Myocardial ischemic-fibrotic injury after human heart transplantation is associated with increased progression of vasculopathy, decreased cellular rejection and poor long-term outcome

AbstractObjectivesWe sought to assess the influence of peritransplant ischemia and fibrosis on the development of allograft vasculopathy, acute cellular rejection and long-term outcome.BackgroundAllograft vasculopathy is a common long-term complication of cardiac transplantation. One of the potential risk factors is peritransplant allograft ischemia.MethodsOne hundred forty heart transplant recipients had baseline and one-year intravascular ultrasound analysis done to assess the progression of allograft vasculopathy. Serial endomyocardial biopsies were evaluated for cellular rejection, vascular rejection, ischemia and fibrosis. Based on histology, patients were classified into one of the following groups: nonischemic (n = 32), ischemia (n = 24), fibrosis (n = 62) or vascular rejection (n = 22). Three-color flow cytometry crossmatching (FCXM) was used to assess donor-specific human lymphocyte antigens (HLA) sensitization. Long-term outcome of patients in each group was assessed by estimating incidence of graft failure or deaths over a seven-year follow up.ResultsPatients in the fibrosis group had the lowest incidence of donor-specific HLA sensitization (40%, p = 0.008) and lowest average episodes of cellular rejection (1.7 ± 1.4, p = 0.04), but they had increased coronary vasculopathy progression (change in coronary intimal thickness = 0.59 ± 0.28 mm, p < 0.0001) and poor seven-year event-free survival (49%, p = 0.01).ConclusionsThe development of fibrosis after cardiac transplantation is associated with advanced coronary vasculopathy, although a low incidence of acute cellular rejection is noted, suggesting the presence of nonimmune mechanisms in mediating the pathogenesis of allograft vasculopathy

Citrus of the world: a Citrus directory

De nombreuses classifications ont tenté de structurer le genre citrus qui constitue un groupe végétal complexe. L'importance des noms locaux, issus de la tradition orale, et plus récemment, l'apparition de dénominations commerciales augmentent encore le nombre des appellations. Cet annuaire représente une tentative d'identification et de standardisation du groupe. Il s'appuie sur la classification très détaillée du Japonais Tanaka, les équivalences avec celle de l'Américain Swingle sont données en annexes. Les tableaux indiquent pour chaque nom rencontré (nom local, appellation commerciale, variante orthographique...) son binôme latin et son nom standardisé. Un synthèse des appellations hybrides complète cet annuair

Evaluation of flow after transcatheter aortic valve replacement in patients with low-flow aortic stenosis : a secondary analysis of the PARTNER randomized clinical trial

Importance: Low-flow (LF) severe aortic stenosis (AS) is an independent predictor of mortality in patients undergoing aortic valve replacement (AVR). Little is known about improvement in flow after AVR and its effects on survival. Objective: To determine whether higher flow (left-ventricular stroke volume index [LVSVI]) after transcatheter AVR (TAVR) would indicate better clinical outcomes in this at-risk population. Design, Setting, and Participants: A substudy analysis of data from the Placement of Aortic Transcatheter Valves (PARTNER) randomized clinical trial and continued-access registry was conducted. A total of 984 participants with evaluable echocardiograms and baseline LF AS (LVSVI =35 mL/m2) were included. The trial was conducted at 26 sites in the United States and Canada. Patients were stratified after TAVR into tertiles by discharge LVSVI status (severe low flow [SLF], moderate low flow [MLF], and normal flow [(NF]). The present study was conducted from May 11, 2007, to January 9, 2012, with data analysis performed from April 25, 2014, to January 21, 2016. Main Outcomes and Measures: The primary end point was all-cause mortality at 1 year. Results: Baseline characteristics of 984 patients with LF AS included mean (SD) age, 84 (7) years; 582 (59.1%) men; mean Society of Thoracic Surgeons (STS) score, 11.4% (4.0%); and mean LVSVI, 27.6 (5.0) mL/m2. The discharge LVSVI values by group were SLF, 23.1 (3.5) mL/m2; MLF, 31.7 (2.2) mL/m2; and NF, 43.1 (7.0). All-cause mortality at 1 year was SLF, 26.5%; MLF, 20.1%; and NF, 19.6% (P¿=¿.045). Mean LVSVI normalized by 6 months in the MLF (35.9 [9.3] mL/m2) and NF (38.8 [11.1] mL/m2) groups, but remained low in the SLF group at 6 months and 1 year (31.4 [8.4] and 33.0 [8.3] mL/m2], respectively) (P¿<¿.001 for all groups). Reported as multivariate hazard ratio, mortality at 1 year was higher in the SLF group compared with the other groups (1.61; 95% CI, 1.17-2.23; P¿=¿.004). In addition to SLF, sex (1.59; 95% CI, 1.18-2.13; P¿=¿.002), presence of atrial fibrillation (1.41; 95% CI, 1.06-1.87; P¿=¿.02), STS score (1.03; 95% CI, 1.01-1.06; P¿=¿.02), presence of moderate or severe mitral regurgitation at discharge (1.65; 95% CI, 1.21-2.26; P¿=¿.001), pre-TAVR mean transvalvular gradient (0.98; 95% CI, 0.97-0.99; P¿=¿.004), and effective orifice area index (1.87; 95% CI, 1.09-3.19; P¿=¿.02) were independent predictors of 1-year mortality.CONCLUSIONS AND RELEVANCE: Severe LF at discharge is associated with an increased risk of mortality following TAVR in patients with severe AS and preexisting LF. The identification of remedial causes of persistent LF after TAVR may represent an opportunity to improve the outcome of these patients

