Adenylate cyclase type 9 antagonizes cAMP accumulation and regulates endothelial signalling involved in atheroprotection.

AIMS: The adenylate cyclase type 9 (ADCY9) gene appears to determine atherosclerotic outcomes in patients treated with dalcetrapib. In mice, we recently demonstrated that Adcy9 inactivation potentiates endothelial function and inhibits atherogenesis. The objective of this study was to characterize the contribution of ADCY9 to the regulation of endothelial signalling pathways involved in atherosclerosis. METHODS AND RESULTS: We show that ADCY9 is expressed in the endothelium of mouse aorta and femoral arteries. We demonstrate that ADCY9 inactivation in cultured endothelial cells paradoxically increases cAMP accumulation in response to the adenylate cyclase activators forskolin and vasoactive intestinal peptide (VIP). Reciprocally, ADCY9 overexpression decreases cAMP production. Using mouse femoral artery arteriography, we show that Adcy9 inactivation potentiates VIP-induced endothelial-dependent vasodilation. Moreover, Adcy9 inactivation reduces mouse atheroma endothelial permeability in different vascular beds. ADCY9 overexpression reduces forskolin-induced phosphorylation of Ser157-vasodilator-stimulated phosphoprotein (VASP) and worsens thrombin-induced fall of RAP1 activity, both leading to increased endothelial permeability. ADCY9 inactivation in thrombin-stimulated human coronary artery endothelial cells results in cAMP accumulation, increases p-Ser157-VASP, and inhibits endothelial permeability. MLC2 phosphorylation and actin stress fibre increases in response to thrombin were reduced by ADCY9 inactivation, suggesting actin cytoskeleton regulation. Finally, using the Miles assay, we demonstrate that Adcy9 regulates thrombin-induced endothelial permeability in vivo in normal and atherosclerotic animals. CONCLUSION: Adcy9 is expressed in endothelial cells and regulates local cAMP and endothelial functions including permeability relevant to atherogenesis.

Impact of the 21-Gene Recurrence Score Assay on Treatment Decisions and Cost in Patients with Node-Positive Breast Cancer: A Multicenter Study in Quebec.

BACKGROUND: The 21-gene Breast Recurrence Score (RS) assay, "the assay", has led to a paradigm shift for patients with hormone receptor-positive, node-negative early breast cancer and is emerging as an important tool to assist physician-patient decisions in foregoing chemotherapy in node-positive patients. We wanted to better understand the impact of the RS assay in node-positive patients upon physician treatment decisions and treatment cost in Quebec, Canada. PATIENTS AND METHODS: We conducted a multicenter, prospective observational trial for Estrogen/Progesterone Receptor (ER/PR)- positive, Human Epidermal Growth Factor Receptor 2 (HER2)-negative breast cancer patients with 1-3 positive lymph nodes. Physicians completed a questionnaire indicating treatment choice prior to and post availability of RS results. The primary endpoint was change in the physician's recommendation for chemotherapy prior to and post assay results. Secondary endpoints included change in physician's expressed level of confidence, and changes in estimated cost of recommended treatments prior to and post assay results. RESULTS: For the entire cohort, physician recommendation for chemotherapy was reduced by an absolute 67.1% by knowledge of the RS assay result (P < .0001). Physician recommendation of chemotherapy was decreased by 75.9% for patients RS result <14 (P < .0001); and 67.5% for patients with RS result 14-25 (P < .0001). Changes in treatment recommendations were associated with an overall reduction in cost by 73.7% per patient, and after incorporating the cost of the RS test, a cost benefit of $823 CAN at 6-month follow-up. CONCLUSION: Altogether, we established that the assay led to a two-third reduction in the use of chemotherapy, and was a cost-effective approach for hormone receptor-positive, node-positive breast cancer.

A new prediction model for ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy.

