Impact of Complex Anatomy and Patient Risk Profile in Minimally Invasive Mitral Valve Surgery.

BACKGROUND: We aimed to assess the impact of complex mitral valve disease and patient risk profile on operative outcomes in the large cohort of the Mini-Mitral International Registry. METHODS: Patients were assigned to categories of complex degenerative mitral valve regurgitation (DMR; bileaflet or anterior mitral leaflet prolapse/flail) and simple DMR (posterior mitral leaflet prolapse/flail). Subgroup analyses was performed in low-risk (EuroSCORE II <8%) and high-risk (EuroSCORE II >8%) cohorts. A logistic regression model was applied to investigate the impact of valve anatomy and patient risk factors on valve repair rate and operative risk. RESULTS: The study cohort consisted of 4524 patients with DMR (complex DMR, 1296; simple DMR, 3228). Valve repair rate was 87.3% and 91% in complex DMR and simple DMR, respectively. Predictors of valve replacement were anterior leaflet prolapse/flail, bileaflet flail, female sex, age, and reoperation, whereas Barlow disease was protective. Clinical results were comparable between complex DMR and simple DMR. On subgroup analyses, high-risk patients showed less satisfactory outcomes with respect to both the valve repair and operative mortality rates. CONCLUSIONS: Our findings suggest that complex DMR can be satisfactorily addressed by minimally invasive techniques. However, whereas complex disease was associated with low operative risk, anterior leaflet lesions and bileaflet flail remain negative predictors of successful valve repair. Conversely, valve repair rate was less satisfactory in high-risk patients, regardless of DMR complexity.

HIF-2α-dependent induction of miR-29a restrains TH1 activity during T cell dependent colitis.

Metabolic imbalance leading to inflammatory hypoxia and stabilization of hypoxia-inducible transcription factors (HIFs) is a hallmark of inflammatory bowel diseases. We hypothesize that HIF could be stabilized in CD4+ T cells during intestinal inflammation and alter the functional responses of T cells via regulation of microRNAs. Our assays reveal markedly increased T cell-intrinsic hypoxia and stabilization of HIF protein during experimental colitis. microRNA screen in primary CD4+ T cells points us towards miR-29a and our subsequent studies identify a selective role for HIF-2α in CD4-cell-intrinsic induction of miR-29a during hypoxia. Mice with T cell-intrinsic HIF-2α deletion display elevated T-bet (target of miR-29a) levels and exacerbated intestinal inflammation. Mice with miR-29a deficiency in T cells show enhanced intestinal inflammation. T cell-intrinsic overexpression of HIF-2α or delivery of miR-29a mimetic dampen TH1-driven colitis. In this work, we show a previously unrecognized function for hypoxia-dependent induction of miR-29a in attenuating TH1-mediated inflammation.

An antibody to IL-1 receptor 7 protects mice from LPS-induced tissue and systemic inflammation.

Introduction: Interleukin-18 (IL-18), a pro-inflammatory cytokine belonging to the IL-1 Family, is a key mediator ofautoinflammatory diseases associated with the development of macrophage activation syndrome (MAS).High levels of IL-18 correlate with MAS and COVID-19 severity and mortality, particularly in COVID-19patients with MAS. As an inflammation inducer, IL-18 binds its receptor IL-1 Receptor 5 (IL-1R5), leadingto the recruitment of the co-receptor, IL-1 Receptor 7 (IL-1R7). This heterotrimeric complex subsequentlyinitiates downstream signaling, resulting in local and systemic inflammation. Methods: We reported earlier the development of a novel humanized monoclonal anti-human IL-1R7 antibody whichspecifically blocks the activity of human IL-18 and its inflammatory signaling in human cell and wholeblood cultures. In the current study, we further explored the strategy of blocking IL-1R7 inhyperinflammation in vivo using animal models. Results: We first identified an anti-mouse IL-1R7 antibody that significantly suppressed mouse IL-18 andlipopolysaccharide (LPS)-induced IFNg production in mouse splenocyte and peritoneal cell cultures. Whenapplied in vivo, the antibody reduced Propionibacterium acnes and LPS-induced liver injury and protectedmice from tissue and systemic hyperinflammation. Importantly, anti-IL-1R7 significantly inhibited plasma,liver cell and spleen cell IFNg production. Also, anti-IL-1R7 downregulated plasma TNFa, IL-6, IL-1b,MIP-2 production and the production of the liver enzyme ALT. In parallel, anti-IL-1R7 suppressed LPSinducedinflammatory cell infiltration in lungs and inhibited the subsequent IFNg production andinflammation in mice when assessed using an acute lung injury model. Discussion: Altogether, our data suggest that blocking IL-1R7 represents a potential therapeutic strategy to specificallymodulate IL-18-mediated hyperinflammation, warranting further investigation of its clinical application intreating IL-18-mediated diseases, including MAS and COVID-19.

