrupted time series analysis showed a significant increase in LAAO rate after implementation (p=0.009). CONCLUSIONS: LAAO in patients with atrial fibrillation undergoing isolated CABG did not add operative risk versus isolated CABG without LAAO. A statewide quality improvement initiative was successful in increasing the rate of concomitant LAAO and could be further evaluated as a potential quality metric in cardiac surgery.

Evaluation of sex differences in the receipt of concomitant atrial fibrillation procedures during nonmitral cardiac surgery.

OBJECTIVE: Women are less likely to receive guideline-recommended cardiovascular care, but evaluation of sex-based disparities in cardiac surgical procedures is limited. Receipt of concomitant atrial fibrillation (AF) procedures during nonmitral cardiac surgery was compared by sex for patients with preoperative AF. METHODS: Patients with preoperative AF undergoing coronary artery bypass grafting and/or aortic valve replacement at any of the 33 hospitals in Michigan from 2014 to 2022 were included. Patients with prior cardiac surgery, transcatheter AF procedure, or emergency/salvage status were excluded. Hierarchical logistic regression identified predictors of concomitant AF procedures, account for hospital and surgeon as random effects. RESULTS: Of 5460 patients with preoperative AF undergoing nonmitral cardiac surgery, 24% (n = 1291) were women with a mean age of 71 years. Women were more likely to have paroxysmal (vs persistent) AF than men (80% vs 72%; P < .001) and had a higher mean predicted risk of mortality (5% vs 3%; P < .001). The unadjusted rate of concomitant AF procedure was 59% for women and 67% for men (P < .001). After risk adjustment, women had 26% lower adjusted odds of concomitant AF procedure than men (adjusted odds ratio, 0.74; 95% CI, 0.64-0.86; P < .001). Female sex was the risk factor associated with the lowest odds of concomitant AF procedure. CONCLUSIONS: Women are less likely to receive guideline recommended concomitant AF procedure during nonmitral surgery. Identification of barriers to concomitant AF procedure in women may improve treatment of AF.

Vulnerability to APOBEC3G linked to the pathogenicity of deltaretroviruses.

Human retroviruses are derived from simian ones through cross-species transmission. These retroviruses are associated with little pathogenicity in their natural hosts, but in humans, HIV causes AIDS, and human T-cell leukemia virus type 1 (HTLV-1) induces adult T-cell leukemia-lymphoma (ATL). We analyzed the proviral sequences of HTLV-1, HTLV-2, and simian T-cell leukemia virus type 1 (STLV-1) from Japanese macaques (Macaca fuscata) and found that APOBEC3G (A3G) frequently generates G-to-A mutations in the HTLV-1 provirus, whereas such mutations are rare in the HTLV-2 and STLV-1 proviruses. Therefore, we investigated the mechanism of how HTLV-2 is resistant to human A3G (hA3G). HTLV-1, HTLV-2, and STLV-1 encode the so-called antisense proteins, HTLV-1 bZIP factor (HBZ), Antisense protein of HTLV-2 (APH-2), and STLV-1 bZIP factor (SBZ), respectively. APH-2 efficiently inhibits the deaminase activity of both hA3G and simian A3G (sA3G). HBZ and SBZ strongly suppress sA3G activity but only weakly inhibit hA3G, suggesting that HTLV-1 is incompletely adapted to humans. Unexpectedly, hA3G augments the activation of the transforming growth factor (TGF)-ß/Smad pathway by HBZ, and this activation is associated with ATL cell proliferation by up-regulating BATF3/IRF4 and MYC. In contrast, the combination of APH-2 and hA3G, or the combination of SBZ and sA3G, does not enhance the TGF-ß/Smad pathway. Thus, HTLV-1 is vulnerable to hA3G but utilizes it to promote the proliferation of infected cells via the activation of the TGF-ß/Smad pathway. Antisense factors in each virus, differently adapted to control host cellular functions through A3G, seem to dictate the pathogenesis.

HTLV-1 and blood donation.