AIMS: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is characterized by ventricular arrhythmias (VAs) and sudden cardiac death (SCD). We aimed to develop a model for individualized prediction of incident VA/SCD in ARVC patients. METHODS AND RESULTS: Five hundred and twenty-eight patients with a definite diagnosis and no history of sustained VAs/SCD at baseline, aged 38.2 ± 15.5 years, 44.7% male, were enrolled from five registries in North America and Europe. Over 4.83 (interquartile range 2.44-9.33) years of follow-up, 146 (27.7%) experienced sustained VA, defined as SCD, aborted SCD, sustained ventricular tachycardia, or appropriate implantable cardioverter-defibrillator (ICD) therapy. A prediction model estimating annual VA risk was developed using Cox regression with internal validation. Eight potential predictors were pre-specified: age, sex, cardiac syncope in the prior 6 months, non-sustained ventricular tachycardia, number of premature ventricular complexes in 24 h, number of leads with T-wave inversion, and right and left ventricular ejection fractions (LVEFs). All except LVEF were retained in the final model. The model accurately distinguished patients with and without events, with an optimism-corrected C-index of 0.77 [95% confidence interval (CI) 0.73-0.81] and minimal over-optimism [calibration slope of 0.93 (95% CI 0.92-0.95)]. By decision curve analysis, the clinical benefit of the model was superior to a current consensus-based ICD placement algorithm with a 20.3% reduction of ICD placements with the same proportion of protected patients (P < 0.001). CONCLUSION: Using the largest cohort of patients with ARVC and no prior VA, a prediction model using readily available clinical parameters was devised to estimate VA risk and guide decisions regarding primary prevention ICDs (www.arvcrisk.com).

The impact of bolus versus continuous infusion of intravenous ketamine on bispectral index variations and desflurane administration during major surgery: The KETABIS study.

BACKGROUND: Although ketamine, a NMDA-receptor antagonist, tends to increase the bispectral index (BIS), it remains a widely used analgesic whenever administered in low doses during major surgery. OBJECTIVE: The objective of this study was to compare the impact of intravenous ketamine (given either as a continuous infusion or as a bolus) on BIS and to compare desflurane administration and postoperative outcomes between the groups. DESIGN: Prospective, randomised, parallel-group, open-label study. SETTING: University hospital, operating room. PARTICIPANTS: Fifty patients, scheduled for major abdominal surgery. INTERVENTIONS AND MAIN OUTCOMES MEASURES: Patients were randomised into two groups: ketamine by intravenous continuous infusion - group (KI) and ketamine by i.v. bolus - group (KB). In the KI group, ketamine at a rate of 0.25 mg kg-1 h-1 was commenced at skin incision (T0) and maintained at this rate for the duration of surgery. In group KB, a ketamine bolus of 0.25 mg kg-1was administered at T0 and repeated every hour. The difference in BIS between the groups was compared from T0 onwards. The amount of desflurane administered to keep BIS within the usual recommended range (40-60) was compared, as were the doses of phenylephrine and remifentanil. Postoperative pain and recovery outcomes were also assessed. RESULTS: After T0, the BIS increased significantly from baseline in group KB compared with group KI: the rise in BIS was 20 ±â€Š8 vs. 11 ±â€Š6, respectively (P = 0.0001). The between-group mean difference (95% confidence interval (CI), was 9 (5 to 13). In group KB, desflurane administration significantly increased for the first 15 min after T0: 6.3 ±â€Š1.8 vs. 3.8 ±â€Š1.3 ml (P < 0.0001) with a mean intergroup group difference (95% CI) of 2.4 (1.5 to 3.4) ml. There was no difference in desflurane administration when considering the full hour from T0 to T60 min: 16 ±â€Š9 vs. 15 ±â€Š5 ml (P = 0.63) with a mean intergroup difference (95% CI) of 1 (-3 to 5) ml. After surgery, pain scores, opioid consumption, incidence of nausea and vomiting and recovery scores were similar between groups. CONCLUSION: Compared with a continuous ketamine infusion, a ketamine bolus significantly increased the BIS after T0. In order to keep the BIS below 60, significantly more desflurane was administered from T0 to T15 min in group KB. To prevent such higher desflurane administration and its related atmospheric pollution, our results suggest administering intra-operative intravenous ketamine as an infusion rather than a bolus. TRIAL REGISTRATION: Clinicaltrials.gov registration identifier: NCT03781635.

Effect of electroencephalography-guided anesthesia on neurocognitive disorders in elderly patients undergoing major non-cardiac surgery: A trial protocol The POEGEA trial (POncd Elderly GEneral Anesthesia).