Savings associated with surgical aortic valve replacement with a RESILIA tissue valve based on seven-year COMMENCE trial results.

BACKGROUND: Bioprostheses with RESILIA tissue demonstrate a reduction in calcification and improve health outcomes in pre-clinical and clinical studies. Prior economic analyses which relied on 5 years of evidence from the COMMENCE trial demonstrate financial savings for RESILIA tissue valves relative to mechanical valves after surgical aortic valve replacement (SAVR). Given the recent release of 7-year COMMENCE data, this economic evaluation updates the estimate for long-run savings of bioprosthetic valves with RESILIA. METHODS: Simulation models estimated disease progression across two hypothetical SAVR cohorts (tissue vs. mechanical) of 10,000 patients each in the US. The primary comparison calculated the SAVR-related expenditures associated with each valve type ($US, 2023). Health outcome probabilities were based on the COMMENCE trial though year 7 and projected for an additional 8 years based on prior studies of tissue and mechanical SAVR. Costs for key outcomes (mortality, reoperation, bleeding, thromboembolism, endocarditis) and anticoagulant monitoring were sourced from the literature. Incidence rates of health outcomes associated with mechanical valves relied on relative risks of tissue valve versus mechanical valve patients. RESULTS: Seven-year savings are $13,415 (95% CI = $10,472-$17,321) per patient when comparing RESILIA versus mechanical SAVR. Projected 15-year savings were $23,001 ($US, 2023; 95% CI = $17,802-$30,421). Most of the 15-year savings are primarily attributed to lower anti-coagulation monitoring costs ($21,073 in ACM savings over 15 years), but lower bleeding cost (savings: $2,294) and thromboembolism-related expenditures (savings: $852) also contribute. Reoperation and endocarditis expenditures were slightly larger in the RESILIA cohort. If reoperation relative risk reverts from 1.1 to 2.2 (the level in legacy tissue valves) after year 7, savings are $18,064. RESILIA SAVR also reduce costs relative to legacy tissue valves. CONCLUSION: Patients receiving RESILIA tissue valves are projected to have lower SAVR-related health expenditures relative to mechanical and legacy tissue valves.

3-Year Outcomes for Degenerative Mitral Regurgitation Repair in a Medicare Population.

OBJECTIVE: Mitral valve repair (MVr) has become the standard therapy for degenerative mitral regurgitation (DMR), but real-world late mortality, reintervention, and readmission data are lacking. This study estimates MVr outcomes for DMR to 3 years in the Medicare fee-for-service population. METHODS: There were 4,219 DMR patients older than 65 years undergoing MVr within the Medicare 100% standard analytic file from October 2015 to December 2018 who were evaluated. Outcomes were analyzed for isolated MVr patients (n = 2,433) and patients undergoing MVr with certain concomitant procedures: MVr + tricuspid valve surgery (TVS; n = 619), MVr + cardiac ablation (CA; n = 540), and MVr + left atrial appendage closure (n = 627). Outcomes over a 3-year period included all-cause mortality, reintervention, rehospitalization, and common complications. All outcomes were modeled with adjustments for patient demographics and comorbid conditions. RESULTS: The average age for all patients was 71.9 ± 5.2 years. Adjusted all-cause mortality and MV reintervention (surgery or transcatheter) at 3 years for the primary cohort of isolated MVr was 3.5% and 1.6%, respectively. Directionally higher mortality at 3 years was observed in patients with concomitant TVS or CA. All-cause readmission and cardiac readmission for isolated MVr was 37.0% and 14.1%, with the highest rates for those with concomitant TVS or CA. Acute kidney injury and stroke/transient ischemic attack were the most common adverse events over 3 years for all patients. CONCLUSIONS: The 3-year mortality and reintervention rates in Medicare patients undergoing degenerative MVr are low. Those undergoing concomitant TVS or CA had directionally higher mortality and cardiac readmission rates. These results help refine outcome benchmarks as new transcatheter MVr procedures continue to emerge.