Human T-cell leukaemia virus type 1 (HTLV-1) is a human retrovirus that causes adult T-cell lymphoma and HTLV-associated myelopathy. In this issue, Rosadas et al. use data from a recent WHO report to describe how blood banks test for HTLV-1 and how this testing contributes to public health surveillance for the virus. Commentary on: Rosadas et al. HTLV-1 screening of blood donations: we are systematically missing opportunities. Br J Haematol 2023;202:1220-1223.

Differential Transcriptomic Signatures of Small Airway Cell Cultures Derived from IPF and COVID-19-Induced Exacerbation of Interstitial Lung Disease.

Idiopathic pulmonary fibrosis (IPF) is a pathological condition wherein lung injury precipitates the deposition of scar tissue, ultimately leading to a decline in pulmonary function. Existing research indicates a notable exacerbation in the clinical prognosis of IPF patients following infection with COVID-19. This investigation employed bulk RNA-sequencing methodologies to describe the transcriptomic profiles of small airway cell cultures derived from IPF and post-COVID fibrosis patients. Differential gene expression analysis unveiled heightened activation of pathways associated with microtubule assembly and interferon signaling in IPF cell cultures. Conversely, post-COVID fibrosis cell cultures exhibited distinctive characteristics, including the upregulation of pathways linked to extracellular matrix remodeling, immune system response, and TGF-ß1 signaling. Notably, BMP signaling levels were elevated in cell cultures derived from IPF patients compared to non-IPF control and post-COVID fibrosis samples. These findings underscore the molecular distinctions between IPF and post-COVID fibrosis, particularly in the context of signaling pathways associated with each condition. A better understanding of the underlying molecular mechanisms holds the promise of identifying potential therapeutic targets for future interventions in these diseases.

Is the public ready for a tobacco-free Ireland? A national survey of public knowledge and attitudes to tobacco endgame in Ireland.

AIM: Ireland will not meet the tobacco endgame goal set in its 2013 Tobacco-Free Ireland (TFI) policy of reducing smoking prevalence to less than 5% by 2025. Public opinion on tobacco endgame, a key lever to realise this goal, is uncharted in Ireland. This study aimed to measure public knowledge and attitudes to tobacco endgame. METHODS: A telephone-administered cross-sectional survey of 1000 randomly dialled members of the general public was conducted in 2022. Prevalence of awareness, perceived achievability and support for the TFI goal and tobacco endgame measures was calculated and compared across tobacco product use status. Logistic regression identified factors independently associated with goal support. FINDINGS: Although TFI goal awareness was low (34.0%), support was high (74.6%), although most (60.2%) believed it achievable beyond 2025. Product-focused measures were popular while support for supply-focused measures was mixed: for example, 86.1% supported nicotine content reduction while 40.3% supported user licencing. Phasing out tobacco sales was highly supported (82.8%); for most, this was contingent on support for currently addicted users. TFI goal support was independently associated with female sex (adjusted odds ratio (aOR) 1.47, 95% CI 1.05 to 2.07), higher education (aOR 1.80, 95% CI 1.21 to 2.66) and non-tobacco product use (aOR 2.67, 95% CI 1.66 to 4.30). CONCLUSIONS: Despite low awareness, tobacco endgame support is strong in Ireland. Public appetite for radically reducing tobacco product appeal and availability combined with public views on endgame achievability subject to extended timelines should be used to re-invigorate tobacco endgame discussion and planning in countries at risk of failing to meet declared targets.

Public attitudes to implementing financial incentives in stopsmoking services in Ireland.

