JunD/AP-1 Antagonizes the Induction of DAPK1 To Promote the Survival of v-Src-Transformed Cells.

The increase in AP-1 activity is a hallmark of cell transformation by tyrosine kinases. Previously, we reported that blocking AP-1 using the c-Jun dominant negative mutant TAM67 induced senescence, adipogenesis, or apoptosis in v-Src-transformed chicken embryo fibroblasts (CEFs) whereas inhibition of JunD by short hairpin RNA (shRNA) specifically induced apoptosis. To investigate the role of AP-1 in Src-mediated transformation, we undertook a gene profiling study to characterize the transcriptomes of v-Src-transformed CEFs expressing either TAM67 or the JunD shRNA. Our study revealed a cluster of 18 probe sets upregulated exclusively in response to AP-1/JunD impairment and v-Src transformation. Four of these probe sets correspond to genes involved in the interferon pathway. One gene in particular, death-associated protein kinase 1 (DAPK1), is a C/EBPß-regulated mediator of apoptosis in gamma interferon (IFN-γ)-induced cell death. Here, we show that inhibition of DAPK1 abrogates cell death in v-Src-transformed cells expressing the JunD shRNA. Chromatin immunoprecipitation data indicated that C/EBPß was recruited to the DAPK1 promoter while the expression of a dominant negative mutant of C/EBPß abrogated the induction of DAPK1 in response to the inhibition of AP-1. In contrast, as determined by chromatin immunoprecipitation (ChIP) assays, JunD was not detected on the DAPK1 promoter under any conditions, suggesting that JunD promotes survival by indirectly antagonizing the expression of DAPK1 in v-Src transformed cells. IMPORTANCE: Transformation by the v-Src oncoprotein causes extensive changes in gene expression in primary cells such as chicken embryo fibroblasts. These changes, determining the properties of transformed cells, are controlled in part at the transcriptional level. Much attention has been devoted to transcription factors such as AP-1 and NF-κB and the control of genes associated with a more aggressive phenotype. In this report, we describe a novel mechanism of action determined by the JunD component of AP-1, a factor enhancing cell survival in v-Src-transformed cells. We show that the loss of JunD results in the aberrant activation of a genetic program leading to cell death. This program requires the activation of the tumor suppressor death-associated protein kinase 1 (DAPK1). Since DAPK1 is phosphorylated and inhibited by v-Src, these results highlight the importance of this kinase and the multiple mechanisms controlled by v-Src to antagonize the tumor suppressor function of DAPK1.

Safety of Direct Drug Provocation for the Evaluation of Penicillin Allergy in Low-Risk Adults.

BACKGROUND: About 10% of patients have a penicillin allergy label, but less than 5% of them are actually allergic. Unnecessary penicillin avoidance is associated with serious medical consequences. Given the growing number of these labels, it is imperative that our diagnostic strategy for penicillin allergy be as efficient as possible. The validity of traditionally used skin tests (STs) has been questioned, whereas drug provocation testing (DPT), the criterion standard, without previous ST appears very safe in most cases. OBJECTIVE: To evaluate the safety of direct DPT without consideration for ST results and the validity of ST in the diagnosis of penicillin allergy. METHODS: In this prospective cohort study without a control group, we recruited patients consulting an allergist for penicillin allergy. Patients underwent ST followed by DPT regardless of ST results. Patients with anaphylaxis to penicillin within the past 5 years or a severe delayed reaction were excluded, as were those with significant cardiorespiratory comorbidity. RESULTS: None of the 1002 recruited patients had a serious reaction to DPT. Ten (1.0%) had a mild immediate reaction, of whom only 1 (0.1%) was considered likely IgE-mediated. The positive and negative predictive values of ST for an immediate reaction were 3.6% and 99.1%, respectively. CONCLUSIONS: In a low-risk adult population reporting penicillin allergy, ST has very poor positive predictive value. Direct DPT without ST is safe and appears to be an ideal diagnostic strategy to remove penicillin allergy labels that could be implemented in first-line practice.

Cerebral microembolization after bioprosthetic aortic valve replacement: comparison of warfarin plus aspirin versus aspirin only.