Activating Point Mutations in the MET Kinase Domain Represent a Unique Molecular Subset of Lung Cancer and Other Malignancies Targetable with MET Inhibitors.

Activating point mutations in the MET tyrosine kinase domain (TKD) are oncogenic in a subset of papillary renal cell carcinomas. Here, using comprehensive genomic profiling among >600,000 patients, we identify activating MET TKD point mutations as putative oncogenic driver across diverse cancers, with a frequency of ∼0.5%. The most common mutations in the MET TKD defined as oncogenic or likely oncogenic according to OncoKB resulted in amino acid substitutions at positions H1094, L1195, F1200, D1228, Y1230, M1250, and others. Preclinical modeling of these alterations confirmed their oncogenic potential and also demonstrated differential patterns of sensitivity to type I and type II MET inhibitors. Two patients with metastatic lung adenocarcinoma harboring MET TKD mutations (H1094Y, F1200I) and no other known oncogenic drivers achieved confirmed partial responses to a type I MET inhibitor. Activating MET TKD mutations occur in multiple malignancies and may confer clinical sensitivity to currently available MET inhibitors. Significance: The identification of targetable genomic subsets of cancer has revolutionized precision oncology and offers patients treatments with more selective and effective agents. Here, we demonstrate that activating, oncogenic MET tyrosine kinase domain mutations are found across a diversity of cancer types and are responsive to MET tyrosine kinase inhibitors.

Lessons Learned From TranslateCovid, a Multilingual Online Resource Hub for Asian American and Pacific Islander Communities and Beyond.

The COVID-19 pandemic exacerbated health disparities among immigrant communities. Delivering accurate information and addressing misinformation on protective measures and vaccination to linguistically disadvantaged groups was critical for mitigating the effects of the pandemic. One group that was especially vulnerable to miscommunication about COVID-19 was non-native English-speaking immigrants. To address these disparities, the Asian American Studies Center and the Fielding School of Public Health at the University of California, Los Angeles, partnered to create a multilingual resource hub, TranslateCovid.org, to disseminate credible and reliable information about COVID-19 safety measures, the science behind the vaccines, and vaccine safety. We identified >1300 verified resources in 60 languages from government, academic, and nonprofit organizations and reposted them on the TranslateCovid website. We also developed public service announcement videos on handwashing, use of face masks, and social distancing in 10 languages and a fact sheet for frequently asked questions in 20 languages. We used a participatory approach to develop strategies for disseminating these resources. We discuss lessons learned, including strategies for forming government, community, and academic partnerships to support the timely development and dissemination of information. We conclude with a discussion on the unique role of universities in promoting equitable access to public health resources among immigrant communities in times of crisis.

Pacemaker implantation after concomitant tricuspid valve repair in patients undergoing minimally invasive mitral valve surgery: Results from the Mini-Mitral International Registry.

