Type-II IFN inhibits SARS-CoV-2 replication in human lung epithelial cells and ex vivo human lung tissues through indoleamine 2,3-dioxygenase-mediated pathways.

Interferons (IFNs) are critical for immune defense against pathogens. While type-I and -III IFNs have been reported to inhibit SARS-CoV-2 replication, the antiviral effect and mechanism of type-II IFN against SARS-CoV-2 remain largely unknown. Here, we evaluate the antiviral activity of type-II IFN (IFNγ) using human lung epithelial cells (Calu3) and ex vivo human lung tissues. In this study, we found that IFNγ suppresses SARS-CoV-2 replication in both Calu3 cells and ex vivo human lung tissues. Moreover, IFNγ treatment does not significantly modulate the expression of SARS-CoV-2 entry-related factors and induces a similar level of pro-inflammatory response in human lung tissues when compared with IFNß treatment. Mechanistically, we show that overexpression of indoleamine 2,3-dioxygenase 1 (IDO1), which is most profoundly induced by IFNγ, substantially restricts the replication of ancestral SARS-CoV-2 and the Alpha and Delta variants. Meanwhile, loss-of-function study reveals that IDO1 knockdown restores SARS-CoV-2 replication restricted by IFNγ in Calu3 cells. We further found that the treatment of l-tryptophan, a substrate of IDO1, partially rescues the IFNγ-mediated inhibitory effect on SARS-CoV-2 replication in both Calu3 cells and ex vivo human lung tissues. Collectively, these results suggest that type-II IFN potently inhibits SARS-CoV-2 replication through IDO1-mediated antiviral response.

A molecularly engineered, broad-spectrum anti-coronavirus lectin inhibits SARS-CoV-2 and MERS-CoV infection in vivo.

"Pan-coronavirus" antivirals targeting conserved viral components can be designed. Here, we show that the rationally engineered H84T-banana lectin (H84T-BanLec), which specifically recognizes high mannose found on viral proteins but seldom on healthy human cells, potently inhibits Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (including Omicron), and other human-pathogenic coronaviruses at nanomolar concentrations. H84T-BanLec protects against MERS-CoV and SARS-CoV-2 infection in vivo. Importantly, intranasally and intraperitoneally administered H84T-BanLec are comparably effective. Mechanistic assays show that H84T-BanLec targets virus entry. High-speed atomic force microscopy depicts real-time multimolecular associations of H84T-BanLec dimers with the SARS-CoV-2 spike trimer. Single-molecule force spectroscopy demonstrates binding of H84T-BanLec to multiple SARS-CoV-2 spike mannose sites with high affinity and that H84T-BanLec competes with SARS-CoV-2 spike for binding to cellular ACE2. Modeling experiments identify distinct high-mannose glycans in spike recognized by H84T-BanLec. The multiple H84T-BanLec binding sites on spike likely account for the drug compound's broad-spectrum antiviral activity and the lack of resistant mutants.

Proximalization of Frozen Elephant Trunk Procedure: Zone 0 or 1 versus Zone 2 or 3 Arch Repair.

BACKGROUND: Total arch replacement with the frozen elephant trunk (FET) procedure has changed the landscape of therapy for aortic arch diseases. The optimal landing zone for a FET is controversial. We sought to share our early and midterm results of the FET procedure as well as compare the clinical outcomes of proximal and distal FET anastomosis. METHODS: A total of 100 patients who underwent total arch replacement using the FET technique were identified between November 2014 and August 2021. According to the FET anastomosis over the aortic arch, patients were classified into two groups (zone 0/1 vs. zone 2/3). In-hospital mortality, complications, and midterm outcomes were assessed based on patient characteristics. RESULTS: The overall in-hospital mortality was 8%. Major complications occurred in 32% of patients, including spinal cord injury (5%), stroke (7%), and acute kidney injury requiring dialysis (7%). Zone 2/3 FET (odds ratio: 6.491, 95% confidence interval: 1.930-21.835, p = 0.003) was an independent predictor of the composite endpoint of major complications. The rate of complete false lumen thrombosis was comparable (64.3% vs. 71.4%, p = 0.567). All patients, patients with zone 0/1 FET, and patients with zone 2/3 FET had 3-year freedom from aorta-related events of 73.0, 70.2, and 75.0%, respectively. There were no significant differences (log-rank test, p = 0.500). CONCLUSION: Compared with zone 2/3, proximalization of FET using zone 0/1 for anastomosis was associated with better early outcomes and comparable rates of midterm aorta-related events. To substantiate its use, more research on this approach is required.

