Fibrosis is a common pathology in cardiovascular disease. In the heart, fibrosis causes mechanical and electrical dysfunction and in the kidney, it predicts the onset of renal failure. Transforming ...growth factor β1 (TGFβ1) is the principal pro-fibrotic factor, but its inhibition is associated with side effects due to its pleiotropic roles. We hypothesized that downstream effectors of TGFβ1 in fibroblasts could be attractive therapeutic targets and lack upstream toxicity. Here we show, using integrated imaging-genomics analyses of primary human fibroblasts, that upregulation of interleukin-11 (IL-11) is the dominant transcriptional response to TGFβ1 exposure and required for its pro-fibrotic effect. IL-11 and its receptor (IL11RA) are expressed specifically in fibroblasts, in which they drive non-canonical, ERK-dependent autocrine signalling that is required for fibrogenic protein synthesis. In mice, fibroblast-specific Il11 transgene expression or Il-11 injection causes heart and kidney fibrosis and organ failure, whereas genetic deletion of Il11ra1 protects against disease. Therefore, inhibition of IL-11 prevents fibroblast activation across organs and species in response to a range of important pro-fibrotic stimuli. These results reveal a central role of IL-11 in fibrosis and we propose that inhibition of IL-11 is a potential therapeutic strategy to treat fibrotic diseases.
OBJECTIVES
To review our experience of surgical management of infective endocarditis (IE) over a 13-year period and analyse the outcomes and associated prognostic factors.
METHODS
A retrospective ...review was conducted for 191 consecutive patients who underwent surgery for native and prosthetic valve endocarditis (PVE) between January 2000 and December 2012. Surgical outcomes were reviewed to include survival and postoperative complications. Follow-up was complete for 172 of 179 patients (96.1%) surviving to hospital discharge, with a mean follow-up of 6.6 ± 3.7 years.
RESULTS
Mean age was 47.4 ± 14.9 years with 113 (63.9%) males. Native valve endocarditis was present in 177 patients (92.7%). Sixty-three patients (33.0%) presented with embolic complications. The brain was the most common site of embolism, involving 25 patients (13.1%). Streptococcus viridans was the most common infective organism, isolated in 68 patients (35.7%), followed by Staphylococcus aureus in 30 patients (15.7%). Eighty-seven patients (45.5%) had active endocarditis at the time of surgery. The mitral valve was infected in 136 patients (71.2%), the aortic valve in 66 (34.6%), the tricuspid valve in 29 (15.2%) and multiple valves in 38 (19.9%). Nineteen patients (9.9%) were intravenous drug users (IVDU). Twelve IVDUs (63.2%) suffered from tricuspid valve IE, compared with 7 of 162 patients (4.3%) in the non-IVDU population (P < 0.001). The most common indication for early surgery was intractable cardiac failure. Twelve patients (6.3%) died during the hospital stay for surgical treatment of IE. Logistic multivariate analysis identified preoperative creatinine clearance and stroke as independent predictors of in-hospital mortality. Overall 10-year survival and freedom from valve-related reoperation were 74.8 and 90.3%, respectively. Age, PVE, S. aureus endocarditis and postoperative left ventricular ejection fraction (LVEF) ≤45% were factors influencing long-term survival.
CONCLUSIONS
Surgical management of endocarditis continues to be challenging and is associated with significant morbidity and mortality. This report of 191 patients who underwent valve surgery for IE shows that in-hospital mortality is influenced by preoperative renal function and stroke at the time of presentation. The optimal timing for surgery in patients with stroke remains controversial. Long-term survival was negatively influenced by increasing age, moderate to severely impaired LVEF, prosthetic valve IE and S. aureus infection.