Objective: Randomized evidence suggests a high risk of pacemaker implantation for patients undergoing mitral valve (MV) surgery with concomitant tricuspid valve repair (cTVR). We investigated the impact of cTVR on outcomes in the Mini-Mitral International Registry. Methods: From 2015 to 2021, 7513 patients underwent minimally invasive MV with or without cTVR in 17 international centers (MV: n = 5609, cTVR: n = 1113). Propensity matching generated 1110 well-balanced pairs. Multivariable analysis was applied. Results: Patients with cTVR were older and had more comorbidities. Propensity matching eliminated most differences except for more TR in patients who underwent cTVR (77.2% vs 22.1% MV, P < .001). Mean matched age was 71 years, and 45% were male. European System for Cardiac Operative Risk Evaluation II was still 2.68% (interquartile range [IQR], 0.80-2.63) vs 1.9% (IQR, 1.12-3.9) in matched MV (P < .001). MV replacement (30%) and atrial fibrillation surgery (32%) were similar in both groups. Cardiopulmonary bypass (161 minutes [IQR, 133-203] vs MV: 130 minutes [IQR, 103-166]; P < .001) and crossclamp times (93 minutes [IQR, 66-123] vs MV: 83 minutes [IQR, 64-107]; P < .001) were longer with cTVR. Although in-hospital mortality was similar (cTVR: 3.3% vs MV: 2.2%; P = .5), postoperative pacemaker implantations (9% vs MV: 5.8%; P = .02), low cardiac output syndrome (7.7% vs MV: 4.4%; P = .02), and acute kidney injury (13.8% vs MV: 10%; P = .01) were more frequent with cTVR. cTVR eliminated relevant TR in most patients (greater-than-moderate TR: 6.8%). Multivariable analysis identified MV replacement, atrial fibrillation, and cTVR as risk factors of postoperative pacemaker implantation. Conclusions: cTVR in minimally invasive MV surgery is an independent risk factor for pacemaker implantation in this international registry. It is also associated with more bleeding, low output syndrome, and acute kidney injury. It remains unclear whether technical or patient factors (or both) explain these differences.

Impact of transcatheter heart valve type on outcomes of surgical explantation after failed transcatheter aortic valve replacement: the EXPLANT-TAVR international registry.

BACKGROUND: There are limited data on the impact of transcatheter heart valve (THV) type on the outcomes of surgical explantation after THV failure. AIMS: We sought to determine the outcomes of transcatheter aortic valve replacement (TAVR) explantation for failed balloon-expandable valves (BEV) versus self-expanding valves (SEV). METHODS: From November 2009 to February 2022, 401 patients across 42 centres in the EXPLANT-TAVR registry underwent TAVR explantation during a separate admission from the initial TAVR. Mechanically expandable valves (N=10, 2.5%) were excluded. The outcomes of TAVR explantation were compared for 202 (51.7%) failed BEV and 189 (48.3%) failed SEV. RESULTS: Among 391 patients analysed (mean age: 73.0±9.8 years; 33.8% female), the median time from index TAVR to TAVR explantation was 13.3 months (interquartile range 5.1-34.8), with no differences between groups. Indications for TAVR explantation included endocarditis (36.0% failed SEV vs 55.4% failed BEV; p<0.001), paravalvular leak (21.2% vs 11.9%; p=0.014), structural valve deterioration (30.2% vs 21.8%; p=0.065) and prosthesis-patient mismatch (8.5% vs 10.4%; p=0.61). The SEV group trended fewer urgent/emergency surgeries (52.0% vs 62.3%; p=0.057) and more root replacement (15.3% vs 7.4%; p=0.016). Concomitant cardiac procedures were performed in 57.8% of patients, including coronary artery bypass graft (24.8%), and mitral (38.9%) and tricuspid (14.6%) valve surgery, with no differences between groups. In-hospital, 30-day, and 1-year mortality and stroke rates were similar between groups (allp>0.05), with no differences in cumulative mortality at 3 years (log-rank p=0.95). On multivariable analysis, concomitant mitral surgery was an independent predictor of 1-year mortality after BEV explant (hazard ratio [HR] 2.00, 95% confidence interval [CI]: 1.07-3.72) and SEV explant (HR 2.00, 95% CI: 1.08-3.69). CONCLUSIONS: In the EXPLANT-TAVR global registry, BEV and SEV groups had different indications for surgical explantation, with more root replacements in SEV failure, but no differences in midterm mortality and morbidities. Further refinement of TAVR explantation techniques are important to improving outcomes.