Coronaviruses exploit a host cysteine-aspartic protease for replication.

Highly pathogenic coronaviruses, including severe acute respiratory syndrome coronavirus 2 (refs. 1,2) (SARS-CoV-2), Middle East respiratory syndrome coronavirus3 (MERS-CoV) and SARS-CoV-1 (ref. 4), vary in their transmissibility and pathogenicity. However, infection by all three viruses results in substantial apoptosis in cell culture5-7 and in patient tissues8-10, suggesting a potential link between apoptosis and pathogenesis of coronaviruses. Here we show that caspase-6, a cysteine-aspartic protease of the apoptosis cascade, serves as an important host factor for efficient coronavirus replication. We demonstrate that caspase-6 cleaves coronavirus nucleocapsid proteins, generating fragments that serve as interferon antagonists, thus facilitating virus replication. Inhibition of caspase-6 substantially attenuates lung pathology and body weight loss in golden Syrian hamsters infected with SARS-CoV-2 and improves the survival of mice expressing human DPP4 that are infected with mouse-adapted MERS-CoV. Our study reveals how coronaviruses exploit a component of the host apoptosis cascade to facilitate virus replication.

A bipotential organoid model of respiratory epithelium recapitulates high infectivity of SARS-CoV-2 Omicron variant.

The airways and alveoli of the human respiratory tract are lined by two distinct types of epithelium, which are the primary targets of respiratory viruses. We previously established long-term expanding human lung epithelial organoids from lung tissues and developed a 'proximal' differentiation protocol to generate mucociliary airway organoids. However, a respiratory organoid system with bipotential of the airway and alveolar differentiation remains elusive. Here we defined a 'distal' differentiation approach to generate alveolar organoids from the same source for the derivation of airway organoids. The alveolar organoids consisting of type I and type II alveolar epithelial cells (AT1 and AT2, respectively) functionally simulate the alveolar epithelium. AT2 cells maintained in lung organoids serve as progenitor cells from which alveolar organoids derive. Moreover, alveolar organoids sustain a productive SARS-CoV-2 infection, albeit a lower replicative fitness was observed compared to that in airway organoids. We further optimized 2-dimensional (2D) airway organoids. Upon differentiation under a slightly acidic pH, the 2D airway organoids exhibit enhanced viral replication, representing an optimal in vitro correlate of respiratory epithelium for modeling the high infectivity of SARS-CoV-2. Notably, the higher infectivity and replicative fitness of the Omicron variant than an ancestral strain were accurately recapitulated in these optimized airway organoids. In conclusion, we have established a bipotential organoid culture system able to reproducibly expand the entire human respiratory epithelium in vitro for modeling respiratory diseases, including COVID-19.

Concomitant Hepatorenal Dysfunction and Malnutrition in Valvular Heart Surgery: Long-Term Prognostic Implications for Death and Heart Failure.