INTRODUCTION: Financial incentives improve stop-smoking service outcomes. Views on acceptability can influence implementation success. To inform implementation planning in Ireland, public attitudes on financial incentives to stop smoking were measured. METHODS: A cross-sectional telephone survey was administered to 1000 people in Ireland aged ≥15 years in 2022, sampled through random digit dialing. The questionnaire included items on support for financial incentives under different conditions. Prevalence of support was calculated with 95% Confidence Intervals (CIs) and multiple logistic regression identified associated factors using adjusted odds ratios (AORs) with 95% CIs. RESULTS: Almost half (47.0%, 95% CI: 43.9-50.1) of the participants supported at least one type of financial incentive to stop smoking, with support more prevalent for shopping vouchers (43.3%, 95% CI: 40.3-46.5) than cash payments (32.1%, 95% CI: 29.2-35.0). Support was similar for universal and income-restricted schemes. Of those who supported financial incentives, the majority (60.6%) believed the maximum amount given on proof of stopping smoking should be under €250 (median=100, range: 1-7000). Compared to their counterparts, those of lower education level (AOR=1.49; 95% CI: 1.10-2.03, p=0.010) and tobacco/e-cigarette users (AOR=1.43; 95% CI: 1.02-2.03, p=0.041) were significantly more likely to support either financial incentive type, as were younger people. CONCLUSIONS: While views on financial incentives to stop smoking in Ireland were mixed, the intervention is more acceptable in groups experiencing the heaviest burden of smoking-related harm and most capacity to benefit. Engagement and communication must be integral to planning for successful implementation to improve stop-smoking service outcomes.

Del Nido Cardioplegia in Ascending Aortic Surgery.

Del Nido cardioplegia offers equivalent myocardial protection and clinical outcomes to blood cardioplegia in adult isolated CABG and valve patients, but the safety and efficacy of del Nido in complex cases with prolonged aortic cross-clamp times is still unknown. 443 patients at our center underwent replacement of the ascending aorta using either del Nido (n = 182) or blood (n = 261) cardioplegia. Two surgeons used del Nido exclusively and 6 used blood exclusively over the study period. Propensity matching of preoperative characteristics yielded 172 well matched pairs. Emergency and reoperative cases were included. Clinical data were extracted from our local database. Troponin levels were drawn at 12 hours postop in all patients. Rates of perioperative mortality (4.7% vs 5.2%), stroke (5.8% vs 7.0%), renal failure (11.6% vs 12.2%), atrial fibrillation (36.0% vs 31.4%), intra-aortic balloon pump insertion (2.3% vs1.2%), and extra corporeal membrane oxygenation use (4.7% vs 4.1%) did not differ between blood and del Nido groups. Postop Troponin T levels were 0.50[0.35, 0.86] ng/mL and 0.40[0.20, 0.70] ng/mL for blood and del Nido, respectively (P < 0.0001). Postop echocardiography was available in 333 of 344 (96.8%) patients, and there was no difference in change in EF from pre- to postop between blood 0.0[-6.0, 5.0]% and del Nido 0.0 [-6.0, 3.5]% (P = 0.201). Subgroup analysis of patients with aortic cross-clamp time greater than 180 minutes (blood = 77, del Nido = 27) revealed no difference in troponins, ejection fraction, or clinical outcomes. Five-year survival was 85.9[76.8, 91.7]% and 79.8[71.2, 86.1]% for blood and del Nido, respectively (P = 0.151). In ascending aortic surgery with prolonged operative times, no differences were observed in myocardial protection or clinical outcomes with the use of del Nido cardioplegia compared to blood cardioplegia.

Racial disparities in mitral valve surgery: A statewide analysis.

OBJECTIVE: Racial disparities in health care have come to the forefront. We hypothesized that Black race was associated with worse preoperative risk, lower repair rates, and worse outcomes among patients who underwent mitral valve surgery. METHODS: All patients who underwent mitral valve repair or replacement with or without coronary artery bypass grafting from 2011 to 2020 in a statewide collaborative database were stratified into 3 racial groups, White, Black, and other. Preoperative characteristics, procedure type, and outcomes were evaluated. RESULTS: A total of 9074 mitral valve operations were performed at 33 centers (Black 1009 [11.1%], White 7862 [86.6%]). Preoperative combined Society of Thoracic Surgeons morbidity and mortality was higher for Black patients (Black 32%, White 22%, other 23%, [P < .001]) because of a greater proportion of diabetes, hypertension, and chronic lung disease. White patients were more likely to undergo mitral repair (White 66%, Black 53.3%, other 57%; P < .001). Operative mortality was similar across racial groups (White 3.7%, Black 4.6%, other 4.5%; P = .36). After adjusting for preoperative factors, mitral etiology, and hospitals, race was not associated with mitral valve repair, complications, or mortality, but Black patients had higher odds of extended care facility utilization and readmission. CONCLUSIONS: Contrary to our hypothesis, there was no difference in the odds of repair or operative mortality across races after accounting for risk and etiology. However, Black patients were more likely to be readmitted after discharge. These findings support a greater focus on reducing disparities in mitral valve surgery.