Heat shock factor 1 drives regulatory T-cell induction to limit murine intestinal inflammation.

The heat shock response is a critical component of the inflammatory cascade that prevents misfolding of new proteins and regulates immune responses. Activation of clusters of differentiation (CD)4+ T cells causes an upregulation of heat shock transcription factor, heat shock factor 1 (HSF1). We hypothesized that HSF1 promotes a pro-regulatory phenotype during inflammation. To validate this hypothesis, we interrogated cell-specific HSF1 knockout mice and HSF1 transgenic mice using in vitro and in vivo techniques. We determined that while HSF1 expression was induced by anti-CD3 stimulation alone, the combination of anti-CD3 and transforming growth factor ß, a vital cytokine for regulatory T cell (Treg) development, resulted in increased activating phosphorylation of HSF1, leading to increased nuclear translocation and binding to heat shock response elements. Using chromatin immunoprecipitation (ChIP), we demonstrate the direct binding of HSF1 to foxp3 in isolated murine CD4+ T cells, which in turn coincided with induction of FoxP3 expression. We defined that conditional knockout of HSF1 decreased development and function of Tregs and overexpression of HSF1 led to increased expression of FoxP3 along with enhanced Treg suppressive function. Adoptive transfer of CD45RBHigh CD4 colitogenic T cells along with HSF1 transgenic CD25+ Tregs prevented intestinal inflammation when wild-type Tregs did not. Finally, overexpression of HSF1 provided enhanced barrier function and protection from murine ileitis. This study demonstrates that HSF1 promotes Treg development and function and may represent both a crucial step in the development of induced regulatory T cells and an exciting target for the treatment of inflammatory diseases with a regulatory T-cell component. SIGNIFICANCE STATEMENT: The heat shock response (HSR) is a canonical stress response triggered by a multitude of stressors, including inflammation. Evidence supports the role of the HSR in regulating inflammation, yet there is a paucity of data on its influence in T cells specifically. Gut homeostasis reflects a balance between regulatory clusters of differentiation (CD)4+ T cells and pro-inflammatory T-helper (Th)17 cells. We show that upon activation within T cells, heat shock factor 1 (HSF1) translocates to the nucleus, and stimulates Treg-specific gene expression. HSF1 deficiency hinders Treg development and function and conversely, HSF1 overexpression enhances Treg development and function. While this work, focuses on HSF1 as a novel therapeutic target for intestinal inflammation, the findings have significance for a broad range of inflammatory conditions.

Initial Chemotherapy for Locally Advanced and Metastatic NUT Carcinoma.

INTRODUCTION: NUT carcinoma (NC) is an underdiagnosed and aggressive poorly differentiated or squamous cell cancer. A subset of NC is sensitive to chemotherapy, but the optimal regimen is unknown. Experts have recommended platinum- and ifosfamide-based therapy based on case reports. METHODS: Patients with pathologically confirmed NC with known survival outcomes after chemotherapy and consented to participate in a worldwide registry were studied. Results were summarized using descriptive methods. RESULTS: The study included 118 patients with NC. Median age was 34 (range: 1-82) years, 39% were women, and 61% harbored a BRD4::NUTM1 fusion. Patients received platinum (74%) or ifosfamide (26%, including regimens with both, 13%). Of 62 patients with nonmetastatic disease, 40% had a thoracic primary. Compared with platinum-based chemotherapy, patients who received ifosfamide-based chemotherapy had nominally higher progression-free survival (12 mo: 59% [95% CI: 32-87] versus 37% [95% CI: 22-52], hazard ratio = 0.68 [0.32, 1.42], p = 0.3) but not overall survival (OS). Among the 56 patients with metastatic disease, 80% had a thoracic primary. Ifosfamide had an objective response rate (ORR) of 75% (six of eight) and platinum had an ORR of 31% (11 of 36). Nevertheless, there was no difference in progression-free survival or OS. The 3-year OS of the entire cohort was 19% (95% CI: 10%-28%). Of the 11 patients alive greater than 3 years, all presented with nonmetastatic and operable or resectable disease. CONCLUSION: There is a numerically higher ORR for ifosfamide-based therapy compared with platinum-based therapy, with limited durability. OS at 3 years is only 19%, and development of effective therapies is an urgent unmet need for this patient population.