Background Strategies to improve long-term prediction of heart failure and death in valvular surgery are urgently needed because of an increasing number of procedures globally. This study sought to report the prevalence, changes, and prognostic implications of concomitant hepatorenal dysfunction and malnutrition in valvular surgery. Methods and Results In 909 patients undergoing valvular surgery, 3 groups were defined based on hepatorenal function (the modified model for end-stage liver disease excluding international normalized ratio score) and nutritional status (Controlling Nutritional Status score): normal hepatorenal function and nutrition (normal), hepatorenal dysfunction or malnutrition alone (mild), and concomitant hepatorenal dysfunction and malnutrition (severe). Overall, 32%, 46%, and 19% of patients were classified into normal, mild, and severe groups, respectively. Over a 4.1-year median follow-up, mild and severe groups incurred a higher risk of mortality (hazard ratio [HR], 3.17 [95% CI, 1.40-7.17] and HR, 9.30 [95% CI, 4.09-21.16], respectively), cardiovascular death (subdistribution HR, 3.29 [95% CI, 1.14-9.52] and subdistribution HR, 9.29 [95% CI, 3.09-27.99]), heart failure hospitalization (subdistribution HR, 2.11 [95% CI, 1.25-3.55] and subdistribution HR, 3.55 [95% CI, 2.04-6.16]), and adverse outcomes (HR, 2.11 [95% CI, 1.25-3.55] and HR, 3.55 [95% CI, 2.04-6.16]). Modified model for end-stage liver disease excluding international normalized ratio and controlling nutritional status scores improved the predictive ability of European System for Cardiac Operative Risk Evaluation (area under the curve: 0.80 versus 0.73, P<0.001) and Society of Thoracic Surgeons score (area under the curve: 0.79 versus 0.72, P=0.004) for all-cause mortality. One year following surgery (n=707), patients with persistent concomitant hepatorenal dysfunction and malnutrition (severe) experienced worse outcomes than those without. Conclusions Concomitant hepatorenal dysfunction and malnutrition was frequent and strongly linked to heart failure and mortality in valvular surgery.

Prevalence and Prognostic Importance of Massive Tricuspid Regurgitation in Patients Undergoing Tricuspid Annuloplasty With Concomitant Left-Sided Valve Surgery: A Study on Rheumatic Valvular Heart Disease.

BACKGROUND: The presence of tricuspid regurgitation (TR) is very common in patients with concomitant left-sided valve disease. Recent studies have advocated an additional grading of massive TR that is beyond severe. The present study sought to characterize the spectrum of TR in patients undergoing tricuspid annuloplasty (TA) and to evaluate the prognostic value of TR severity for post-operative outcome following TA. METHODS: A total of 176 patients who underwent TA with combined left-sided valve surgery, secondary to rheumatic valvular heart disease, were prospectively evaluated. The severity of TR was quantified by effective regurgitant orifice area (EROA) using the proximal isovelocity surface area method. Patients were categorized as having non-massive TR (EROA < 0.6 cm2) or massive TR (EROA ≥ 0.6 cm2). Adverse outcome was defined as all-cause mortality or heart failure requiring hospital admission following TA. RESULTS: A total of 55 (31%) patients were considered to have massive TR. Patients with massive TR had a greater right ventricular dimension but a smaller left ventricular dimension compared with those with non-massive TR. After a median follow-up of 39 months, 35 adverse events occurred. Cox-regression analysis showed that both continuous EROA and dichotomized EROA (massive vs. non-massive TR) were independently associated with adverse events even after multivariable adjustment. Further, Harrell C index demonstrated that the addition of massive TR provided better discrimination ability of a prediction model to known prognosticators following TA. CONCLUSIONS: Massive TR is common and up to 31% of study population had massive TR. Massive TR was associated with adverse outcome in patients undergoing TA. Classification of the severity of TR by quantitative measures and identification of massive TR in patients with concomitant left-sided valve disease are essential when considering the optimal timing of corrective surgery.

Trends in contemporary advanced heart failure management: an in-depth review over 30 years of heart transplant service in Hong Kong.