BACKGROUND: No human physiological data exists on whether aspirin only is as effective as warfarin plus aspirin in preventing cerebral microembolization in the early postoperative period after bioprosthetic aortic valve replacement (bAVR). METHODS AND RESULTS: We prospectively enrolled 56 patients who had no other indication for oral anticoagulation, who underwent bAVR and received, in an open-label fashion, either daily warfarin (for INR 2.0-3.0) plus 81 mg of aspirin (n=28) or 325 mg of aspirin only (n=28). Cerebral microembolization was quantified at 4 hours (baseline) and at 1 month postoperatively, by recording 1-hour bilateral middle cerebral artery (MCA) microembolic signals (MES). Platelet-function analysis (PFA) of closure times (CT) on collagen was also used as a marker of platelet-dependent activation. Follow-up to 1 year was complete. Preoperative demographics and baseline platelet function were equivalent in both groups. There was no mortality, stroke, or transient ischemic attack at 1 year in either group. No significant differences were found in the proportion of patients with MES among those receiving warfarin plus aspirin versus aspirin only, at baseline (68% versus 82%, respectively; P=0.4) and at 1 month (46% versus 43%; P=1.0) after bAVR. The total MES and PFA were also equivalent between groups, at baseline and follow-up. CONCLUSIONS: Early after bAVR, the effects of these 2 antithrombotic regimens on cerebral microembolization and platelet function are equivalent. These data bring new mechanistic support to the premise that aspirin only may safely be used early after bAVR in patients who have no other indication for oral anticoagulation.

Pleiotropic action of AP-1 in v-Src-transformed cells.

The activation of AP-1 is a hallmark of cell transformation by tyrosine kinases. In this study, we characterize the role of AP-1 proteins in the transformation of chicken embryo fibroblasts (CEF) by v-Src. In normal CEF, the expression of a dominant negative mutant of c-Jun (TAM67) induced senescence. In contrast, three distinct phenotypes were observed when TAM67 was expressed in v-Src-transformed CEF. While senescent cells were also present, the inhibition of AP-1 caused apoptosis in a fraction of the v-Src-transformed cells. In addition, cells containing lipid-rich vesicles accumulated, suggesting that a subpopulation of the v-Src-transformed cells underwent differentiation in response to the inhibition of AP-1. JunD and Fra-2 were the main components of this factor, while c-Jun accounted for a minor fraction of AP-1 in v-Src-transformed CEF. The downregulation of c-Jun expression by short hairpin RNA (shRNA) induced senescence in normal and v-Src-transformed cells. In contrast, a high incidence of apoptosis was caused by the downregulation of JunD, suggesting that it is required for the survival of v-Src-transformed CEF. Levels of the p53 tumor suppressor were elevated under conditions of JunD inhibition. Repression of p53 by shRNA enhanced the survival and anchorage-independent proliferation of v-Src-transformed CEF with JunD/AP-1 inhibition. The inhibition of Fra-2 had no visible phenotype in normal CEF but caused the appearance of lipid-rich vesicles in v-Src-transformed CEF. Therefore, AP-1 facilitated transformation by acting as a survival factor, by inhibiting premature entry into senescence, and by blocking the differentiation of v-Src-transformed CEF.

The Impact of Information Presentation and Cognitive Dissonance on Processing Systematic Review Summaries: A Randomized Controlled Trial on Bicycle Helmet Legislation.

Background: Summaries of systematic reviews are a reference method for the dissemination of research evidence on the effectiveness of public health interventions beyond the scientific community. Motivated reasoning and cognitive dissonance may interfere with readers' ability to process the information included in such summaries. Methods: We conducted a web experiment on a panel of university-educated North Americans (N = 259) using a systematic review of the effectiveness of bicycle helmet legislation as a test case. The outcome variables were the perceived tentativeness of review findings and attitude toward bicycle helmet legislation. We manipulated two types of uncertainty: (i) deficient uncertainty (inclusion vs. non-inclusion of information on limitations of the studies included in the review) and (ii) consensus uncertainty (consensual findings showing legislation effectiveness vs. no evidence of effectiveness). We also examined whether reported expertise in helmet legislation and the frequency of wearing a helmet while cycling interact with the experimental factors. Results: None of the experimental manipulations had a main effect on the perceived tentativeness. The presentation of consensual efficacy findings had a positive main effect on the attitude toward the legislation. Self-reported expertise had a significant main effect on the perceived tentativeness, and exposing participants with reported expertise to results showing a lack of evidence of efficacy increased their favorable attitude toward the legislation. Participants' helmet use was positively associated with their attitude toward the legislation (but not with perceived tentativeness). Helmet use did not interact with the experimental manipulations. Conclusions: Motivated reasoning and cognitive dissonance influence a reader's ability to process information contained in a systematic review summary.