INTRODUCTION: The number of elderly patients undergoing major surgery is rapidly increasing. They are particularly at risk of developing postoperative neurocognitive disorders (NCD). Earlier studies suggested that processed electroencephalographic (EEG) monitors may reduce the incidence of postoperative NCD. However, none of these studies controlled for intraoperative nociception levels or personalized blood pressure targets. Their results remain unclear if the reduction in the incidence of postoperative NCD relates to avoidance of any electroencephalographic pattern suggesting excessive anesthesia depth. OBJECTIVE: The objective of this trial is to investigate-in patients ≥ 70 years old undergoing major non-cardiac surgery-the effect of EEG-guided anesthesia on postoperative NCD while controlling for intraoperative nociception, personalized blood pressure targets, and using detailed information provided by the EEG monitor (including burst suppression ratio, density spectral array, and raw EEG waveform). MATERIAL AND METHODS: This prospective, randomized, controlled trial will be conducted in a single Canadian university hospital. Patients ≥ 70 years old undergoing elective major non-cardiac surgery will be included in the trial. The administration of sevoflurane will be adjusted to maintain a BIS index value between 40 and 60, to keep a Suppression Ratio (SR) at 0%, to keep a direct EEG display without any suppression time and a spectrogram with most of the EEG wave frequency within the alpha, theta, and delta frequencies in the EEG-guided group. In the control group, sevoflurane will be administered to achieve an age-adjusted minimum alveolar concentration of [0.8-1.2]. In both groups, a nociception monitor will guide intraoperative opioid administration, individual blood pressure targets will be used, and cerebral oximetry used to tailor intraoperative hemodynamic management. The primary endpoint will be the incidence of NCD at postoperative day 1, as evaluated by the Montreal Cognitive Assessment (MoCA). Secondary endpoints will include the incidence of postoperative NCD at different time points and the evaluation of cognitive trajectories up to 90 days after surgery among EEG-guided and control groups. STUDY REGISTRATION: NCT04825847 on ClinicalTrials.gov.

A randomized controlled trial comparing nociception level (NOL) index, blood pressure, and heart rate responses to direct laryngoscopy versus videolaryngoscopy for intubation: the NOLint project.

PURPOSE: The effect of direct laryngoscopy using a Macintosh blade (MAC) vs GlideScope™ videolaryngoscopy using a Spectrum LoPro blade (GVL) on nociceptive stimulation has not been quantitatively studied. This study used the new nociception level (NOL) index to compare the nociceptive response induced by GVL or MAC during laryngoscopy with or without intubation. METHODS: Patients underwent two laryngoscopies at four-minute intervals (L1, L2), one with GVL and the other with MAC (first randomization). A third laryngoscopy (L3) followed by tracheal intubation was performed four minutes after L2 (GVL or MAC, second randomization). Nociception was quantitatively assessed by NOL and standard hemodynamic parameters (heart rate [HR] and mean arterial pressure). For the crossover design, blade comparisons accounted for sequence and blade type. A possible carryover effect between laryngoscopies was assessed. RESULTS: In the 50 patients randomized, there was no carryover effect from one laryngoscopy to the next for all analyzed parameters. Nociception level index peak values were higher with MAC than GVL. Analysis of ΔNOL showed a lower nociceptive response with GVL for L1+L2 combined. Mean peak NOL values were significantly higher after L3+intubation than after L1+L2, for both GVL and MAC groups. Analysis of ΔHR values did not show a significant difference between GVL and MAC for any laryngoscopy. CONCLUSION: Laryngoscopy alone with GVL induces less nociception than with MAC. The NOL was more sensitive than HR at detecting nociceptive responses to MAC vs GVL. Additionally, and irrespective of which technique/blade was used, the combination of laryngoscopy + tracheal intubation produced a much greater nociceptive response than the laryngoscopy alone. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT03277872); registered 29 August 2017.