Background: The year 2022 marks the 30th anniversary of heart transplant service in Hong Kong (HK). In this study, we describe prevailing trends and outcomes of advanced heart failure (AHF), including heart transplantations (HTx), in HK over the past 30 years. Methods: Trends in heart failure prevalence in HK from 1993 to 2021 were analyzed based on data from the Hospital Authority Clinical Data and Reporting System. All AHF patients referred for HTx consideration between 1992 and 2021 were reviewed. The bridge-to-transplant (BTT) utilization of short-term mechanical circulatory support (ST-MCS) devices, including venoarterial extracorporeal membrane oxygenation (VA-ECMO) and durable left ventricular assist devices (LVADs), from 2010 to 2021 was reviewed. Results: Overall, 237 heart transplants were performed in HK, with 10-year posttransplant and median survival of 68.1% and 18.7 years, respectively. An increase in AHF clinic referrals was correlated with increasing heart failure prevalence (R2=0.635, P<0.001). In total, 146 referrals were made for ST-MCS, and an observed increase in ST-MCS referrals was correlated with increasing VA-ECMO utilization (R2=0.849, P<0.001). Among 62 patients accepted for AHF therapy, those with durable LVAD implementation had better 1-year survival (71.5%) than those receiving an extracorporeal CentriMag (Levitronix) device as BTT (40%, P=0.008). In total, 143 LVADs were implanted, with 130 as BTT or bridge-to-candidacy (BTC) methods. The survival rate among the 130 BTT/BTC LVAD patients resembled that of HTx recipients (73.8% vs. 69.8% at 9 years, P=0.296). Conclusions: The burden of AHF management has increased and gained complexity over the past 30 years in Hong Kong.

Emerging roles of left ventricular assist device therapy as bridge to transplant in an Asian city with scarce heart transplant donor.

BACKGROUND: Left ventricular assist device (LVAD) has been increasingly used in patients with advanced heart failure. This study aimed to assess the impact of implementation of LVAD therapy on heart transplantation (HTx) service in Hong Kong (HK). METHODS: LVAD program was started in 2010 in HK and patients who had been put on HTx waiting list since the start of HTx program in HK from 1992 to 2020 were included for analysis. Survival on HTx waiting list between pre-LVAD era 1992-2009 and post-LVAD era 2010-2020 were analyzed by Kaplan-Meier method and compared by log-rank test. Multivariate analysis by time-dependent Cox-proportional hazard model was used to identify independent predictors of HTx waiting list mortality. RESULTS: A total of 478 heart transplant listing episodes involving 457 patients were included for analysis. There were 232 heart transplantations (HTxs), including one re-transplantation, during the study period. There were 110 patients who received LVAD as bridge to transplantation (BTT) and 30 of them had undergone subsequent HTx. The 1-, 2- and 3-year survival on waiting list were 82.3%, 61.7% and 43.0% respectively in the pre-LVAD era (n=178), while the 1-, 2- and 3-year survival were significantly improved at 85.7%, 81.8% and 78% respectively in the post-LVAD era (n=300), (P=0.003). Time-dependent multivariate analysis revealed that LVAD support was independently associated with significant reduction of waiting list mortality [odds ratio (OR): 0.21; 95% confidence interval (CI): 0.10-0.44, P<0.001]. There was no significant difference when comparing survival after LVAD as BTT and survival after HTx up to 8 years (76.1% vs. 72% at 8 years respectively, P=0.732). CONCLUSIONS: Waiting list survival improved in the post-LVAD era driven by the implementation of LVAD service. Long-term survival for LVAD recipients as BTT were comparable to heart transplant recipients in HK.

Clofazimine broadly inhibits coronaviruses including SARS-CoV-2.

