Safe and Inclusive Cities final evaluation

Executive summary catalogued separately. See Safe and Inclusive Cities final evaluation : executive summary: http://hdl.handle.net/10625/56535The evaluation assesses the relevance, effectiveness and efficiency of the programme (including its overall value-for-money), as well as the quality of the research. It covers program-level activities, outputs and outcomes, while also drawing on information from all 15 Safe and Inclusive Cities (SAIC) funded projects. This evaluation serves an accountability purpose, validating the extent to which SAIC has achieved its objectives, while also providing learning for potential future programming on urban violence. From a policy-oriented and pragmatic perspective, the research is considered a valuable source of new data shedding light on key issues of urban violence. Recommendations are included

Posttranscriptional regulation of UGT2B10 hepatic expression and activity by alternative splicing

The detoxification enzyme UDP-glucuronosyltransferase UGT2B10 is specialized in the N-linked glucuronidation of many drugs and xenobiotics. Preferred substrates possess tertiary aliphatic amines and heterocyclic amines such as tobacco carcinogens and several anti-depressants and anti-psychotics. We hypothesized that alternative splicing (AS) constitutes a mean to regulate steady state levels of UGT2B10 and enzyme activity. We established the transcriptome of UGT2B10 in normal and tumoral tissues of multiple individuals. Highest expression was in the liver, where ten AS transcripts represented 50% of the UGT2B10 transcriptome in 50 normal livers and 44 hepatocellular carcinomas. One abundant class of transcripts involves a novel exonic sequence and leads to two alternative (alt.) variants with novel in-frame C-termini of 10 or 65 amino acids. Their hepatic expression was highly variable among individuals, correlated with canonical transcript levels, and was 3.5 fold higher in tumors. Evidence for their translation in liver tissues was acquired by mass spectrometry. In cell models, they co-localized with the enzyme and influenced the conjugation of amitriptyline and levomedetomidine by repressing or activating the enzyme (40-70%; P<0.01), in a cell context-specific manner. A high turnover rate for the alt. proteins, regulated by the proteasome, was observed in contrast to the more stable UGT2B10 enzyme. Moreover, a drug-induced remodelling of UGT2B10 splicing was demonstrated in the HepaRG hepatic cell model, which favored alt. variants expression over the canonical transcript. Our findings support a significant contribution of AS in the regulation of UGT2B10 expression in the liver with an impact on enzyme activity

Evaluation of IDRC's contribution to building leading organisations final report

The International Development Research Centre (IDRC), a Canadian Crown corporation, commissioned this cross-program evaluation to understand if, how and to what extent its strategies and support have contributed to building leading Research-for-Development (R4D) organisations. The evaluation had a threefold intent: a) to identify results and contributions to building leading organisations, b) to assess aspects that demonstrate the contribution and sustainability of these investments, and c) to inform IDRC’s reflections on how to support the building of leading organisations. A set of evaluation questions was agreed upon to reflect these priorities

Coronary-artery bypass surgery in patients with ischemic cardiomyopathy

BACKGROUND The survival benefit of a strategy of coronary-artery bypass grafting (CABG) added to guideline-directed medical therapy, as compared with medical therapy alone, in patients with coronary artery disease, heart failure, and severe left ventricular systolic dysfunction remains unclear. METHODS From July 2002 to May 2007, a total of 1212 patients with an ejection fraction of 35% or less and coronary artery disease amenable to CABG were randomly assigned to undergo CABG plus medical therapy (CABG group, 610 patients) or medical therapy alone (medical-therapy group, 602 patients). The primary outcome was death from any cause. Major secondary outcomes included death from cardiovascular causes and death from any cause or hospitalization for cardiovascular causes. The median duration of follow-up, including the current extended-follow-up study, was 9.8 years. RESULTS A primary outcome event occurred in 359 patients (58.9%) in the CABG group and in 398 patients (66.1%) in the medical-therapy group (hazard ratio with CABG vs. medical therapy, 0.84; 95% confidence interval [CI], 0.73 to 0.97; P=0.02 by log-rank test). A total of 247 patients (40.5%) in the CABG group and 297 patients (49.3%) in the medical-therapy group died from cardiovascular causes (hazard ratio, 0.79; 95% CI, 0.66 to 0.93; P=0.006 by log-rank test). Death from any cause or hospitalization for cardiovascular causes occurred in 467 patients (76.6%) in the CABG group and in 524 patients (87.0%) in the medical-therapy group (hazard ratio, 0.72; 95% CI, 0.64 to 0.82; P&lt;0.001 by log-rank test). CONCLUSIONS In a cohort of patients with ischemic cardiomyopathy, the rates of death from any cause, death from cardiovascular causes, and death from any cause or hospitalization for cardiovascular causes were significantly lower over 10 years among patients who underwent CABG in addition to receiving medical therapy than among those who received medical therapy alone. (Funded by the National Institutes of Health; STICH [and STICHES] ClinicalTrials.gov number, NCT00023595.