RéSUMé: OBJECTIF: L'effet de la laryngoscopie directe avec une lame Macintosh (MAC) par rapport à la vidéolaryngoscopie à l'aide d'un GlideScope™ avec lame Spectrum LoPro (GVL) sur la stimulation nociceptive n'a pas été quantitativement étudié. Cette étude a utilisé le nouvel indice de niveau de nociception (NOL) pour comparer la réponse nociceptive induite par une laryngoscopie avec GVL ou MAC avec ou sans intubation. MéTHODE: Les patients ont subi deux laryngoscopies à des intervalles de quatre minutes (L1, L2), l'une par GVL et l'autre par MAC (première randomisation). Une troisième laryngoscopie (L3) suivie d'une intubation trachéale a été effectuée quatre minutes après L2 (GVL ou MAC, deuxième randomisation). La nociception a été quantitativement évaluée à l'aide de l'indice NOL, et les paramètres hémodynamiques standard (fréquence cardiaque [FC] et pression artérielle moyenne) ont été mesurés. Dans le volet croisé de l'étude, les comparaisons de lames ont tenu compte de la séquence et du type de lame. La possibilité d'un effet de persistance entre les laryngoscopies a été évaluée. RéSULTATS: Chez les 50 patients randomisés, il n'y a eu aucun effet de persistance d'une laryngoscopie à la suivante pour tous les paramètres analysés. Les valeurs maximales de l'indice de nociception étaient plus élevées avec les lames MAC qu'avec la vidéolaryngoscopie GVL. L'analyse de ΔNOL a montré une réponse nociceptive inférieure avec la vidéolaryngoscopie GVL pour L1+L2 combinés. Les valeurs maximales moyennes de NOL étaient significativement plus élevées après L3+intubation qu'après L1+L2, tant pour les groupes GVL que MAC. L'analyse des valeurs ΔFC n'a pas montré de différence significative entre les techniques GVL et MAC pour quelque laryngoscopie que ce soit. CONCLUSION: La laryngoscopie seule avec le GlideScope induit moins de nociception qu'avec une lame MAC. L'indice NOL était plus sensible que les FC pour détecter les réponses nociceptives à la laryngoscopie MAC vs GVL. En outre, et indépendamment de la technique/lame utilisée, la combinaison de laryngoscopie + intubation trachéale a produit une réponse nociceptive beaucoup plus importante que la laryngoscopie seule. ENREGISTREMENT DE L'éTUDE: www.clinicaltrials.gov (NCT03277872); enregistrée le 29 août 2017.

Sequential multidetector computed tomography assessments after venous graft treatment solution in coronary artery bypass grafting.

OBJECTIVES: To assess the effect of DuraGraft (Somahlution Inc, Jupiter, Fla), an intraoperative graft treatment, on saphenous vein grafts in patients undergoing isolated coronary artery bypass grafting. METHODS: Within patients, 2 saphenous vein grafts were randomized to DuraGraft or heparinized saline. Multidetector computed tomography angiography at 1, 3, and 12 months assessed change in wall thickness (primary end point at 3 months), lumen diameter, and maximum narrowing for the whole graft and the proximal 5-cm segment. Safety end points included graft occlusion, death, myocardial infarction, and repeat revascularization. RESULTS: At 3 months, no significant changes were observed between DuraGraft- and saline-treated grafts (125 each) for wall thickness, lumen diameter, and maximum narrowing. At 12 months, DuraGraft-treated grafts demonstrated smaller mean wall thickness, overall (0.12 ± 0.06 vs 0.20 ± 0.31 mm; P = .02) and in the proximal segment (0.11 ± 0.03 vs 0.21 ± 0.33 mm; P = .01). Changes in wall thickness were greater in the proximal segment of saline-treated grafts (0.09 ± 0.29 vs 0.00 ± 0.03 mm; P = .04). Increase in maximum graft narrowing was larger in the proximal segment in the saline-treated grafts (4.7% ± 12.7% vs 0.2% ± 3.8%; P = .01). Nine DuraGraft and 11 saline grafts had occluded or thrombosed. One myocardial infarction was associated with a saline graft occlusion. No deaths or revascularizations were observed. CONCLUSIONS: DuraGraft demonstrated a favorable effect on wall thickness at 12 months, particularly in the proximal segment. Longer-term follow-up in larger studies is needed to evaluate the effect on clinical outcomes.

Allodepleted T-cell immunotherapy after haploidentical haematopoietic stem cell transplantation without severe acute graft-versus-host disease (GVHD) in the absence of GVHD prophylaxis.