The COVID-19 pandemic is the third outbreak this century of a zoonotic disease caused by a coronavirus, following the emergence of severe acute respiratory syndrome (SARS) in 20031 and Middle East respiratory syndrome (MERS) in 20122. Treatment options for coronaviruses are limited. Here we show that clofazimine-an anti-leprosy drug with a favourable safety profile3-possesses inhibitory activity against several coronaviruses, and can antagonize the replication of SARS-CoV-2 and MERS-CoV in a range of in vitro systems. We found that this molecule, which has been approved by the US Food and Drug Administration, inhibits cell fusion mediated by the viral spike glycoprotein, as well as activity of the viral helicase. Prophylactic or therapeutic administration of clofazimine in a hamster model of SARS-CoV-2 pathogenesis led to reduced viral loads in the lung and viral shedding in faeces, and also alleviated the inflammation associated with viral infection. Combinations of clofazimine and remdesivir exhibited antiviral synergy in vitro and in vivo, and restricted viral shedding from the upper respiratory tract. Clofazimine, which is orally bioavailable and comparatively cheap to manufacture, is an attractive clinical candidate for the treatment of outpatients and-when combined with remdesivir-in therapy for hospitalized patients with COVID-19, particularly in contexts in which costs are an important factor or specialized medical facilities are limited. Our data provide evidence that clofazimine may have a role in the control of the current pandemic of COVID-19 and-possibly more importantly-in dealing with coronavirus diseases that may emerge in the future.

Host and viral determinants for efficient SARS-CoV-2 infection of the human lung.

Understanding the factors that contribute to efficient SARS-CoV-2 infection of human cells may provide insights on SARS-CoV-2 transmissibility and pathogenesis, and reveal targets of intervention. Here, we analyze host and viral determinants essential for efficient SARS-CoV-2 infection in both human lung epithelial cells and ex vivo human lung tissues. We identify heparan sulfate as an important attachment factor for SARS-CoV-2 infection. Next, we show that sialic acids present on ACE2 prevent efficient spike/ACE2-interaction. While SARS-CoV infection is substantially limited by the sialic acid-mediated restriction in both human lung epithelial cells and ex vivo human lung tissues, infection by SARS-CoV-2 is limited to a lesser extent. We further demonstrate that the furin-like cleavage site in SARS-CoV-2 spike is required for efficient virus replication in human lung but not intestinal tissues. These findings provide insights on the efficient SARS-CoV-2 infection of human lungs.

Comparative Replication and Immune Activation Profiles of SARS-CoV-2 and SARS-CoV in Human Lungs: An Ex Vivo Study With Implications for the Pathogenesis of COVID-19.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging coronavirus that has resulted in more than 2 000 000 laboratory-confirmed cases including over 145 000 deaths. Although SARS-CoV-2 and SARS-CoV share a number of common clinical manifestations, SARS-CoV-2 appears to be highly efficient in person-to-person transmission and frequently causes asymptomatic or presymptomatic infections. However, the underlying mechanisms that confer these viral characteristics of high transmissibility and asymptomatic infection remain incompletely understood. METHODS: We comprehensively investigated the replication, cell tropism, and immune activation profile of SARS-CoV-2 infection in human lung tissues with SARS-CoV included as a comparison. RESULTS: SARS-CoV-2 infected and replicated in human lung tissues more efficiently than SARS-CoV. Within the 48-hour interval, SARS-CoV-2 generated 3.20-fold more infectious virus particles than did SARS-CoV from the infected lung tissues (P < .024). SARS-CoV-2 and SARS-CoV were similar in cell tropism, with both targeting types I and II pneumocytes and alveolar macrophages. Importantly, despite the more efficient virus replication, SARS-CoV-2 did not significantly induce types I, II, or III interferons in the infected human lung tissues. In addition, while SARS-CoV infection upregulated the expression of 11 out of 13 (84.62%) representative proinflammatory cytokines/chemokines, SARS-CoV-2 infection only upregulated 5 of these 13 (38.46%) key inflammatory mediators despite replicating more efficiently. CONCLUSIONS: Our study provides the first quantitative data on the comparative replication capacity and immune activation profile of SARS-CoV-2 and SARS-CoV infection in human lung tissues. Our results provide important insights into the pathogenesis, high transmissibility, and asymptomatic infection of SARS-CoV-2.

Pediatric ventricular assist device therapy for advanced heart failure-Hong Kong experience.