The landscape of aortic valve replacement (AVR) has evolved dramatically over the years, but time-varying outcomes have yet to be comprehensively explored. This study aimed to compare the all-cause ...mortality among 3 AVR techniques: transcatheter (TAVI), minimally invasive (MIAVR), and conventional AVR (CAVR). An electronic literature search was performed for randomized controlled trials (RCTs) comparing TAVI with CAVR and RCTs or propensity score-matched (PSM) studies comparing MIAVR with CAVR or MIAVR to TAVI. Individual patient data for all-cause mortality were derived from graphical reconstruction of Kaplan-Meier curves. Pairwise comparisons and network meta-analysis were conducted. Sensitivity analyses were performed in the TAVI arm for high risk and low/intermediate risk, as well as patients who underwent transfemoral (TF) TAVI. A total of 27 studies with 16,554 patients were included. In the pairwise comparisons, TAVI showed superior mortality to CAVR until 37.5 months, beyond which there was no significant difference. When restricted to TF TAVI versus CAVR, a consistent mortality benefit favoring TF TAVI was seen (shared frailty hazard ratio HR = 0.86, 95% confidence interval CI = 0.76 to 0.98, p = 0.024). In the network meta-analysis involving majority PSM data, MIAVR demonstrated significantly lower mortality than TAVI (HR = 0.70, 95% CI = 0.59 to 0.82) and CAVR (HR = 0.69, 95% CI = 0.59 to 0.80); this association remained compared with TF TAVI but with a lower extent of benefit (HR = 0.80, 95% CI = 0.65 to 0.99). In conclusion, the initial short- to medium-term mortality benefit for TAVI over CAVR was attenuated over the longer term. In the subset of patients who underwent TF TAVI, a consistent benefit was found. Among majority PSM data, MIAVR showed improved mortality compared with TAVI and CAVR but less than the TF TAVI subset, which requires validation by robust RCTs.
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Entrapment of the elephant trunk graft within the false lumen is a rare complication of surgical repair of an aortic dissection. This is normally retrieved by emergent open surgery. We describe a ...technique of endovascular retrieval of the dislodged graft, during hybrid aortic arch repair. The elephant trunk was cannulated through and through from a femoral access and the free end of the wire was snared and retrieved from a brachial access. The wire was externalised from both accesses and was used to reposition the graft into the true lumen using a body flossing technique.
Traditionally, chiller plants are controlled and monitored by a predetermined control strategy to ensure appropriate operation based on the designed system configuration. With the use of new ...technology of variable speed drive (VSD) for compressors, smart control strategies could be leveraged to enhance the system efficiency in lieu of traditional control strategies. For example, using orderly and straightforward switching procedures without considering various factors in switching the units, including the high-efficiency partial load range benefitted from the VSD, the actual performance of the units as a whole and the variable chilled water flow rate, result in the chiller plant not operating at maximum performance and efficiency. To address these issues, a hybrid predictive operational chiller plant control strategy is proposed to optimize the performance of the chiller plant. Artificial intelligence is employed as the data mining algorithm, with big data analysis based on the actual acquired voluminous operation data by fully considering the characteristics of chiller plants without additional installation of large-sized and high-priced equipment. Artificial neural network (ANN) was employed in the control strategy to predict the future outdoor temperature, building cooling load demand and the corresponding power consumption of the chiller plants. At the same time, particle swarm optimization (PSO) was applied to search for the optimized setpoints, e.g., chilled water supply temperature, operating sequence, chilled water flow rate, for the chiller plants. The developed control strategy has been launched in a chiller plant with a cooling capacity of 7,700 kW installed in a hospital in Hong Kong. The system coefficient of performance (COP) and overall energy consumption of the chiller plants were enhanced by about 8.6% and reduced by about 7.9%, respectively, compared with the traditional control strategy. This real-time, continuous, automatic optimization control strategy can determine the most efficient combination of operating parameters of a chiller plant with different control settings. This ensures that the chiller plant operates in its most efficient mode year-round under various operational conditions.
Copy number loss of PIK3R1 (p85α) most commonly occurs in ovarian cancer among all cancer types. Here we report that ovarian cancer cells manifest a spectrum of tumorigenic phenotypes upon knockdown ...of PIK3R1. PIK3R1 loss activates AKT and p110-independent JAK2/STAT3 signaling through inducing changes in the phosphorylation of the docking protein Gab2, thereby relieving the negative inhibition on AKT and promoting the assembly of JAK2/STAT3 signalosome, respectively. Additional mechanisms leading to AKT activation include enhanced p110α kinase activity and a decrease in PTEN level. PIK3R1 loss renders ovarian cancer cells vulnerable to inhibition of AKT or JAK2/STAT3. The combination of AKT and STAT3 inhibitors significantly increases the anti-tumor effect compared to single-agent treatments. Together, our findings provide a rationale for mechanism-based therapeutic approach that targets tumors with loss of PIK3R1.