Graft-versus-host disease (GVHD) is a major cause of transplant-related mortality (TRM) after allogeneic haematopoietic stem cell transplantation (HSCT) and presents a challenge in haploidentical HSCT. GVHD may be prevented by ex vivo graft T-cell depletion or in vivo depletion of proliferating lymphocytes. However, both approaches pose significant risks, particularly infections and relapse, compromising survival. A photodepletion strategy to eliminate alloreactive T cells from mismatched donor lymphocyte infusions (enabling administration without immunosuppression), was used to develop ATIR101, an adjunctive therapy for use after haploidentical HSCT. In this phase I dose-finding study, 19 adults (median age: 54 years) with high-risk haematological malignancies were treated with T-cell-depleted human leucocyte antigen-haploidentical myeloablative HSCT followed by ATIR101 at doses of 1 × 104 -5 × 106  CD3+  cells/kg (median 31 days post-transplant). No patient received post-transplant immunosuppression or developed grade III/IV acute GVHD, demonstrating the feasibility of ATIR101 infusion for evaluation in two subsequent phase 2 studies. Additionally, we report long-term follow -up of patients treated with ATIR101 in this study. At 1 year, all 9 patients receiving doses of 0·3-2 × 106  CD3+  cells/kg ATIR101 remained free of serious infections and after more than 8 years, TRM was 0%, relapse-related mortality was 33% and overall survival was 67% in these patients.

A new prediction model for ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy.

AIMS: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is characterized by ventricular arrhythmias (VAs) and sudden cardiac death (SCD). We aimed to develop a model for individualized prediction of incident VA/SCD in ARVC patients. METHODS AND RESULTS: Five hundred and twenty-eight patients with a definite diagnosis and no history of sustained VAs/SCD at baseline, aged 38.2 ± 15.5 years, 44.7% male, were enrolled from five registries in North America and Europe. Over 4.83 (interquartile range 2.44-9.33) years of follow-up, 146 (27.7%) experienced sustained VA, defined as SCD, aborted SCD, sustained ventricular tachycardia, or appropriate implantable cardioverter-defibrillator (ICD) therapy. A prediction model estimating annual VA risk was developed using Cox regression with internal validation. Eight potential predictors were pre-specified: age, sex, cardiac syncope in the prior 6 months, non-sustained ventricular tachycardia, number of premature ventricular complexes in 24 h, number of leads with T-wave inversion, and right and left ventricular ejection fractions (LVEFs). All except LVEF were retained in the final model. The model accurately distinguished patients with and without events, with an optimism-corrected C-index of 0.77 [95% confidence interval (CI) 0.73-0.81] and minimal over-optimism [calibration slope of 0.93 (95% CI 0.92-0.95)]. By decision curve analysis, the clinical benefit of the model was superior to a current consensus-based ICD placement algorithm with a 20.6% reduction of ICD placements with the same proportion of protected patients (P < 0.001). CONCLUSION: Using the largest cohort of patients with ARVC and no prior VA, a prediction model using readily available clinical parameters was devised to estimate VA risk and guide decisions regarding primary prevention ICDs (www.arvcrisk.com).

ADCY9 (Adenylate Cyclase Type 9) Inactivation Protects From Atherosclerosis Only in the Absence of CETP (Cholesteryl Ester Transfer Protein).

BACKGROUND: Pharmacogenomic studies have shown that ADCY9 genotype determines the effects of the CETP (cholesteryl ester transfer protein) inhibitor dalcetrapib on cardiovascular events and atherosclerosis imaging. The underlying mechanisms responsible for the interactions between ADCY9 and CETP activity have not yet been determined. METHODS: Adcy9-inactivated ( Adcy9Gt/Gt) and wild-type (WT) mice, that were or not transgenic for the CETP gene (CETPtg Adcy9Gt/Gt and CETPtg Adcy9WT), were submitted to an atherogenic protocol (injection of an AAV8 [adeno-associated virus serotype 8] expressing a PCSK9 [proprotein convertase subtilisin/kexin type 9] gain-of-function variant and 0.75% cholesterol diet for 16 weeks). Atherosclerosis, vasorelaxation, telemetry, and adipose tissue magnetic resonance imaging were evaluated. RESULTS: Adcy9Gt/Gt mice had a 65% reduction in aortic atherosclerosis compared to WT ( P<0.01). CD68 (cluster of differentiation 68)-positive macrophage accumulation and proliferation in plaques were reduced in Adcy9Gt/Gt mice compared to WT animals ( P<0.05 for both). Femoral artery endothelial-dependent vasorelaxation was improved in Adcy9Gt/Gt mice (versus WT, P<0.01). Selective pharmacological blockade showed that the nitric oxide, cyclooxygenase, and endothelial-dependent hyperpolarization pathways were all responsible for the improvement of vasodilatation in Adcy9Gt/Gt ( P<0.01 for all). Aortic endothelium from Adcy9Gt/Gt mice allowed significantly less adhesion of splenocytes compared to WT ( P<0.05). Adcy9Gt/Gt mice gained more weight than WT with the atherogenic diet; this was associated with an increase in whole body adipose tissue volume ( P<0.01 for both). Feed efficiency was increased in Adcy9Gt/Gt compared to WT mice ( P<0.01), which was accompanied by prolonged cardiac RR interval ( P<0.05) and improved nocturnal heart rate variability ( P=0.0572). Adcy9 inactivation-induced effects on atherosclerosis, endothelial function, weight gain, adipose tissue volume, and feed efficiency were lost in CETPtg Adcy9Gt/Gt mice ( P>0.05 versus CETPtg Adcy9WT). CONCLUSIONS: Adcy9 inactivation protects against atherosclerosis, but only in the absence of CETP activity. This atheroprotection may be explained by decreased macrophage accumulation and proliferation in the arterial wall, and improved endothelial function and autonomic tone.