Ventricular assist devices (VADs) are life-saving options for children with heart failure unresponsive to medical therapy as a bridge to transplantation or cardiac recovery. We present a retrospective review of 13 consecutive children who underwent implantation of VAD between 2001 and 2018 in our center. The median age was 12 years (1-17 years), weight was 45 kg (10-82 kg). Etiologies of heart failure were dilated cardiomyopathy (CMP) (n = 8), myocarditis (n = 2), ischemic CMP (n = 1), restrictive CMP (n = 1) and congenital heart disease (n = 1). Pre-implantation ECMO was used in 5, mechanical ventilation in 4, renal replacement therapy in 2 and IABP in 1. Devices used were: Berlin Heart EXCOR left VAD (LVAD), biventricular VAD (BIVAD) (n = 5, 2), CentriMag LVAD, BIVAD (n = 1, 2), HeartWare (n = 2), HeartMate II (n = 1). Median duration of support was 45 days (3-823 days). Overall survival was 85%. Four patients were successfully bridged to transplantation, 2 died while on a device, 4 remain on support and 3 were weaned from VAD. Late death occurred in 2 transplanted patients. Complications included bleeding requiring reoperation in 1, neurologic events in 3, driveline infections and pericardial effusion in 2 each. In one patient, CentriMag BIVAD provided support for 235 days, which is longest reported duration on such a VAD in the Asia Pacific region. Survival for pediatric patients of all ages is excellent using VADs. Given the severity of illness in these children morbidity and mortality is acceptable. VADs could potentially be used as a long-term bridge to transplantation in view of the donor shortage in the pediatric population.

Prognostic Value of Tricuspid Valve Geometry and Leaflet Coaptation Status in Patients Undergoing Tricuspid Annuloplasty: A Three-Dimensional Echocardiography Study.

BACKGROUND: The advent of three-dimensional echocardiography (3DE) enables detailed evaluation of the tricuspid valve (TV) apparatus; nonetheless, the clinical value of preoperative 3DE is unknown in patients undergoing tricuspid annuloplasty (TA). The aim of this study was to evaluate the prognostic value of TV geometric parameters and leaflet coaptation status evaluated by 3DE in patients undergoing TA. METHODS: A total of 122 patients who underwent TA during left-sided heart valve surgery were prospectively evaluated. Detailed 3DE was performed before surgery. Adverse outcome was defined as the occurrence of heart failure requiring hospital admission or all-cause mortality following TA. RESULTS: A total of 33 adverse events (17 heart failures and 16 deaths) occurred during a median follow-up of 36 months. Tethering volume (hazard ratio = 1.32; 95% CI = 1.05-1.66; P = .01) and ratio of total leaflet length to closure length (hazard ratio = 1.07; 95% CI = 1.03-1.12; P < .01) were associated with adverse events after adjustment for age, sex, and tricuspid regurgitation vena contracta width. Receiver-operator characteristic curve analysis revealed that tethering volume (area under curve = 0.73) and ratio of total leaflet length to closure length (area under curve = 0.75) were most associated with adverse events at 1-year follow-up. The presence of either a large tethering volume or a low ratio of total leaflet length to closure length was predictive of an adverse outcome 1 year following TA. CONCLUSIONS: Our study suggests that 3DE-derived TV tethering volume and ratio of total leaflet length to closure length are important preoperative measures associated with adverse events in patients undergoing TA.

Porcine Versus Pericardial Pulmonary Valve Replacement in Adults With Prior Congenital Cardiac Surgery: Midterm Outcomes.

