The proto-oncogene RAS, coding for a 21 kDa protein (p21), is mutated in 20% of lung cancer. However, the literature remains controversial on its prognostic significance for survival in lung cancer. We performed a systematic review of the literature with metaanalysis to assess its possible prognostic value on survival. Published studies on lung cancer assessing prognostic value of RAS mutation or p21 overexpression on survival were identified by an electronic search. After a methodological assessment, we estimated individual hazard ratios (HR) estimating RAS protein alteration or RAS mutation effect on survival and combined them using metaanalytic methods. In total, 53 studies were found eligible, with 10 concerning the same cohorts of patients. Among the 43 remaining studies, the revelation method was immunohistochemistry (IHC) in nine and polymerase chain reaction (PCR) in 34. Results in terms of survival were significantly pejorative, significantly favourable, not significant and not conclusive in 9, 1, 31, 2, respectively. In total, 29 studies were evaluable for meta-analysis but we aggregated only the 28 dealing with non-small-cell lung cancer (NSCLC) and not the only one dealing with small-cell-lung cancer (SCLC). The quality scores were not statistically significantly different between studies with or without significant results in terms of survival, allowing us to perform a quantitative aggregation. The combined HR was 1.35 (95% CI: 1.16 -1.56), showing a worse survival for NSCLC with KRAS2 mutations or p21 overexpression and, particularly, in adenocarcinomas (ADC) (HR 1.59; 95% CI 1.26 -2.02) and in studies using PCR (HR 1.40; 95% CI 1.18 -1.65) but not in studies using IHC (HR 1.08; 95% CI 0.86 -1.34). RAS appears to be a pejorative prognostic factor in terms of survival in NSCLC globally, in ADC and when it is studied by PCR.

Authors' contributions: NA contributed to the design of the study, recruited the patients, interpreted the results and wrote the manuscript. KF provided significant contributions to the design of the study, data interpretation, co-wrote the manuscript and had a significant role in the development of the OS-technique applied to cardiac patients. TH played a significant role in the software development and in the interpretation of the data. He reviewed the manuscript and provided significant feedback to improve the content. MF contributed to the design of the study; had a significant role in the development of the OS-technique applied to cardiac patients and provided the software needed to interpret this data. FPM contributed to the data analysis and interpretations, provided in depth review of the manuscript to improve the intellectual content.MW co-supervised the graduate student (NI) with MF, contributed to recruiting the patients, provided multiple reviews of the manuscript to improve the intellectual content, provided the funding for the realization of the study. Conflict of interestMGF is a board member, advisor and shareholder of Circle Cardiovascular Imaging Inc., the manufacturer of the software used for CMR image evaluation. MGF, and KF were inventors of but no longer hold the international patent: "Measuring oxygenation changes in tissue as a marker

W e report a case of a 74-year-old man who presented with progressive dyspnea and hypertension (200/ 63 mm Hg) without any chest pain. He had a history of chronic hypertension and heart murmur several years ago. Physical examination revealed a diastolic murmur with an acute pulmonary edema that required admission in the intensive care unit. The ECG results were normal. There was no fever and no inflammatory syndrome; hemocultures were sterile. Transthoracic echocardiography ( Figure 1, online-only Data Supplement Movies I and II) showed a severe aortic regurgitation on a mildly thickened valve with a mild dilatation of the aortic root (Valsalva aortic diameterϭ46 mm; 25 mm/m 2 ) with a normal annulus diameter (22 mm) and suspected intra-aortic mobile linear echoes.Transesophageal echocardiography (Figure 2, online-only Data Supplement Movies III through VI) showed a tricuspid aortic valve with a large coaptation defect resulting in a massive aortic regurgitation with a mild dilatation of the aortic root and a normal annulus. Several linear mobile echoes looking like chordae tendineae strands were connecting the Valsalva aortic root to the sigmoid cusps, without any