Sudden cardiac death in patients with ischemic heart failure undergoing coronary artery bypass grafting results from the STICH randomized clinical trial (Surgical Treatment for Ischemic Heart Failure)

Background—The risk of sudden cardiac death (SCD) in patients with heart failure following CABG has not been examined in a contemporary clinical trial of surgical revascularization. This analysis describes the incidence, timing and clinical predictors of SCD after CABG. Methods—Patients enrolled in the Surgical Treatment of Ischemic Heart Failure (STICH) trial who underwent CABG with or without surgical ventricular reconstruction (SVR) were included. We excluded patients with prior ICD and those randomized only to medical therapy. The primary outcome was SCD as adjudicated by a blinded committee. A Cox model was used to examine and identify predictors of SCD. The Fine and Gray method was used to estimate the incidence of SCD accounting for the competing risk of other deaths. Results—Over a median follow-up of 46 months, 113 patients of 1411 patients who received CABG without (n = 934) or with SVR (n = 477) had SCD; 311 died of other causes. The mean LVEF at enrollment was 28±9%. The 5-year cumulative incidence of SCD was 8.5%. Patients who had SCD and those who did not die were younger and had fewer comorbid conditions than those who died for reasons other than SCD. In the first 30 days after CABG, SCD (n=5) accounted for 7% of all deaths. The numerically greatest monthly rate of SCD was in the 31-90 day time period. In a multivariable analysis including baseline demographics, risk factors, coronary anatomy and LV function, ESVI and BNP were most strongly associated with SCD. Conclusions—The monthly risk of SCD shortly after CABG among patients with a low LVEF is highest between the first and third month, suggesting that risk stratification for SCD should occur early in the postoperative period, particularly in patients with increased preoperative ESVI and/or BNP