TNF-α Antagonist and Vascular Inflammation in Patients with Psoriasis Vulgaris: A Randomized Placebo-Controlled Study.

Vascular inflammation is increased in patients with psoriasis. This randomized, double-blind, multicenter study evaluated the effects of tumor necrosis factor-α antagonist adalimumab on vascular inflammation in patients with psoriasis. A total of 107 patients were randomized (1:1) to receive adalimumab for 52 weeks or placebo for 16 weeks followed by adalimumab for 52 weeks. Vascular inflammation was assessed with positron emission tomography-computed tomography. There were no differences in the change from baseline in vessel wall target-to-background ratio (TBR) from the ascending aorta (primary endpoint) (adalimumab: TBR = 0.002, 95% confidence interval [CI] = -0.048 to 0.053; placebo: TBR = -0.002, 95% CI = -0.053 to 0.049; P = 0.916) and the carotids (adalimumab: TBR = 0.031, 95% CI = -0.005 to 0.066; placebo: TBR = 0.018, 95% CI = -0.019 to 0.055; P = 0.629) at week 16 between adalimumab and placebo. After 52 weeks of treatment with adalimumab there was no significant change from start of treatment in TBR from the ascending aorta (TBR = -0.006, 95% CI = -0.049 to 0.038; P = 0.796), but there was an increase in TBR in carotids (TBR = 0.027, 95% CI = 0.000 to 0.054; P = 0.046). This study showed no difference over 16 weeks in vascular inflammation in patients treated with a tumor necrosis factor-α antagonist or placebo and a modest increase in vascular inflammation in carotids after 52 weeks of treatment with adalimumab.

Clinical outcomes and economic impact of transcatheter mitral leaflet repair in heart failure patients.

BACKGROUND: Mitral regurgitation (MR) is a common valvular heart disorder requiring intervention once it becomes severe. Transcatheter mitral repair with the MitraClip device is a safe and effective therapy for selected patients denied surgery. The authors sought to evaluate the clinical outcomes and economic impact of this therapy compared to medical management in heart-failure patients with symptomatic mitral regurgitation. METHODS AND RESULTS: The study was comprised of two phases; an observational study of patients with heart failure and mitral regurgitation treated with either medical therapy or the MitraClip, and an economic model. Results of the observational study were used to estimate parameters for the decision model, which estimated costs, and benefits in a hypothetical cohort of patients with heart failure and moderate-to-severe mitral regurgitation treated with either standard medical therapy or MitraClip. The cohort of patients treated with the MitraClip was propensity matched to a population of heart failure patients, and their outcomes compared. At a mean follow-up of 22 months, all-cause mortality was 21% in the MitraClip cohort and 42% in the medical management cohort (p = .007). The decision model demonstrated that MitraClip increased life expectancy from 1.87-3.60 years and quality-adjusted life years (QALY) from 1.13-2.76 years. The incremental cost was $52,500 Canadian dollars, corresponding to an incremental cost-effectiveness ratio (ICER) of $32,300.00 per QALY gained. Results were sensitive to the survival benefit. CONCLUSION: In heart failure patients with symptomatic moderate-severe mitral regurgitation, therapy with the MitraClip is associated with superior survival and is cost-effective compared to medical therapy.