Cellular processes of v-Src transformation revealed by gene profiling of primary cells--implications for human cancer.

BACKGROUND: Cell transformation by the Src tyrosine kinase is characterized by extensive changes in gene expression. In this study, we took advantage of several strains of the Rous sarcoma virus (RSV) to characterize the patterns of v-Src-dependent gene expression in two different primary cell types, namely chicken embryo fibroblasts (CEF) and chicken neuroretinal (CNR) cells. We identified a common set of v-Src regulated genes and assessed if their expression is associated with disease-free survival using several independent human tumor data sets. METHODS: CEF and CNR cells were infected with transforming, non-transforming, and temperature sensitive mutants of RSV to identify the patterns of gene expression in response to v-Src-transformation. Microarray analysis was used to measure changes in gene expression and to define a common set of v-Src regulated genes (CSR genes) in CEF and CNR cells. A clustering enrichment regime using the CSR genes and two independent breast tumor data-sets was used to identify a 42-gene aggressive tumor gene signature. The aggressive gene signature was tested for its prognostic value by conducting survival analyses on six additional tumor data sets. RESULTS: The analysis of CEF and CNR cells revealed that cell transformation by v-Src alters the expression of 6% of the protein coding genes of the genome. A common set of 175 v-Src regulated genes (CSR genes) was regulated in both CEF and CNR cells. Within the CSR gene set, a group of 42 v-Src inducible genes was associated with reduced disease- and metastasis-free survival in several independent patient cohorts with breast or lung cancer. Gene classes represented within this group include DNA replication, cell cycle, the DNA damage and stress responses, and blood vessel morphogenesis. CONCLUSION: By studying the v-Src-dependent changes in gene expression in two types of primary cells, we identified a set of 42 inducible genes associated with poor prognosis in breast and lung cancer. The identification of these genes provides a set of biomarkers of aggressive tumor behavior and a framework for the study of cancer cells characterized by elevated Src kinase activity.

Menin: the protein behind the MEN1 syndrome.

The cloning of the MEN1 gene in 1997 led to the characterization of menin, the protein behind the multiple endocrine neoplasia Type 1 syndrome. Menin, a novel nuclear protein with no homology to other gene products, is expressed ubiquitously. MEN1 missense mutations are dispersed along the coding region of the gene but are more common in the most conserved regions. Likewise, domains of protein interaction often correspond to the more conserved segments of menin. These protein interactions are generally facilitated by multiple domains or encompass a large portion of menin. The exception to this rule is a small stretch of amino acids mediating the interaction of menin with the mSin3A corepressor and histone deacetylase complexes. The C-terminal region of menin harbors several nuclear localization signals that play redundant functions in the localization of menin to the nuclear compartment. The nuclear localization signals are also important for the interaction of menin with the nuclear matrix. Menin is the target of several kinases and a candidate substrate of the ATM/ATR kinases, implying a role for this tumor suppressor in the DNA damage response. Menin is highly conserved from Drosophila to human but is absent in the nematode and in yeast.

Very long-term survival implications of heart valve replacement with tissue versus mechanical prostheses in adults <60 years of age.