Systemic cytokines and GlycA discriminate disease status and predict corticosteroid response in HTLV-1-associated neuroinflammation.

BACKGROUND: HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is an incapacitating neuroinflammatory disorder for which no disease-modifying therapy is available, but corticosteroids provide some clinical benefit. Although HAM/TSP pathogenesis is not fully elucidated, older age, female sex and higher proviral load are established risk factors. We investigated systemic cytokines and a novel chronic inflammatory marker, GlycA, as possible biomarkers of immunopathogenesis and therapeutic response in HAM/TSP, and examined their interaction with established risk factors. PATIENTS AND METHODS: We recruited 110 People living with HTLV-1 (PLHTLV-1, 67 asymptomatic individuals and 43 HAM/TSP patients) with a total of 946 person-years of clinical follow-up. Plasma cytokine levels (IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-γ, TNF) and GlycA were quantified by Cytometric Bead Array and 1NMR, respectively. Cytokine signaling and prednisolone response were validated in an independent cohort by nCounter digital transcriptomics. We used multivariable regression, machine learning algorithms and Bayesian network learning for biomarker identification. RESULTS: We found that systemic IL-6 was positively correlated with both age (r = 0.50, p < 0.001) and GlycA (r = 0.45, p = 0.00049) in asymptomatics, revealing an 'inflammaging" signature which was absent in HAM/TSP. GlycA levels were higher in women (p = 0.0069), but cytokine levels did not differ between the sexes. IFN-γ (p = 0.007) and IL-17A (p = 0.0001) levels were increased in untreated HAM/TSP Multivariable logistic regression identified IL-17A and proviral load as independent determinants of clinical status, resulting in modest accuracy of predicting HAM/TSP status (64.1%), while a machine learning-derived decision tree classified HAM/TSP patients with 90.7% accuracy. Pre-treatment GlycA and TNF levels significantly predicted clinical worsening (measured by Osame Motor Disability Scale), independent of proviral load. In addition, a poor prednisolone response was significantly correlated with higher post-treatment IFN-γ levels. Likewise, a transcriptomic IFN signaling score, significantly correlated with previously proposed HAM/TSP biomarkers (CASP5/CXCL10/FCGR1A/STAT1), was efficiently blunted by in vitro prednisolone treatment of PBMC from PLHTLV-1 and incident HAM/TSP. CONCLUSIONS: An age-related increase in systemic IL-6/GlycA levels reveals inflammaging in PLHTLV-1, in the absence of neurological disease. IFN-γ and IL-17A are biomarkers of untreated HAM/TSP, while pre-treatment GlycA and TNF predict therapeutic response to prednisolone pulse therapy, paving the way for a precision medicine approach in HAM/TSP.

Mixed methods evaluation of the 'real-world' implementation of group-based behavioral stop smoking support through Facebook.