Genotype-Dependent Effects of Dalcetrapib on Cholesterol Efflux and Inflammation: Concordance With Clinical Outcomes.

BACKGROUND: Dalcetrapib effects on cardiovascular outcomes are determined by adenylate cyclase 9 gene polymorphisms. Our aim was to determine whether these clinical end point results are also associated with changes in reverse cholesterol transport and inflammation. METHODS AND RESULTS: Participants of the dal-OUTCOMES and dal-PLAQUE-2 trials were randomly assigned to receive dalcetrapib or placebo in addition to standard care. High-sensitivity C-reactive protein was measured at baseline and at end of study in 5243 patients from dal-OUTCOMES also genotyped for the rs1967309 polymorphism in adenylate cyclase 9. Cholesterol efflux capacity of high-density lipoproteins from J774 macrophages after cAMP stimulation was determined at baseline and 12 months in 171 genotyped patients from dal-PLAQUE-2. Treatment with dalcetrapib resulted in placebo-adjusted geometric mean percent increases in high-sensitivity C-reactive protein from baseline to end of trial of 18.1% (P=0.0009) and 18.7% (P=0.00001) in participants with the GG and AG genotypes, respectively, but the change was -1.0% (P=0.89) in those with the protective AA genotype. There was an interaction between the treatment arm and the genotype groups (P=0.02). Although the mean change in cholesterol efflux was similar among study arms in patients with GG genotype (mean: 7.8% and 7.4%), increases were 22.3% and 3.5% with dalcetrapib and placebo for those with AA genotype (P=0.005). There was a significant genetic effect for change in efflux for dalcetrapib (P=0.02), but not with placebo. CONCLUSIONS: Genotype-dependent effects on C-reactive protein and cholesterol efflux are supportive of dalcetrapib benefits on atherosclerotic cardiovascular outcomes in patients with the AA genotype at polymorphism rs1967309. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov; Unique Identifiers: NCT00658515 and NCT01059682.

Factors associated with failure of emergency department management in children with acute moderate or severe asthma: a prospective, multicentre, cohort study.

BACKGROUND: The management of paediatric asthma exacerbations is based on trials in children of all ages. Recent studies from 2009 raised the possibility that preschoolers (younger than 6 years) with viral-induced wheezing and children exposed to tobacco smoke might be at an increased risk of treatment failure. The study objective was to identify factors associated with management failure in children presenting to the emergency department with moderate or severe asthma exacerbations. METHODS: We undertook a prospective, multicentre cohort study of children aged 1-17 years presenting to five emergency departments with moderate or severe asthma (defined as a Pediatric Respiratory Assessment Measure [PRAM] of 4 to 12). Children received oral corticosteroids and severity-specific inhaled bronchodilator therapy. The primary outcome was emergency department management failure (hospital admission, prolonged emergency department therapy [≥8 h], or relapse within 72 h of discharge from the emergency department with admission to hospital or prolonged emergency department stay). Viral cause was ascertained by PCR on nasopharyngeal specimens and environmental tobacco smoke exposure by salivary cotinine concentration. This study is registered at ClinicalTrials.gov (NCT02013076). FINDINGS: Between Feb 14, 2011, and Dec 20, 2013, we screened 1893 children and enrolled 1012 eligible children. Of those eligible children, 973 participants were included in the analysis. 165 (17%) of 965 children experienced management failure in the emergency department, which was significantly associated with viral detection (110 [19%] of 579 participants with virus detection vs 46 [13%] of 354 participants without viral detection, odds ratio [OR] 1·57; 95% CI 1·04-2·37), fever (24% vs 15%, 1·96; 1·32-2·92), baseline PRAM (OR 1·38 per 1-point increase; 1·22-1·56), oxygen saturation of less than 92% (50% vs 12%, 3·94; 1·97-7·89), and presence of symptoms between exacerbations (21% vs 16%, 1·73; 1·13-2·64). Age, salivary cotinine concentration, and oral corticosteroids dose were not significantly associated with management failure. Viral detection (67% vs 46%, p<0·0001) and fever (31% vs 16%, p<0·0001) occurred more frequently in preschoolers than in older children. Viral detection was also associated with reduced speed of recovery over the 10 days after discharge. INTERPRETATION: In children presenting with moderate or severe asthma, viral detection, but not age, was associated with failure of symptom management, independently from exacerbation severity (ie, baseline PRAM and oxygen saturation), fever, and symptom chronicity (viral detection). Although it did not reach statistical significance, the association between treatment management failure and exposure to tobacco smoke warrants further investigation. FUNDING: Canadian Institutes of Health Research.