BACKGROUND: Several centers favor replacing a diseased native heart valve with a tissue rather than a mechanical prosthesis, even in younger adult patients. However, long-term data supporting this approach are lacking. We examined the survival implications of selecting a tissue versus a mechanical prosthesis at initial left-heart valve replacement in a cohort of adults <60 years of age who were followed for over 20 years. METHODS AND RESULTS: Comorbid and procedural data were available from 6554 patients who underwent valve replacement at our institution over the last 35 years. Of these, 1512 patients contributed follow-up data beyond 20 years, of whom 567 were adults <60 years of age at first left-heart valve operation (mean survivor follow-up, 24.0+/-3.1 years). Late outcomes were examined with Cox regression. Valve reoperation, often for prostheses that are no longer commercially available, occurred in 89% and 84% of patients by 20 years after tissue aortic and mitral valve replacement, respectively, and was associated with a mortality of 4.3%. There was no survival difference between patients implanted with a tissue versus a mechanical prosthesis at initial aortic valve replacement (hazard ratio 0.95; 95% CI: 0.7, 1.3; P=0.7). For mitral valve replacement patients, long-term survival was poorer than after aortic valve replacement (hazard ratio 1.4; 95% CI: 1.1, 1.8; P=0.003), but again no detrimental effect was associated with use of a tissue versus a mechanical prosthesis (hazard ratio 0.9; 95% CI 0.5, 1.4; P=0.5). CONCLUSIONS: In our experience, selecting a tissue prosthesis at initial operation in younger adults does not negatively impact survival into the third decade of follow-up, despite the risk of reoperation.

Menin is a regulator of the stress response in Drosophila melanogaster.

Menin, the product of the multiple endocrine neoplasia type I gene, has been implicated in several biological processes, including the control of gene expression and apoptosis, the modulation of mitogen-activated protein kinase pathways, and DNA damage sensing or repair. In this study, we have investigated the function of menin in the model organism Drosophila melanogaster. We show that Drosophila lines overexpressing menin or an RNA interference for this gene develop normally but are impaired in their response to several stresses, including heat shock, hypoxia, hyperosmolarity and oxidative stress. In the embryo subjected to heat shock, this impairment was characterized by a high degree of developmental arrest and lethality. The overexpression of menin enhanced the expression of HSP70 in embryos and interfered with its down-regulation during recovery at the normal temperature. In contrast, the inhibition of menin with RNA interference reduced the induction of HSP70 and blocked the activation of HSP23 upon heat shock, Menin was recruited to the Hsp70 promoter upon heat shock and menin overexpression stimulated the activity of this promoter in embryos. A 70-kDa inducible form of menin was expressed in response to heat shock, indicating that menin is also regulated in conditions of stress. The induction of HSP70 and HSP23 was markedly reduced or absent in mutant embryos harboring a deletion of the menin gene. These embryos, which did not express the heat shock-inducible form of menin, were also hypersensitive to various conditions of stress. These results suggest a novel role for menin in the control of the stress response and in processes associated with the maintenance of protein integrity.

Requirement of p38 stress-activated MAP kinase for cell death in the developing retina depends on the stage of cell differentiation.

The p38 members of the mitogen-activated protein kinase (MAPK) superfamily are activated by both environmental stress and endogenous signals, and may have either permissive or inhibitory roles upon both cell proliferation and cell death in the retina. We have previously shown that anisomycin, a protein synthesis inhibitor, and 2-aminopurine, a specific inhibitor of the double stranded-RNA dependent protein kinase, block apoptosis of ganglion cells induced by axotomy, and induce apoptosis of cells in the neuroblastic layer in developing rat retina. Using a specific inhibitor, we found that p38-stress activated MAP kinase is required for the death of post-mitotic cells induced by anisomycin, but not for the death of proliferating cells induced by 2-aminopurine, nor of axon-damaged retinal ganglion cells. We also show that p38 activation occurs either upstream of or parallel to the requirement for cyclic AMP to block apoptosis of post-mitotic cells, since the cyclic AMP-producing agent forskolin did not prevent p38 phosphorylation induced by anisomycin. Finally, the lack of immunostaining for phospho-p38 in apoptotic profiles suggests that p38 activation does not kill retinal cells directly, but more likely through the mediation of neighboring cells.

Combined atrial fibrillation ablation with mitral valve surgery.