INTRODUCTION: While promising evidence from trials of social-media-based stop smoking support informs service-planning, there is a need for more prospective, observational studies of smoking cessation interventions to build 'real-world' evidence. Specifically, user experiences have been under-explored with qualitative methods to date. This mixed-method evaluation of a closed Facebook group-based behavioral stop smoking support program, which was conducted in Ireland in 2018, aimed to address these issues. METHODS: Pre- and post-program surveys measured smoking abstinence (self-reported 7-day point prevalence), changes in smoking attitudes and behavior, and participant experiences. Engagement with Facebook was measured through counting 'likes' and comments, and was used to categorize groups as 'more active' and 'less active' over a 12-week period of support. Thematic content analysis of semi-structured participant interviews explored program experience in depth. RESULTS: In total, 13 of 52 participants reported smoking abstinence post-program (25.0%, 95% CI: 14.0-39.0). Participant engagement with Facebook was variable and decreased over the program. Membership of a 'more active' group was associated with better reported participant experience (e.g. 90.9% agreeing 'Facebook group helped me to quit or reduce smoking', versus 33.3% in the 'less active' group, p<0.05). Qualitative analysis identified three over-arching themes: importance of social interactions; perception of health information; and appeal of online support. CONCLUSIONS: Facebook can be used to deliver group-based behavioral stop smoking support in the real world. In Ireland, the one-month post-program abstinence outcomes achieved by other stop smoking services is approximately 50%, and while the outcomes for this service was lower (25%), it is still better than outcomes estimated for unassisted quitting. Engagement and peer-to-peer interactivity should be maximized to support positive participant experience.

Efficacy of del Nido cardioplegia in adult cardiac procedures with prolonged aortic crossclamp time.

OBJECTIVE: Equivalent myocardial protection and clinical outcomes have been shown with the use of del Nido cardioplegia (DC) compared with blood cardioplegia (BC) in adult isolated coronary artery bypass grafting and valve patients. However, its safety and efficacy in cardiac procedures with aortic crossclamp times >90 minutes is still unknown. METHODS: From May 2014 to September 2019, 2506 adult patients at our center underwent cardiac surgery requiring prolonged aortic crossclamp time defined as 90 minutes or longer. Myocardial protection was achieved with BC in 1955 patients and DC in 551 patients. Two surgeons used DC exclusively and 5 used blood exclusively over the study period. BC was delivered anterograde and retrograde whereas DC was delivered anterograde only. Propensity score matching of several preoperative characteristics, including primary cardiac pathology, yielded 526 well matched pairs. Emergency and reoperative cases were included. Troponin T levels were drawn at 12 hours postoperative in all patients. Clinical data were extracted from our local Society of Thoracic Surgeons database. Subgroup analyses were performed on the basis of crossclamp time stratification. RESULTS: For the propensity score-matched cohort, the median crossclamp time was longer in the BC compared with the DC group (114 [interquartile range (IQR), 100-145] minutes for DC vs 153 [IQR, 122-200] minutes for BC; P < .0001) whereas intraoperative peak glucose was higher with BC (173 [IQR, 147-200] g/dL for DC vs 197 [IQR, 171-228] g/dL for BC; P < .001). In addition, perioperative mortality (3.4% vs 3.0%; P = .7273), stroke (3.2% vs 2.1%; P = .2504), renal failure (6.5% vs 4.6%; P = .1767), atrial fibrillation (34% vs 31.4%, P = .3575), intra-aortic balloon pump use (5.3% vs 4.6%, P = .5694), and extracorporeal membrane oxygenation use (3.0% vs 2.9%, P = .8596) did not differ between DC and BC. Postoperative troponin T levels were 0.53 (IQR, 0.30-0.96) ng/mL and 0.62 (IQR, 0.38-1.07) ng/mL for DC and BC, respectively (P = .0024). Subgroup analysis revealed higher troponin T levels with DC for crossclamp times between 150 and 180 minutes. Survival rates at 1, 2, and 5 years were 93.3%, 91.1%, and 78.7% for DC and 94.5%, 91.8%, and 81.5% for BC, respectively (P = .5140). CONCLUSIONS: In adult cardiac surgical procedures with aortic crossclamp times >90 minutes, comparable myocardial protection, perioperative mortality and morbidity, and distant survival were observed with the use of DC compared with BC. Higher troponin levels were seen in DC patients with crossclamp times between 150 and 180 minutes, but this was not associated with increased mortality.

Implementation of an Africa-specific donor health questionnaire for human immunodeficiency virus risk screening.