Abstract Background/objectives This study aims to examine iliofemoral anatomy and predictors of vessel size and tortuosity in Asian patients as transfemoral transcatheter aortic valve implantation ...(TAVI) may be limited by the smaller Asian physique. Methods Characteristics and vessel dimensions of 549 patients undergoing ultrasonography were reviewed. The minimal luminal diameter (MLD) along the iliofemoral vasculature of each side was identified and the larger of the two sides was used to determine suitability for transfemoral TAVI. Results The mean age was 66 ± 11 years (68% males). Mean iliac MLD was 7.6 ± 1.7 mm, females smaller than males (7.2 ± 1.7 vs 7.8 ± 1.7, p < 0.001). Mean iliac MLD decreased with age: 7.9 ± 1.7 mm, 7.4 ± 1.9 mm and 7.3 ± 1.6 mm for ages < 70 years, 70–79 years and ≥ 80 years respectively (p = 0.038). Mean femoral MLD was 7.0 ± 1.7 mm, females smaller than males (6.3 ± 1.5 mm vs 7.3 ± 1.8 mm, p < 0.001). Females were more likely than males to have iliac and femoral MLD < 6 mm (20% vs 12%, p = 0.019 and 34% vs 21%, p = 0.001). Independent predictors of smaller iliofemoral dimensions were female gender, lower body surface area, diabetes mellitus, dyslipidemia and smoking history. Significant iliac tortuosity was present in 11.8%, more frequent in males than females (15% vs 6%, p = 0.005), and in those with logistic EuroSCORE ≥ 15 than < 15 (27% vs 10%, p = 0.001). Conclusions This study establishes the mean iliac and femoral artery diameters in a cohort of relatively young Asian patients. Age and female gender were associated with smaller vessel dimension and several independent predictors of smaller vasculature and tortuosity were identified. These results have implications for TF TAVI in Asia.
Purpose: To report a candy-plug technique using a Zenith Alpha stent-graft to occlude the distal false lumen in a patient with a complicated chronic type B aortic dissection. Case Report: A ...50-year-old male smoker presented with chest pain due to rapidly growing complicated chronic type B aortic dissection. Computed tomography angiography (CTA) showed the dissection extending from distal to the origin of the left subclavian artery (LSA) down to the left femoral artery. There was fusiform aneurysmal dilatation of the proximal descending aorta measuring up to 5.8 cm in diameter. He underwent left carotid–subclavian artery bypass, thoracic endovascular aortic repair with a Zenith Alpha stent-graft, a left common carotid artery chimney, and embolization of the proximal LSA. Serial CTA showed persistent false lumen flow. A decision was made to occlude the distal large false lumen using the candy-plug technique. A 44×125-mm Zenith Alpha stent-graft was used to prepare the candy plug. A gutter leak and a type Ia endoleak were embolized via a left brachial artery approach. At 2.5 years, imaging showed the candy plug in position, no endoleak, and the thrombosed false lumen in the thoracic aorta reduced in size. Conclusion: The candy-plug technique is useful in facilitating complete occlusion of the false lumen in chronic aortic dissection, which avoids an open procedure and the risk of higher morbidity.
PIK3R2 encodes the p85β regulatory subunit of phosphatidylinositol 3-kinase and is frequently amplified in cancers. The signaling mechanism and therapeutic implication of p85β are poorly understood. ...Here we report that p85β upregulates the protein level of the receptor tyrosine kinase AXL to induce oncogenic signaling in ovarian cancer. p85β activates p110 activity and AKT-independent PDK1/SGK3 signaling to promote tumorigenic phenotypes, which are all abolished upon inhibition of AXL. At the molecular level, p85β alters the phosphorylation of TRIM2 (an E3 ligase) and optineurin (an autophagy receptor), which mediate the selective regulation of AXL by p85β, thereby disrupting the autophagic degradation of the AXL protein. Therapeutically, p85β expression renders ovarian cancer cells vulnerable to inhibitors of AXL, p110, or PDK1. Conversely, p85β-depleted cells are less sensitive to these inhibitors. Together, our findings provide a rationale for pharmacological blockade of the AXL signaling axis in PIK3R2-amplified ovarian cancer.
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