Naming the pain in requirements engineering : Contemporary problems, causes, and effects in practice

Requirements Engineering (RE) has received much attention in research and practice due to its importance to software project success. Its interdisciplinary nature, the dependency to the customer, and its inherent uncertainty still render the discipline difficult to investigate. This results in a lack of empirical data. These are necessary, however, to demonstrate which practically relevant RE problems exist and to what extent they matter. Motivated by this situation, we initiated the Naming the Pain in Requirements Engineering (NaPiRE) initiative which constitutes a globally distributed, bi-yearly replicated family of surveys on the status quo and problems in practical RE. In this article, we report on the qualitative analysis of data obtained from 228 companies working in 10 countries in various domains and we reveal which contemporary problems practitioners encounter. To this end, we analyse 21 problems derived from the literature with respect to their relevance and criticality in dependency to their context, and we complement this picture with a cause-effect analysis showing the causes and effects surrounding the most critical problems. Our results give us a better understanding of which problems exist and how they manifest themselves in practical environments. Thus, we provide a first step to ground contributions to RE on empirical observations which, until now, were dominated by conventional wisdom only.Peer reviewe

Stratification of Outcomes After Transcatheter Aortic Valve Replacement According to Surgical Inoperability for Technical Versus Clinical Reasons

ObjectivesThe goal of this study was to examine the impact of reasons for surgical inoperability on outcomes in patients undergoing transcatheter aortic valve replacement (TAVR).BackgroundPatients with severe aortic stenosis may be deemed inoperable due to technical or clinical reasons. The relative impact of each designation on early and late outcomes after TAVR is unclear.MethodsPatients were studied from the inoperable arm (cohort B) of the randomized PARTNER (Placement of Aortic Transcatheter Valve) trial and the nonrandomized continued access registry. Patients were classified according to whether they were classified as technically inoperable (TI) or clinically inoperable (CLI). Reasons for TI included porcelain aorta, previous mediastinal radiation, chest wall deformity, and potential for injury to previous bypass graft on sternal re-entry. Reasons for CLI were systemic factors that were deemed to make survival unlikely.ResultsOf the 369 patients, 23.0% were considered inoperable for technical reasons alone; the remaining were judged to be CLI. For TI, the most common cause was a porcelain aorta (42%); for CLI, it was multiple comorbidities (48%) and frailty (31%). Quality of life and 2-year mortality were significantly better among TI patients compared with CLI patients (mortality 23.3% vs. 43.8%; p < 0.001). Nonetheless, TAVR led to substantial survival benefits compared with standard therapy in both inoperable cohorts.ConclusionsPatients undergoing TAVR based solely on TI have better survival and quality of life improvements than those who are inoperable due to clinical comorbidities. Both TI and CLI TAVR have significant survival benefit in the context of standard therapy. (THE PARTNER TRIAL: Placement of AoRTic TraNscathetER Valve Trial; NCT00530894