BACKGROUND AND OBJECTIVES: We had previously developed an Africa-specific donor health questionnaire (ASDHQ) based on local risk factors and designed a scoring scheme. This study assessed the performance of a new donor health questionnaire by comparing the human immunodeficiency virus (HIV) status in accepted versus deferred donors by ASDHQ and comparing the rate of risk deferrals with historical data. MATERIALS AND METHODS: Data were collected during a cross-sectional study conducted over 15 months at three referral-hospital-based blood services in Cameroon. ASDHQ was administered to blood donors aged 18-65 years in the same screening conditions as the routine questionnaire. The main outcomes of the study were ASDHQ sensitivity and specificity with regard to HIV laboratory testing as well as donor deferral rates for each of the routine screening algorithms and for ASDHQ. RESULTS: Overall, 71/11,120 (0.6%) were confirmed as HIV positive. The mean ASDHQ score was 95.80 ± 4.4 in HIV-negative donors and 94.80 ± 4.4 in HIV-positive donors (p = 0.05). The optimal cut-off provided by the receiver operating characteristic (ROC) curve for the best performance of ASDHQ was 95.04. Using this optimal cut-off, the ASDHQ sensitivity and specificity were 57% and 53%, respectively (area under curve = 0.58 [0.51, 0.64], p = 0.028). Using ASDHQ, the HIV prevalence was 0.7% in deferred donors and 0.6% in accepted donors. CONCLUSION: ASDHQ might be efficient only in specific conditions that maximize truthful donor responses, requiring each blood service to create an environment of trust and transparency to increase donor compliance and improve the accuracy of the questionnaire.

Initial experience of magnetic seed localization for impalpable breast lesion excision: First 100 cases performed in a single Irish tertiary referral centre.

INTRODUCTION: Wire guided localization has been widely utilized as the standard method of pre-operative localization of breast lesions. Magnetic seeds were developed to counter some of the disadvantages associated with wires. This aim of this study was to assess outcomes following the introduction of magnetic seeds at a tertiary specialist breast centre. METHODS: A retrospective review of a prospective database of the first 100 patients who underwent magnetic seed (Magseed) guided breast surgery between November 2018 and November 2019. Data was collected from 17 wire guided cases completed during the trial phase for comparison. The primary outcome measures were successful excision of index lesion and retrieval of the magnetic seed. Secondary outcomes analyzed included time ready for theatre, post-operative complications and breast margin re-excision rate. RESULTS: Of these 100 cases, 85 patients underwent Magseed guided wide local excision for invasive or in-situ carcinoma and 15 underwent Magseed guided diagnostic excision. The primary lesion was excised, and Magseed was retrieved in all 100 cases. 54% of patients were ready to proceed as the first scheduled theatre case of the day, compared to 0% of wire-guided cases. Amongst therapeutic Magseed guided cases, the re-excision rate for margin clearance was 9.4%. CONCLUSION: Magseed guided breast excision is a new technology that has been implemented with relative ease in our unit. We have shown that magnetic seed guided surgery reliably localizes lesions, is associated with low re-excision rates without an increase in patient morbidity or mortality and results in improvements in theatre planning and efficiency.

Freestyle Aortic Bioprostheses in Patients 60 Years old and Younger.

Evaluate outcomes of the Freestyle stentless aortic bioprosthesis in patients 60 years old and younger. All patients, 60 years old and younger, between January 1, 1998 to December 31, 2015 who underwent implantation of a Freestyle aortic valve at a single institution were reviewed. Medical records and telephone interviews were utilized for data collection. 515 patients were identified with an average age of 51.3 years. Mean follow up was 11.1 years. 225 full root replacements and 290 subcoronary implants were performed. Overall survival, including patients with concomitant procedures, at 15 years was 63.7% (95% CI 58.3-68.5). Isolated subcoronary implants (58%,167/290) had a 15-year survival of 71.6% (95% CI 62.6-78.7) vs 78.4% (95% CI 69.7, 84.9) for isolated root replacements (63%,141/225) which was not statistically significant (P = 0.397). No significant difference in operative SVD at 15 years occurred between full root replacements 37.6% (95% CI 27.2-50.2) vs subcoronary implants 39.4% (95% CI31.1, 49.0). 110 patients required reoperation solely for intrinsic SVD. 93% (102/110) failed due to aortic insufficiency. Of reoperative interventions for SVD, 37% (41/110) of patients required urgent reoperation and 4.5% (5/110) required emergent reoperation. Pseudoaneurysms developed in six of the full root replacements. Freestyle aortic valves have a high rate of acute failure requiring urgent or emergent reintervention in patients 60 years old and younger. This has led our group to shift practice away from their implantation.