Coronary bypass surgery with or without surgical ventricular reconstruction

Coronary bypass surgery with or without surgical ventricular reconstruction. Jones RH, Velazquez EJ, Michler RE, Sopko G, Oh JK, O'Connor CM, Hill JA, Menicanti L, Sadowski Z, Desvigne-Nickens P, Rouleau JL, Lee KL; STICH Hypothesis 2 Investigators. Collaborators (379)Bochenek A, Krejca M, Trusz-Gluza M, Wita K, Zembala M, Przybylski R, Kukulski T, Cherniavsky A, Marchenko A, Romanov A, Wos S, Deja M, Golba K, Kot J, Rao V, Iwanochko M, Renton J, Hemeon S, Rogowski J, Rynkiewicz A, Betlejewski P, Sun B, Crestanello J, Binkley P, Chang J, Ferrazzi P, Gavazzi A, Senni M, Sadowski J, Kapelak B, Sobczyk D, Wrobel K, Pirk J, Jandova R, Velazquez E, Smith P, Milano C, Adams P, Menicanti L, Di Donato M, Castelvecchio S, Dagenais F, Dussault G, Dupree C, Sheridan B, Schuler C, Yii M, Prior D, Mack J, Racine N, Bouchard D, Ducharme A, Lavoignat J, Maurer G, Grimm M, Lang I, Adlbrecht C, Religa Z, Biederman A, Szwed H, Sadowski Z, Rajda M, Ali I, Howlett J, MacFarlane M, Siepe M, Beyersdorf F, Cuerten C, Wiechowski S, Mokrzycki K, Hill J, Beaver T, Olitsky D, Bernstein V, Janusz M, O'Neill V, Grayburn P, Hebeler R, Hamman B, Aston S, Gradinac S, Vukovic M, Djokovic L, Benetis R, Jankauskiene L, Friedrich I, Buerke M, Paraforos A, Quaini E, Cirillo M, Chua L, Lim C, Kwok B, Kong S, Stefanelli G, Labia C, Bergh C, Gustafsson C, Daly R, Rodeheffer R, Nelson S, Maitland A, Isaac D, Holland M, Di Benedetto G, Attisano T, Sievers H, Schunkert H, Stierle U, Haddad H, Hendry P, Donaldson J, Birjiniuk V, Harrington M, Nawarawong W, Woragidpunpol S, Kuanprasert S, Mekara W, Konda S, Neva C, Hathaway W, Groh M, Blakely J, Lamy A, Demers C, Rizzo T, Drazner M, DiMaio J, Joy J, Benedik J, Marketa K, Beghi C, De Blasi M, Helou J, Dallaire S, Kron I, Kern J, Bergin J, Phillips J, Aldea G, Verrier E, Harrison L, Piegas L, Paulista P, Farsky P, Veiga-Kantorowitz C, Philippides G, Shemin R, Thompson J, White H, Alison P, Stewart R, Clapham T, Rich J, Herre J, Pine L, Kalil R, Nesralla I, Santos M, Pereira de Moraes M, Michler R, Swayze R, Arnold M, McKenzie N, Smith J, Nicolau J, Oliveira S, Stolf N, Ferraz M, Filgueira J, Batlle C, Rocha A, Gurgel Camara A, Huynh T, Cecere R, Finkenbine S, St-Jacques B, Ilton M, Wittstein I, Conte J, Breton E, Panza J, Boyce S, McNulty M, Starnes V, Lopez B, Biederman R, Magovern J, Dean D, Grant S, Hammon J, Wells G, De Pasquale C, Knight J, Healy H, Maia L, Souza A, McRae R, Pierson M, Gullestad L, Sorensen G, Murphy E, Ravichandran P, Avalos K, Horowitz J, Owen E, Ascheim D, Naka Y, Yushak M, Gerometta P, Arena V, Borghini E, Johnsson P, Ekmehag B, Engels K, Rosenblum W, Swayze R, Amanullah A, Krzeminska-Pakula M, Drozdz J, Larbalestier R, Wang X, Busmann C, Horkay F, Szekely L, Keltai M, Hetzer R, Knosalla C, Nienkarken T, Chiariello L, Nardi P, Arom K, Ruengsakulrach P, Hayward C, Jansz P, Stuart S, Oto O, Sariomanoglu O, Dignan R, French J, Gonzalez M, Edes I, Szathmarine V, Yakub M, Sarip S, Alotti N, Lupkovics G, Smedira N, Pryce J, Cokkinos D, Palatianos G, Kremastinos D, Stewart R, Rinkes L, Esrig B, Baptiste M, Booth D, Ramaiah C, Ferraris V, Menon S, Martin L, Couper G, Rosborough D, Vanhaecke J, Strijckmans A, Carson P, Dupree C, Miller A, Pina I, Selzman C, Wertheimer J, Goldstein S, Cohn F, Hlatky M, Kennedy K, Rankin S, Robbins R, Zaret B, Rouleau J, Desvigne-Nickens P, Jones R, Lee K, Michler R, O'Connor C, Oh J, Rankin G, Velazquez E, Hill J, Beyersdorf F, Bonow R, Desvigne-Nickens P, Jones R, Lee K, Oh J, Panza J, Rouleau J, Sadowski Z, Velazquez E, White H, Jones R, Velazquez E, O'Connor C, Rankin G, Sellers M, Sparrow-Parker B, McCormick A, Albright J, Dandridge R, Rittenhouse L, Wagstaff D, Wakeley N, Burns S, Williams M, Bailey D, Parrish L, Daniels H, Grissom G, Medlin K, Lee K, She L, McDaniel A, Lokhnygina Y, Greene D, Moore V, Pohost G, Agarwal S, Apte P, Bahukha P, Chow M, Chu X, Doyle M, Forder J, Ocon M, Reddy V, Santos N, Tripathi R, Varadarajan P, Oh J, Blahnik F, Bruce C, Lin G, Manahan B, Miller D, Miller F, Pellikka P, Springer R, Welper J, Wiste H, Mark D, Anstrom K, Baloch K, Burnette A, Clapp-Channing N, Cowper P, Davidson-Ray N, Drew L, Harding T, Hunt V, Knight D, Patterson A, Redick T, Sanderford B, Feldman A, Bristow M, Chan T, Diamond M, Maisel A, Mann D, McNamara D, Bonow R, Berman D, Helmer D, Holly T, Leonard S, Woods M, Panza J, McNulty M, Grayburn P, Aston S. SourceDuke Clinical Research Institute, Duke University Medical Center, Durham, NC 27710, USA. [email protected] Abstract BACKGROUND: Surgical ventricular reconstruction is a specific procedure designed to reduce left ventricular volume in patients with heart failure caused by coronary artery disease. We conducted a trial to address the question of whether surgical ventricular reconstruction added to coronary-artery bypass grafting (CABG) would decrease the rate of death or hospitalization for cardiac causes, as compared with CABG alone. METHODS: Between September 2002 and January 2006, a total of 1000 patients with an ejection fraction of 35% or less, coronary artery disease that was amenable to CABG, and dominant anterior left ventricular dysfunction that was amenable to surgical ventricular reconstruction were randomly assigned to undergo either CABG alone (499 patients) or CABG with surgical ventricular reconstruction (501 patients). The primary outcome was a composite of death from any cause and hospitalization for cardiac causes. The median follow-up was 48 months. RESULTS: Surgical ventricular reconstruction reduced the end-systolic volume index by 19%, as compared with a reduction of 6% with CABG alone. Cardiac symptoms and exercise tolerance improved from baseline to a similar degree in the two study groups. However, no significant difference was observed in the primary outcome, which occurred in 292 patients (59%) who were assigned to undergo CABG alone and in 289 patients (58%) who were assigned to undergo CABG with surgical ventricular reconstruction (hazard ratio for the combined approach, 0.99; 95% confidence interval, 0.84 to 1.17; P=0.90). CONCLUSIONS: Adding surgical ventricular reconstruction to CABG reduced the left ventricular volume, as compared with CABG alone. However, this anatomical change was not associated with a greater improvement in symptoms or exercise tolerance or with a reduction in the rate of death or hospitalization for cardiac causes. (ClinicalTrials.gov number, NCT00023595.