BACKGROUND: Postcongenital heart surgery pulmonary regurgitation requires subsequent pulmonary valve replacement. We sought to compare the outcomes of pulmonary valve replacement after using bioprosthetic valves, porcine versus pericardial bioprosthesis. METHOD: Retrospective single-center study of consecutive pulmonary valve replacement in patients with pulmonary regurgitation following initial congenital cardiac surgery. From 2004 to 2016, 82 adult patients (53 males, 29 females) underwent pulmonary valve replacement at a mean age of 28.7 ± 8 years (range 18-52 years) with a mean time to pulmonary valve replacement of 24 ± 7 years (range 13-43 years). Porcine bioprosthetic valves (group 1, n = 32) and pericardial valves (group 2, n = 50) were used. Cardiac magnetic resonance imaging was performed (n = 54) at a mean of 18 ± 13 months before and 24 ± 21 months after pulmonary valve replacement. RESULTS: No significant difference was seen between the groups except that the mean follow-up was longer for group 1 (5.02 ± 2.06 vs 4.08 ± 3.21 years). In-hospital mortality was 1.1%. Follow-up completeness was 100% with no late death. Mean right ventricular end-systolic and end-diastolic volumes reduced significantly in both the groups ( P < .001), whereas right ventricular ejection fraction remained unchanged (group 1, P = .129; group 2, P = .675) . Only the left ventricular end-diastolic volume increased in both the groups, but the increase was significant for group 2 only (group 1, P = .070; group 2, P = .015), whereas the left ventricular end-systolic and ejection fraction remained unchanged in both the groups. There was no reoperation for pulmonary valve replacement. Freedom from intervention was 93.8% (group 1) and 100% (group 2) at eight years after pulmonary valve replacement ( P = .407). CONCLUSION: Midterm outcomes of pulmonary valve replacement in our adult cohort were satisfactory. Both types of bioprosthetic valves performed comparably for eight years and were a good option in adults.

Prognostic Value of Hepatorenal Function By Modified Model for End-stage Liver Disease (MELD) Score in Patients Undergoing Tricuspid Annuloplasty.

BACKGROUND: The Model for End-stage Liver Disease excluding international normalized ratio (MELD-XI) score and the modified MELD score with albumin replacing international normalized ratio (MELD-Albumin) score, which reflect both liver and renal function, have been reported as predictors of adverse events in liver and heart disease. Nonetheless, their prognostic value in patients undergoing tricuspid annuloplasty has not been addressed. METHODS AND RESULTS: A total of 394 patients who underwent tricuspid annuloplasty were evaluated. Baseline clinical, laboratory, and echocardiographic parameters were recorded. Adverse outcome was defined as the occurrence of heart failure requiring admission or all-cause mortality. Patients who underwent tricuspid annuloplasty had a high prevalence of preoperative hepatorenal dysfunction that was more common in patients with severe tricuspid regurgitation than those with mild to moderate tricuspid regurgitation. The MELD-XI and MELD-Albumin scores were excellent predictors of 1-year adverse outcome (area under the curve: 0.69 and 0.75, respectively). Kaplan-Meier survival curve demonstrated that a high score on MELD-XI (≥12.0) and MELD-Albumin (≥10.7) was associated with an increased risk of adverse events. During a median follow-up of 40 months, both MELD-XI and MELD-Albumin scores were significantly associated with adverse outcome, even after adjusting for potential confounding factors. Significant improvement of hepatorenal function at 1 year postoperation was noted only in patients who had no adverse events, not in those who experienced an adverse outcome. CONCLUSIONS: Both MELD-XI score and MELD-Albumin score can provide useful information to predict adverse outcome in patients undergoing tricuspid annuloplasty. The present study supports monitoring of modified MELD score to improve preoperative risk stratification of these patients.

Clinical Benefit of Valvular Surgery in Patients with Chronic Kidney Disease.