BACKGROUND AND AIM OF THE STUDY: The study aim was to evaluate the efficacy and outcome of radiofrequency (RF) atrial fibrillation (AF) ablation in patients undergoing mitral valve (MV) surgery. METHODS: Between March 2002 and December 2004, 61 patients (mean age 65.4 +/- 10 years) underwent isolated endo-left atrial AF ablation using a unipolar RF device (Cardioblate; Medtronic, USA) in conjunction with 34 MV repairs and 27 MV replacements. AF was paroxysmal in 13 patients (21%), and permanent in 48 (79%), with a mean duration of 3.6 +/- 3.5 years. The etiology was degenerative in 35 patients (57%), rheumatic in 17 (28%), and ischemic in nine (17%). All patients received amiodarone postoperatively. RESULTS: No patients died during the study, and there were no thromboembolic complications. All patients had intraoperative conversion. Forty-one patients (67%) presented with postoperative relapse; definitive conversion was achieved in 34 (83%) cases within three months. The overall success rate was 75.4% at 14 +/- 8.8 months; success was greater in the MV repair group (85%) than in the MV replacement group (66.7%), though not significantly so (p = 0.09). Factors associated with definitive conversion included smaller left atrial size (p = 0.007), decreased left ventricular end-diastolic diameter (p = 0.04), and NYHA class I (p = 0.05). Age, AF duration and etiology were not associated with conversion, but associated coronary artery bypass grafting showed a strong trend towards significance (p = 0.07). In these patients, AF duration did not predict conversion to sinus rhythm. CONCLUSION: Combined AF ablation with MV surgery is safe and effective. Although AF ablation seems more beneficial with MV repair, the success rate may vary significantly according to patient characteristics.

Mechanical versus bioprosthetic valve replacement in middle-aged patients.

OBJECTIVE: The current trend towards decreasing the age for selection of a tissue over a mechanical prosthesis has led to a dilemma for patients aged 50-65 years. This cohort study examines the long-term outcomes of mechanical versus bioprosthetic valves in middle-aged patients. METHODS: Patients (N = 659) aged between 50 and 65 years who had first-time aortic valve replacement (AVR) and/or mitral valve replacement (MVR) with contemporary prostheses were followed prospectively after surgery. The total follow-up was 3,402 patient-years (mean 5.1 +/- 4.1 years; maximum 18.3 years). Outcomes were examined with multivariate actuarial methods. A composite outcome of major adverse prosthesis-related events (MAPE) was defined as the occurrence of reoperation, endocarditis, major bleeding, or thromboembolism. RESULTS: Ten-year survival was 73.2 +/- 4.2% after mechanical AVR, 75.1 +/- 12.6% after bioprosthetic AVR, 74.1 +/- 4.6% after mechanical MVR, and 77.9 +/- 7.4% after bioprosthetic MVR (P=NS). Ten-year reoperation rates were 35.4% and 21.3% with aortic and mitral bioprostheses, respectively. Major bleeding occurred more often following mechanical MVR (hazard ratio [HR]: 3.3; 95% confidence interval [CI] 1.2, 9.0; P = 0.022), and the incidence of any thromboembolic event was more common after mechanical MVR (HR: 4.7; CI 1.4, 13.3; P = 0.01). Overall freedom from MAPE at 10 years was 70.2 +/- 4.1% for mechanical AVR patients, 41.0+/-30.3% for bioprosthetic AVR patients, 53.3 +/- 8.8% for mechanical MVR patients, and 61.2 +/- 9.2% for bioprosthetic MVR patients. Although a trend existed towards more MAPE amongst middle-age patients with tissue valves, multivariate analysis did not identify the presence of a bioprosthesis as an independent risk factor for MAPE (HR: 1.3; CI 0.9, 2.0; P = 0.22). CONCLUSIONS: In middle-aged patients, MAPE may occur more often in patients with bioprosthetic valves, but definitive conclusions necessitate the accumulation of additional follow-up. At present, these data do not support lowering the usual cutoff for implantation of a tissue valve below the age of 65.

Persistent misunderstandings about evidence-based (sorry: informed!) policy-making.