Insights from the STICH trial: Change in left ventricular size after coronary artery bypass grafting with and without surgical ventricular reconstruction

ObjectiveThe present analysis of the Surgical Treatment for Ischemic Heart Failure randomized trial data examined the left ventricular volumes at baseline and 4 months after surgery to determine whether any magnitude of postoperative reduction in end-systolic volume affected survival after coronary artery bypass grafting alone compared with bypass grafting plus surgical ventricular reconstruction.MethodsOf the 1000 patients randomized, 555 underwent an operation and had a paired imaging assessment with the same modality at baseline and 4 months postoperatively. Of the remaining 455 patients, 424 either died before the 4-month study or did not have paired imaging tests and were excluded, and 21 were not considered because they had died before surgery or did not receive surgery.ResultsSurgical ventricular reconstruction resulted in improved survival compared with coronary artery bypass grafting alone when the postoperative end-systolic volume index was 70 mL/m2 or less. However, the opposite was true for patients achieving a postoperative volume index greater than 70 mL/m2. A reduction in the end-systolic volume index of 30% or more compared with baseline was an infrequent event in both treatment groups and did not produce a statistically significant survival benefit with ventricular reconstruction.ConclusionsIn patients undergoing coronary artery bypass grafting plus surgical ventricular reconstruction, a survival benefit was realized compared with bypass alone, with the achievement of a postoperative end-systolic volume index of 70 mL/m2 or less. Extensive ventricular remodeling at baseline might limit the ability of ventricular reconstruction to achieve a sufficient reduction in volume and clinical benefit

Severity of Remodeling, Myocardial Viability, and Survival in Ischemic LV Dysfunction After Surgical Revascularization

AbstractObjectivesThis study sought to test the hypothesis that end-systolic volume (ESV), as a marker of severity of left ventricular (LV) remodeling, influences the relationship between myocardial viability and survival in patients with coronary artery disease and LV systolic dysfunction.BackgroundRetrospective studies of ischemic LV dysfunction suggest that the severity of LV remodeling determines whether myocardial viability predicts improved survival with surgical compared with medical therapy, with coronary artery bypass grafting (CABG) only benefitting patients with viable myocardium who have smaller ESV. However, this has not been tested prospectively.MethodsInteractions of end-systolic volume index (ESVI), myocardial viability, and treatment with respect to survival were assessed in patients in the prospective randomized STICH (Comparison of Surgical and Medical Treatment for Congestive Heart Failure and Coronary Artery Disease) trial of CABG versus medical therapy who underwent viability assessment (n = 601; age 61 ± 9 years; ejection fraction ≤35%), with a median follow-up of 5.1 years. Median ESVI was 84 ml/m2. Viability was assessed by single-photon emission computed tomography or dobutamine echocardiography using pre-specified criteria.ResultsMortality was highest among patients with larger ESVI and nonviability (p < 0.001), but no interaction was observed between ESVI, viability status, and treatment assignment (p = 0.491). Specifically, the effect of CABG versus medical therapy in patients with viable myocardium and ESVI ≤84 ml/m2 (hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.56 to 1.29) was no different than in patients with viability and ESVI >84 ml/m2 (HR: 0.87; 95% CI: 0.57 to 1.31). Other ESVI thresholds yielded similar results, including ESVI ≤60 ml/m2 (HR: 0.87; 95% CI: 0.44 to 1.74). ESVI and viability assessed as continuous rather than dichotomous variables yielded similar results (p = 0.562).ConclusionsAmong patients with ischemic cardiomyopathy, those with greater LV ESVI and no substantial viability had worse prognosis. However, the effect of CABG relative to medical therapy was not differentially influenced by the combination of these 2 factors. Lower ESVI did not identify patients in whom myocardial viability predicted better outcome with CABG relative to medical therapy. (Comparison of Surgical and Medical Treatment for Congestive Heart Failure and Coronary Artery Disease [STICH]; NCT00023595