Concomitant chronic kidney disease (CKD) is common in patients with significant valvular heart disease (VHD). This study sought to evaluate the clinical benefit of valvular surgery in patients with concomitant CKD.We evaluated 349 patients with significant VHD who were referred for surgery. Patients were divided into those with CKD stage ≥ 3 (CKD patients; n = 88) and those with CKD stage 1 or 2 (no CKD patients; n = 261). 63 patients did not receive surgery, of which 20 patients had CKD and 43 had no CKD. Mortality and change in eGFR were assessed after a median follow-up of 21 months.In the whole study population, 25% of the patients had CKD and these patients had higher mortality than those with no CKD. The annual mortality rates of patients with CKD who did and did not undergo surgery were 7.9% and 28.0%, respectively. In patients with no CKD, the annual mortality rates of those who did and did not undergo surgery were 1.8% and 2.3%, respectively. Importantly, surgery was associated with significant survival benefit in patients with CKD (log-rank test, P < 0.01), but was neutral in patients with no CKD. Multivariable analysis confirmed the survival benefit of valvular surgery in all patients, which was most significant in patients with CKD. Furthermore, eGFR was preserved in patients who underwent valvular surgery but declined significantly in those who did not.CKD is common in patients with significant VHD and, if left untreated surgically, these patients exhibit a high mortality.

Aberrant large tumor suppressor 2 (LATS2) gene expression correlates with EGFR mutation and survival in lung adenocarcinomas.

BACKGROUND: Large tumor suppressor 2 (LATS2) gene is a putative tumor suppressor gene with potential roles in regulation of cell proliferation and apoptosis in lung cancer. The aim of this study is to explore the association of aberrant LATS2 expression with EGFR mutation and survival in lung adenocarcinoma (AD), and the effects of LATS2 silencing in both lung AD cell lines. METHODS: LATS2 mRNA and protein expression in resected lung AD were correlated with demographic characteristics, EGFR mutation and survival. LATS2-specific siRNA was transfected into four EGFR wild-type (WT) and three EGFR mutant AD cell lines and the changes in LATS2 expression and relevant signaling molecules before and after LATS2 knockdown were assayed. RESULTS: Fifty resected lung AD were included (M:F=23:27, smokers:non-smokers=19:31, EGFR mutant:wild-type=21:29) with LATS2 mRNA levels showed no significant difference between gender, age, smoking and pathological stages while LATS2 immunohistochemical staining on an independent set of 79 lung AD showed similar trend. LATS2 mRNA level was found to be a significant independent predictor for survival status (disease-free survival RR=0.217; p=0.003; Overall survival RR=0.238; p=0.036). siRNA-mediated suppression of LATS2 expression resulted in augmentation of ERK phosphorylation in EGFR wild-type AD cell lines with high basal LATS2 expression, discriminatory modulation of Akt signaling between EGFR wild-type and mutant cells, and induction of p53 accumulation in AD cell lines with low baseline p53 levels. CONCLUSIONS: LATS2 expression level is predictive of survival in patients with resected lung AD. LATS2 may modulate and contribute to tumor growth via different signaling pathways in EGFR mutant and wild-type tumors.

Characterization of functional ion channels in human cardiac c-kit+ progenitor cells.

Cardiac progenitor cells play an important role in cardiac repair and regeneration; however, their cellular biology and electrophysiology are not understood. The present study characterizes the functional ion channels in human cardiac c-kit(+) progenitor cells using whole-cell patch voltage-clamp, RT-PCR, and Western blots. We found that several ionic currents were present in human cardiac c-kit(+) progenitor cells, including a large-conductance Ca(2+)-activated K(+) current (BKCa) in 86 % of cells, an inwardly rectifying K(+) current (I Kir) in 84 % of cells, a transient outward K(+) current (I to) in 47 % of cells, a voltage-gated tetrodotoxin-sensitive Na(+) current (I Na,TTX) in 61 % of cells. Molecular identities of these ionic currents were determined with RT-PCR and Western-blot analysis. KCa.1.1 (for BKCa), Kir2.1 (for I Kir), Kv4.2 and Kv4.3 (for I to), Nav1.3 and Nav1.6 (for I Na.TTX) were abundantly expressed in human cardiac c-kit(+) progenitor cells, which do not resemble cardiomyocytes at all. These results demonstrate for the first time that four types of ionic currents including BKCa, I to, I Kir, and I Na.TTX, are heterogeneously present in human cardiac c-kit(+) cells, which may be involved in regulating cellular physiology.