BACKGROUND: The field of research on knowledge mobilization and evidence-informed policy-making has seen enduring debates related to various fundamental assumptions such as the definition of 'evidence', the relative validity of various research methods, the actual role of evidence to inform policy-making, etc. In many cases, these discussions serve a useful purpose, but they also stem from serious disagreement on methodological and epistemological issues. DISCUSSION: This essay reviews the rationale for evidence-informed policy-making by examining some of the common claims made about the aims and practices of this perspective on public policy. Supplementing the existing justifications for evidence-based policy making, we argue in favor of a greater inclusion of research evidence in the policy process but in a structured fashion, based on methodological considerations. In this respect, we present an overview of the intricate relation between policy questions and appropriate research designs. SUMMARY: By closely examining the relation between research questions and research designs, we claim that the usual points of disagreement are mitigated. For instance, when focusing on the variety of research designs that can answer a range of policy questions, the common critical claim about 'RCT-based policy-making' seems to lose some, if not all of its grip.

Long-term outcomes of valve replacement with modern prostheses in young adults.

OBJECTIVES: To examine the multiple impacts of valve replacement on the lives of young adults. METHODS: Patients (N=500) between age 18 and 50 who had aortic valve replacement (AVR) and/or mitral valve replacement (MVR) with contemporary prostheses were followed annually. Events, functional status, and quality of life were examined with regression models. RESULTS: Median follow-up was 7.1+/-5.3 years (maximum 26.7 years). Five, 10, and 15-year survival was 92.7+/-1.7, 88.3+/-2.4 and 80.1+/-4.7% after AVR, and 93.1+/-2.3, 79.5+/-4.3 and 71.5+/-5.4% after MVR, respectively. Survival decreased with concomitant coronary disease (hazard ratio (HR): 4.5) and preoperative LV grade (HR: 2.0/grade increase) in AVR patients, and with atrial fibrillation (HR: 5.5), coronary disease (HR: 5.7), preoperative left atrial diameter (HR: 3.0/cm increase) and NYHA class (HR: 2.1/class increase) in MVR patients. Despite reoperation, late survival was equivalent between bioprostheses and mechanical valves in both implant positions. The ten-year cumulative incidence of embolic stroke was 6.3+/-2.4% for mechanical AVR patients, 6.4+/-2.9% for bioprosthetic AVR patients, 12.7+/-3.9% for mechanical MVR patients, and 3.1+/-3.1% for bioprosthetic MVR patients. Atrial fibrillation (HR: 2.8) and smoking (HR: 4.0) were risk factors for stroke in MVR patients. In AVR patients, SF-12 physical scores, freedom from recurrent heart failure, and freedom from disability were significantly higher in bioprosthetic than mechanical valve patients. Career or income limitations were more often subjectively linked to a mechanical prosthesis in both implant positions. CONCLUSIONS: Late outcomes of modern prosthetic valves in young adults remain suboptimal. Bioprostheses deserve consideration in the aortic position, as mechanical valves are associated with lower physical capacity, a higher prevalence of disability, and poorer disease perception. Early surgical referral and atrial fibrillation surgery may improve survival after MVR.

Late incidence and predictors of persistent or recurrent heart failure in patients with mitral prosthetic valves.

OBJECTIVE: The study's objective was to examine factors associated with persistent or recurrent congestive heart failure after mitral valve replacement. METHODS: Patients who underwent mitral valve replacement with contemporary prostheses (N = 708) were followed with annual clinical assessment and echocardiography. Cox proportional hazard models were developed to evaluate the impact of demographic, comorbid, and valve-related variables on the occurrence of congestive heart failure after mitral valve replacement, defined as the composite outcome of New York Heart Association class III or IV symptoms or death caused by congestive heart failure postoperatively. Factors associated with all-cause mortality were also examined. Models were bootstrapped 1000 times. RESULTS: The total follow-up was 3376 patient-years (mean 4.8 +/- 3.7 years, range 60 days to 17.1 years). Freedom from New York Heart Association III or IV symptoms or death caused by congestive heart failure was 96.1% +/- 0.8%, 82.7% +/- 1.7%, 66.4% +/- 3.0%, and 38.8% +/- 6.9% at 1, 5, 10, and 15 years, respectively. Preoperative New York Heart Association class, left ventricular grade, atrial fibrillation, coronary artery disease, smoking, persistent tricuspid regurgitation, and redo status predicted congestive heart failure postoperatively (all P <.05). Patients who underwent mitral valve replacement for pure mitral stenosis had less congestive heart failure events after surgery than those with regurgitation or mixed disease. Prosthesis size and elevated transprosthesis gradients were not predictive of freedom from congestive heart failure after mitral valve replacement. Atrial fibrillation, persistent tricuspid regurgitation, and surgical referral for mitral valve replacement at an advanced functional stage were also risk factors for all-cause mortality. CONCLUSIONS: This study identifies the incidence of and risk factors for congestive heart failure and death late after mitral valve replacement. Although prosthesis size has no effect, other potentially modifiable factors such as atrial fibrillation, persistent tricuspid regurgitation, and late surgical referral have a negative impact on freedom from congestive heart failure and overall survival after mitral valve replacement.