A novel high performing multiplex immunoassay Multi-HTLV for serological confirmation and typing of HTLV infections.

BACKGROUND: Human T-Cell Lymphotropic Viruses (HTLV) type 1 and type 2 account for an estimated 5 to 10 million infections worldwide and are transmitted through breast feeding, sexual contacts and contaminated cellular blood components. HTLV-associated syndromes are considered as neglected diseases for which there are no vaccines or therapies available, making it particularly important to ensure the best possible diagnosis to enable proper counselling of infected persons and avoid secondary transmission. Although high quality antibody screening assays are available, currently available confirmatory tests are costly and have variable performance, with high rates of indeterminate and non-typable results reported in many regions of the world. The objective of this project was to develop and validate a new high-performance multiplex immunoassay for confirmation and discrimination of HTLV-1 and HTLV-2 strains. METHODOLOGY/PRINCIPAL FINDINGS: The multiplex platform was used first as a tool to identify suitable antigens and in a second step for assay development. With data generated on over 400 HTLV-positive blood donors sourced from USA and French blood banks, we developed and validated a high-precision interpretation algorithm. The Multi-HTLV assay demonstrated very high performance for confirmation and strain discrimination with 100% sensitivity, 98.1% specificity and 100% of typing accuracy in validation samples. The assay can be interpreted either visually or automatically with a colorimetric image reader and custom algorithm, providing highly reliable results. CONCLUSIONS/SIGNIFICANCE: The newly developed Multi-HTLV is very competitive with currently used confirmatory assays and reduces considerably the number of indeterminate results. The multiparametric nature of the assay opens new avenues to study specific serological signatures of each patient, follow the evolution of infection, and explore utility for HTLV disease prognosis. Improving HTLV diagnostic testing will be critical to reduce transmission and to improve monitoring of seropositive patients.

Undisclosed HIV status and antiretroviral therapy use among South African blood donors.

BACKGROUND: Undisclosed antiretroviral drug (ARV) use among blood donors who tested HIV antibody positive, but RNA negative, was previously described by our group. Undisclosed ARV use represents a risk to blood transfusion safety. We assessed the prevalence of and associations with undisclosed ARV use among HIV-positive donors who donated during 2017. STUDY DESIGN AND METHODS: South African National Blood Service (SANBS) blood donors are screened by self-administered questionnaire, semi-structured interview, and individual donation nucleic acid amplification testing for HIV. Stored samples from HIV-positive donations were tested for ARV and characterized as recent/longstanding using lag avidity testing. RESULTS: Of the 1462 HIV-positive donations in 2017, 1250 had plasma availability for testing of which 122 (9.8%) tested positive for ARV. Undisclosed ARV use did not differ by gender (p = .205) or ethnicity (p = .505) but did differ by age category (p < .0001), donor (p < .0001), clinic type (p = .012), home province (p = .01), and recency (p < .0001). Multivariable logistic regression found older age (adjusted odds ratio [aOR] 3.73, 95% confidence interval [CI] 1.98-7.04 for donors >40 compared with those <21), first-time donation (aOR 5.24; 95% CI 2.48-11.11), and donation in a high HIV-prevalence province (aOR 9.10; 95% CI 2.70-30.72) compared with Northern Rural provinces to be independently associated with undisclosed ARV use. DISCUSSION: Almost 1 in 10 HIV-positive blood donors neglected to disclose their HIV status and ARV use. Demographic characteristics of donors with undisclosed ARV use differed from those noted in other study. Underlying motivations for nondisclosure among blood donors remain unclear and may differ from those in other populations with significant undisclosed ARV use.