Background Recent changes in the demographic of cardiac donors and recipients have modulated the rate and risk, associated with posttransplant diabetes mellitus (PTDM). We investigated the secular trends of the risk of PTDM at 1 year and 3 years after transplantation over 30 years and explored its effect on major outcomes. Methods Three hundred and three nondiabetic patients were followed for a minimum of 36 months, after a first cardiac transplantation performed between 1983 and 2011. Based on the year of their transplantation, the patients were divided into 3 eras: (1983-1992 [era 1], 1993-2002 [era 2], and 2003-2011 [era 3]). Results In eras 1, 2, and 3, the proportions of patients with PTDM at 1 versus 3 years were 23% versus 39%, 21% versus 26%, and 33% versus 38%, respectively. Independent risk factors predicting PTDM at one year were recipient's age, duration of cold ischemic time, treatment with furosemide, and tacrolimus. There was a trend for overall survival being worse for patients with PTDM in comparison to patients without PTDM (p = 0.08). Patients with PTDM exhibited a significantly higher rate of renal failure over a median follow-up of 10 years (p = 0.03). Conclusion The development of PTDM following cardiac transplantation approaches 40% at 3 years and has not significantly changed over thirty years. The presence of PTDM is weakly associated with an increased mortality and is significantly associated with a worsening in renal function long-term following cardiac transplantation.

Previous studies have suggested good adaptation of cardiac transplant (CTx) recipients to exposure to a high altitude. No studies have investigated the cardiopulmonary and biomarker responses to acute hypoxic challenges following CTx. Thirty-six CTx recipients and 17 age-matched healthy controls (HC) were recruited. Sixteen (16) patients (42%) had cardiac allograft vasculopathy (CAV). Cardiopulmonary responses to maximal and submaximal exercise at 21% O , 20-minutes hypoxia (11.5% O ), and following a 10-minute exposure to 11.5% O using 30% of peak power output were completed. Vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), suppression of tumorigenicity 2 (ST2) were measured at baseline and at peak stress. Endothelial peripheral function was assessed using near-infrared spectroscopy. Compared with HC, CTx presented a lesser O desaturation both at rest (-19.4 ± 6.8 [CTx] vs -24.2 ± 6.0% O [HC], P < 0.05) and following exercise (-23.2 ± 4.9 [CTx] vs -26.2 ± 4.7% O [HC], P < 0.05). CTx patients exhibited a significant decrease in peak oxygen uptake. IL-6 and VEGF levels were significantly higher in CTx recipients in basal conditions but did not change in response to acute stress. CTx patients exhibit a favorable ventilatory and overall response to hypoxic stress. These data provide further insights on the good adaptability of CTx to exposure to high altitude.

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U tests were used to calculate significance for continuous variables. The significance level was set at 0.05. Results: We reviewed 124 consecutive OHTs performed at our hospital from 2004-2014. Of these, 50 cases (40.3%) experienced UEDVT. PE occurred in one patient (2%) and UEDVT recurred in 11 (22%). 20 patients were anticoagulated (40%) and 19 (38%) suffered bleeding complications. There was no significant difference in survival, UEDVT recurrence, PE, or number of bleeding complications at one year between those on anticoagulation versus those who were not. In those with UEDVT, there were 1,357 total days spent on anticoagulation and 9 bleeding events for an average of one bleeding event per 150.7 days. In comparison, there were 16,893 total days without anticoagulation, and 16 bleeding events during this time, yielding an average of one bleed every 1,055.8 days. Additionally, patients who suffered bleeding complications had a 15.8% lower one year survival rate (p = 0.049). Conclusion: UEDVT was common in our post-OHT population. We found no significant difference in recurrent UEDVT or PE between those who were anticoagulated and those who were not. However, we discovered an increased daily bleeding risk of approximately seven-fold while on anticoagulation. Also, survival one year from OHT was significantly lower in those who experienced a bleed. The decision of whether to anticoagulate OHT patients with UEDVT should be made with careful attention to bleeding risk.

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