Late incidence and predictors of persistent or recurrent heart failure in patients with aortic prosthetic valves.

BACKGROUND: We examined factors associated with persistent or recurrent congestive heart failure after aortic valve replacement. METHODS: Patients who underwent aortic valve replacement with contemporary prostheses (n = 1563) were followed up with annual clinical assessment and echocardiography. The effect of demographic, comorbid, and valve-related variables on the composite outcome of New York Heart Association class III or IV symptoms or congestive heart failure death after surgery was evaluated with stratified log-rank tests, Cox proportional hazard models, and logistic regression. Factors associated with all-cause death were also examined. Prediction models were bootstrapped 1000 times. RESULTS: Total follow-up was 6768 patient-years (mean, 4.3 +/- 3.3 years; range, 60 days to 17.1 years). Freedom from congestive heart failure or congestive heart failure death was 98.6% +/- 0.3%, 88.6% +/- 1.0%, 73.9% +/- 2.3%, and 45.2% +/- 8.5% at 1, 5, 10, and 15 years, respectively. Age, preoperative New York Heart Association class, left ventricular grade, atrial fibrillation, coronary artery disease, smoking, and redo status predicted congestive heart failure after surgery (all P <.05). Larger prosthesis size and effective orifice area, both absolute and indexed for body surface area, were independently associated with freedom from congestive heart failure. Increased transprosthesis gradients were predicted by prosthesis-patient mismatch and were associated with congestive heart failure after surgery. Mismatch defined as an effective orifice area/body surface area of 0.80 cm(2)/m(2) or less was a significant predictor of congestive heart failure events after surgery, but mismatch defined as an effective orifice area/body surface area of 0.85 cm(2)/m(2) or less was not. Small prosthesis size and mismatch were not significantly associated with all-cause mortality. CONCLUSIONS: These analyses identify independent predictors of congestive heart failure symptoms and congestive heart failure death late after aortic valve replacement and indicate that prosthesis size has a significant effect on this cardiac end point, but not on overall survival after aortic valve replacement.

Late incidence and determinants of reoperation in patients with prosthetic heart valves.

OBJECTIVES: Reoperation is a relatively common event in patients with prosthetic heart valves, but its actual occurrence can vary widely from one patient to another. With a focus on bioprosthetic valves, this study examines risk factors for reoperation in a large patient cohort. METHODS: Patients (N=3233) who underwent a total of 3633 operations for aortic (AVR) or mitral valve replacement (MVR) between 1970 and 2002 were prospectively followed (total 21,179 patient-years; mean 6.6+/-5.0 years; maximum 32.4 years). The incidence of prosthetic valve reoperation and the impact of patient- and valve-related variables were determined with actual and actuarial methods. RESULTS: Fifteen-year actual freedom from all-cause reoperation was 94.1% for aortic mechanical valves, 61.4% for aortic bioprosthetic valves, 94.8% for mitral mechanical valves, and 63.3% for mitral bioprosthetic valves. In both aortic and mitral positions, current bioprosthesis models had significantly better durability than discontinued bioprostheses (15-year reoperation odds-ratio 0.11+/-0.04; P<0.01 for aortic, and 0.42+/-0.14; P=0.009 for mitral). Current bioprostheses were significantly more durable in the aortic position than in the mitral position (14.3+/-6.8% more freedom from 15-year reoperation; (P=0.018)). Older age was protective, but smoking was an independent risk factor for reoperation after bioprosthetic AVR and MVR (hazard ratio for smoking 2.58 and 1.78, respectively). In patients with aortic bioprostheses, persistent left ventricular hypertrophy at follow-up and smaller prosthesis size predicted an increased incidence of reoperation, while this was not observed in patients with mitral bioprostheses. CONCLUSIONS: These analyses indicate that current bioprostheses have significantly better durability than discontinued bioprostheses, reveal a detrimental impact for smoking after AVR and MVR, and indicate an increased reoperation risk in patients with a small aortic bioprosthesis or with persistent left ventricular hypertrophy after AVR.