Phenotypic and Functional Analyses Guiding Combination Immune Checkpoint Immunotherapeutic Strategies in HTLV-1 Infection.

Human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) develops in 1-5% of HTLV-1-infected individuals. Previous studies by us and others have shown that the expression of negative immune checkpoint receptors (NCRs) is significantly increased on CD8 T cells in various chronic viral infections and are associated with poor anti-viral immunity. We have previously identified the differential expression of NCRs on CD8 T cells in blood from patients with HAM/TSP and in central nervous system (CNS) tissues of HTLV-1 infected humanized mice and defined the association with neurological complications. In this study, we determined the co-expression patterns of several key NCRs (PD-1, TIGIT, TIM-3, and LAG-3) and their cognate ligands in HTLV-1 infection and assessed how combination strategies targeting these pathways would impact HTLV-1-specific CD8 T-cell effector functions as an approach to reduce CNS disease outcomes. We found that global CD8 T cells from HAM/TSP patients co-express multiple NCRs at significantly higher frequencies than asymptomatic carriers (AC). Moreover, NCR ligands (PVR and PD-LI) on both plasmacytoid and myeloid dendritic cells were also expressed at higher frequencies in HAM/TSP compared to AC. In both AC and HAM/TSP subjects, combination dual PD-L1/TIGIT or triple PD-L1/TIGIT/TIM-3 blockade with monoclonal antibodies resulted in increases in intracellular cytokine expression in CD8 T cells after virus stimulation, particularly CD107a, a marker of degranulation, and TNF-α, a key cytokine that can directly inhibit viral replication. Interestingly, almost all blockade combinations resulted in reduced IL-2+ HTLV-1-specific CD8 T cell frequencies in HAM/TSP subjects, but not in AC. These results define a novel combinatorial NCR immunotherapeutic blockade strategy to reduce HAM/TSP disease burden.

Long-term outcomes of etiology specific annuloplasty ring repair of ischemic mitral regurgitation.

BACKGROUND: Reductive annuloplasty repair of ischemic mitral regurgitation (IMR) is associated with high rates of recurrent MR, which may be improved with etiology-specific annuloplasty rings. METHODS: From October 2005 to May 2015, 128 consecutive patients underwent repair of IMR with the GeoForm ring. Clinical data was extracted from our local Society of Thoracic Surgeons database and electronic medical records. Mortality data was obtained from the Michigan State Social Security Death Index. RESULTS: The average age of patients was 65±11 years with mean pre-op left ventricular ejection fraction (LVEF) of 30%±10% and MR grade of 3.1±0.9 (0-4+). Thirty-day mortality was 4.7%, rate of renal failure 7.9%, rate of atrial fibrillation 27.3%, and no strokes were observed. Of the surviving patients, 89% (109/122) had a follow-up echocardiogram beyond 1 month with a mean echocardiographic follow-up of 59±39 months. LVEF improved from 30%±10% to 38%±14%, P<0.001) while end-diastolic (5.9±0.0 to 5.3±0.9 cm, P<0.001) and end-systolic (5.0±1.0 to 4.4±1.1 cm, P<0.001) left ventricular (LV) diameters decreased, as compared to pre-operative values. Seven patients were found to have recurrent moderate or greater IMR in follow-up to 10 years with three being due to ring dehiscence. One-, 5-, and 10-year freedom from recurrent moderate or severe IMR was 98%, 94%, and 80% respectively. One-, 5-, and 10-year survival was 91%, 77%, and 44%, respectively. CONCLUSIONS: Overall, etiology-specific ring repair of IMR was associated with low rates of recurrent MR on long-term follow-up, coupled with significant LV reverse remodeling and improvement in ejection fraction.