Improving patient outcomes with a mobile digital health platform for patients undergoing transcatheter aortic valve replacement.

PURPOSE: ManageMySurgery (MMS) is a digital health application (app) for patients undergoing surgery, including Transcatheter Aortic Valve Replacement (TAVR). Patients using MMS review procedure-specific education, view FAQs, and report patient-reported outcomes. This study assessed the impact of app use on postoperative outcomes. METHODS: Patients who underwent TAVR and invited to use MMS between March 2019 and November 2021 were identified. Patients received standard perioperative care and were defined as App users if they signed into the app at least once and engaged with at least one task or FAQ. Demographics and postoperative outcomes were collected via medical record review. Multivariable logistic regression models were used to determine odds of 90-day readmission, Emergency Room (ER) visits, and complications. RESULTS: 388 patients met inclusion criteria, of which 238 used the app. The average age at surgery was 76.4±7.7 years for users and 78.1±7.6 for non-users. 63.0% of users and 59.3% of non-users were male. App users had significantly lower 90-day readmission rates, (8.8% vs 16.0%, OR=0.51, p=0.0373), ER visit rates (12.6% vs 27.3%, OR=0.36, p=0.0003), and complication rates (Minor: 12.2% vs 20.7%, OR=0.48, P=0.0126; Major: 8.8% vs. 16%, OR=0.47, P=0.0235). CONCLUSIONS: In this non-randomized, retrospective study, we found significant decreases in 90-day readmissions, ER visits, and complications in TAVR patients using an app compared to traditional care. By engaging patients throughout their interventional journey with structured education and tasks, mobile health platforms may mitigate unnecessary use of emergency and inpatient care, thereby improving patient well-being and lowering the burden on healthcare resources.

Neurological outcomes in minimally invasive mitral valve surgery: risk factors analysis from the Mini-Mitral International Registry.

OBJECTIVES: The aim of this study was to examine the incidence and predictors of stroke after minimally invasive mitral valve surgery (mini-MVS) and to assess the role of preoperative CT scan on surgical management and neurological outcomes in the large cohort of Mini-Mitral International Registry. METHODS: Clinical, operative and in-hospital outcomes in patients undergoing mini-MVS between 2015 and 2021 were collected. Univariable and multivariable analyses were used to identify predictors of stroke. Finally, the impact of preoperative CT scan on surgical management and neurological outcomes was assessed. RESULTS: Data from 7343 patients were collected. The incidence of stroke was 1.3% (n = 95/7343). Stroke was associated with higher in-hospital mortality (11.6% vs 1.5%, P < 0.001) and longer intubation time, ICU and hospital stay (median 26 vs 7 h, 120 vs 24 h and 14 vs 8 days, respectively). On multivariable analysis, age (odds ratio 1.039, 95% confidence interval 1.019-1.060, P < 0.001) and mitral valve replacement (odds ratio 2.167, 95% confidence interval 1.401-3.354, P < 0.001) emerged as independent predictors of stroke. Preoperative CT scan was made in 31.1% of cases. These patients had a higher risk profile and EuroSCORE II (median 1.58 vs 1.1, P < 0.001). CT scan influenced the choice of cannulation site, being ascending aorta (18.5% vs 0.5%, P < 0.001) more frequent in the CT group and femoral artery more frequent in the no CT group (97.8% vs 79.7%, P < 0.001). No difference was found in the incidence of postoperative stroke (CT group 1.5, no CT group 1.4%, P = 0.7). CONCLUSIONS: Mini-MVS is associated with a low incidence of stroke, but when it occurs it has an ominous impact on mortality. Preoperative CT scan affected surgical cannulation strategy but did not led to improved neurological outcomes.