Postoperative naproxen after coronary artery bypass surgery: a double-blind randomized controlled trial.

OBJECTIVE: Non-steroidal anti-inflammatory drugs (NSAIDs) are routinely used after coronary artery bypass surgery (CABG), yet their effects have seldom been evaluated in randomized controlled settings. The aim of this study was to examine the efficacy and safety of a commonly used NSAID, naproxen. We hypothesized that naproxen would reduce postoperative pain following CABG without increasing complications. METHODS: Patients (N=98) undergoing primary CABG were randomized to receive naproxen (500 mg q12hX5 doses via suppository started 1h after operation, followed by oral 250 mg q8hX6 doses) or placebo. Standard analgesic and anti-emetic regimens were available to both patient groups. Interventions were double-blinded. Primary end-points were postoperative pain measured before and after chest physiotherapy by visual analog scale and pulmonary slow vital capacity (SVC). RESULTS: Baseline characteristics were equivalent between the two groups. Over the first 4 postoperative days, naproxen decreased pain by 47+/-17% on average before chest physiotherapy (P=0.034), and 44+/-13% after chest physiotherapy (P=0.0092). Patients who received naproxen also had better preservation of SVC over the first 4 postoperative days (mean loss of SVC from baseline: 2.1+/-0.1 vs. 2.5+/-0.1l, naproxen vs. placebo, P=0.0032). This was concomitant with a lower white blood cell count observed in naproxen patients (9.2+/-0.3 vs. 12.7+/-1.5x10(9)/l, naproxen vs. placebo, P=0.03). Patients who received naproxen had more chest tube drainage after 4h postoperatively, but there was no difference in the incidence or amount of transfusions. There was no difference in medication use, length of stay, or in the incidence of atrial fibrillation, azotemia, and other complications. CONCLUSIONS: Naproxen is an effective and low-cost adjunct for optimization of pain control and lung recovery after CABG. Its use may result in increased chest tube drainage, but no apparent increase in other complications.

A cross-sectional survey of supports for evidence-informed decision-making in healthcare organisations: a research protocol.

BACKGROUND: This protocol builds on the development of a) a framework that identified the various supports (i.e. positions, activities, interventions) that a healthcare organisation or health system can implement for evidence-informed decision-making (EIDM) and b) a qualitative study that showed the current mix of supports that some Canadian healthcare organisations have in place and the ones that are perceived to facilitate the use of research evidence in decision-making. Based on these findings, we developed a web survey to collect cross-sectional data about the specific supports that regional health authorities and hospitals in two Canadian provinces (Ontario and Quebec) have in place to facilitate EIDM. METHODS/DESIGN: This paper describes the methods for a cross-sectional web survey among 32 regional health authorities and 253 hospitals in the provinces of Quebec and Ontario (Canada) to collect data on the current mix of organisational supports that these organisations have in place to facilitate evidence-informed decision-making. The data will be obtained through a two-step survey design: a 10-min survey among CEOs to identify key units and individuals in regard to our objectives (step 1) and a 20-min survey among managers of the key units identified in step 1 to collect information about the activities performed by their unit regarding the acquisition, assessment, adaptation and/or dissemination of research evidence in decision-making (step 2). The study will target three types of informants: CEOs, library/documentation centre managers and all other key managers whose unit is involved in the acquisition, assessment, adaptation/packaging and/or dissemination of research evidence in decision-making. We developed an innovative data collection system to increase the likelihood that only the best-informed respondent available answers each survey question. The reporting of the results will be done using descriptive statistics of supports by organisation type and by province. DISCUSSION: This study will be the first to collect and report large-scale cross-sectional data on the current mix of supports health system organisations in the two most populous Canadian provinces have in place for evidence-informed decision-making. The study will also provide useful information to researchers on how to collect organisation-level data with reduced risk of self-reporting bias.