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

Transcatheter or surgical aortic-valve replacement in intermediate-risk patients

BACKGROUND: Previous trials have shown that among high-risk patients with aortic stenosis, survival rates are similar with transcatheter aortic-valve replacement (TAVR) and surgical aorticvalve replacement. We evaluated the two procedures in a randomized trial involving intermediate-risk patients. METHODS: We randomly assigned 2032 intermediate-risk patients with severe aortic stenosis, at 57 centers, to undergo either TAVR or surgical replacement. The primary end point was death from any cause or disabling stroke at 2 years. The primary hypothesis was that TAVR would not be inferior to surgical replacement. Before randomization, patients were entered into one of two cohorts on the basis of clinical and imaging findings; 76.3% of the patients were included in the transfemoral-access cohort and 23.7% in the transthoracic-access cohort. RESULTS: The rate of death from any cause or disabling stroke was similar in the TAVR group and the surgery group (P=0.001 for noninferiority). At 2 years, the Kaplan–Meier event rates were 19.3% in the TAVR group and 21.1% in the surgery group (hazard ratio in the TAVR group, 0.89; 95% confidence interval [CI], 0.73 to 1.09; P=0.25). In the transfemoralaccess cohort, TAVR resulted in a lower rate of death or disabling stroke than surgery (hazard ratio, 0.79; 95% CI, 0.62 to 1.00; P=0.05), whereas in the transthoracic-access cohort, outcomes were similar in the two groups. TAVR resulted in larger aortic-valve areas than did surgery and also resulted in lower rates of acute kidney injury, severe bleeding, and new-onset atrial fibrillation; surgery resulted in fewer major vascular complications and less paravalvular aortic regurgitation. CONCLUSIONS: In intermediate-risk patients, TAVR was similar to surgical aortic-valve replacement with respect to the primary end point of death or disabling stroke. (Funded by Edwards Lifesciences; PARTNER 2 ClinicalTrials.gov number, NCT01314313

Cardiovascular magnetic resonance for the assessment of patients undergoing transcatheter aortic valve implantation: a pilot study

<p>Abstract</p> <p>Background</p> <p>Before trans-catheter aortic valve implantation (TAVI), assessment of cardiac function and accurate measurement of the aortic root are key to determine the correct size and type of the prosthesis. The aim of this study was to compare cardiovascular magnetic resonance (CMR) and trans-thoracic echocardiography (TTE) for the assessment of aortic valve measurements and left ventricular function in high-risk elderly patients submitted to TAVI.</p> <p>Methods</p> <p>Consecutive patients with severe aortic stenosis and contraindications for surgical aortic valve replacement were screened from April 2009 to January 2011 and imaged with TTE and CMR.</p> <p>Results</p> <p>Patients who underwent both TTE and CMR (n = 49) had a mean age of 80.8 ± 4.8 years and a mean logistic EuroSCORE of 14.9 ± 9.3%. There was a good correlation between TTE and CMR in terms of annulus size (R²= 0.48, p < 0.001), left ventricular outflow tract (LVOT) diameter (R²= 0.62, p < 0.001) and left ventricular ejection fraction (LVEF) (R²= 0.47, p < 0.001) and a moderate correlation in terms of aortic valve area (AVA) (R²= 0.24, p < 0.001). CMR generally tended to report larger values than TTE for all measurements. The Bland-Altman test indicated that the 95% limits of agreement between TTE and CMR ranged from -5.6 mm to + 1.0 mm for annulus size, from -0.45 mm to + 0.25 mm for LVOT, from -0.45 mm²to + 0.25 mm²for AVA and from -29.2% to 13.2% for LVEF.</p> <p>Conclusions</p> <p>In elderly patients candidates to TAVI, CMR represents a viable complement to transthoracic echocardiography.</p

Procyanidins are potent inhibitors of LOX-1: a new player in the French Paradox

Lectin-like oxidized LDL receptor-1 (LOX-1) is an endothelial receptor for oxidized LDL (oxLDL) and plays multiple roles in the development of cardiovascular diseases. We screened more than 400 foodstuff extracts for identifying materials that inhibit oxLDL binding to LOX-1. Results showed that 52 extracts inhibited LOX-1 by more than 70% in cell-free assays. Subsequent cell-based assays revealed that a variety of foodstuffs known to be rich in procyanidins such as grape seed extracts and apple polyphenols, potently inhibited oxLDL uptake in Chinese hamster ovary (CHO) cells expressing LOX-1. Indeed, purified procyanidins significantly inhibited oxLDL binding to LOX-1 while other ingredients of apple polyphenols did not. Moreover, chronic administration of oligomeric procyanidins suppressed lipid accumulation in vascular wall in hypertensive rats fed with high fat diet. These results suggest that procyanidins are LOX-1 inhibitors and LOX-1 inhibition might be a possible underlying mechanism of the well-known vascular protective effects of red wine, the French Paradox