Results of a randomized clinical trial of external beam radiation to prevent restenosis after superficial femoral artery stenting.

OBJECTIVE: The objective of this study was to evaluate the safety and efficacy of external beam radiation (EBR) in preventing restenosis after superficial femoral artery (SFA) stenting in comparison with a control group treated with SFA stenting only. METHODS: In this Institutional Review Board-approved study, patients who provided written informed consent were randomly assigned to 0 Gy or 14 Gy of EBR to the stent site 24 hours after SFA stenting. The primary end point was the angiographic binary restenosis rate 2 years after stenting. Categorical and continuous end points were respectively analyzed using logistic regression models and Wilcoxon tests. End points expressed as time to event were analyzed using a log-rank test. RESULTS: The study included 155 patients, 46 women and 109 men (mean age, 66 years; range, 45-85 years). In the 0 and 14 Gy groups, binary restenosis was present, respectively, in 44% (34/77) and 68% (52/76; P = .003) 2 years after stenting. Stent thrombosis occurred in 13% (10/78) of the 0 Gy group and in 33% (25/77) of the 14 Gy group (P = .003). Target lesion revascularization at 2 years was 26% (25/78) in the 0 Gy group and 30% (23/77) in the 14 Gy group (P = .56). There were no significant differences in total walking distances change from baseline to 2 years (46 ± 100 and 26 ± 79 m, respectively, in the 0 Gy and 14 Gy group; P = .25). There were no procedure-related deaths and no major amputations. CONCLUSIONS: A single 14 Gy dose of EBR to the SFA stenting site did not prevent in-stent restenosis.

Evaluation of a nurse mentoring intervention to family caregivers in the management of delirium after cardiac surgery (MENTOR_D): a study protocol for a randomized controlled pilot trial.

BACKGROUND: Despite the use of evidence-based preventive measures, delirium affects about 40% of patients following cardiac surgery with the potential for serious clinical complications and anxiety for caregivers. There is some evidence that family involvement as a core component of delirium management may be beneficial since familiarity helps patients stay in contact with reality, however, this merits further investigation. There is also currently a gap in the scientific literature regarding objective indicators that could enhance early detection and monitoring of delirium. Therefore, this randomized pilot trial examines the acceptability, feasibility, and preliminary efficacy of an experimental nursing intervention to help family caregivers manage post-cardiac surgery delirium in their relatives. It also explores the validity of a new and innovative measure that has potential as an indicator for delirium. METHODS/DESIGN: In this two-group randomized pilot study (n = 30), the control group will receive usual care and the intervention group will receive the experimental intervention aimed at reducing delirium severity. The intervention nurse's objective will be to foster the family caregiver's self-efficacy in behaving in a supportive manner during delirium episodes. Data will be collected from standard delirium assessment scales and a novel measure of delirium, i.e., cerebral oximetry obtained using near infrared spectroscopy, as well as medical records and participants' responses to questionnaires. DISCUSSION: New strategies for early detection, monitoring, and management of delirium are needed in order to improve outcomes for both patients and families. The present article exposes feasibility issues based on the first few months of the empirical phase of the study that may be useful to the scientific community interested in improving the care of patients with delirium. Another potentially important contribution is in the exploration of cerebral oximetry, a promising measure as an objective indicator for early detection and continuous monitoring of delirium. The proposed pilot study will build towards a larger trial with the potential to improve knowledge about delirium management and monitoring. TRIAL REGISTRATION: This pilot study was registered at Controlled Trials on March 27th 2013 and was assigned #ISRCTN95736036.

Prevalence of and risk factors for persistent postoperative nonanginal pain after cardiac surgery: a 2-year prospective multicentre study.

BACKGROUND: Persistent postoperative pain continues to be an underrecognized complication. We examined the prevalence of and risk factors for this type of pain after cardiac surgery. METHODS: We enrolled patients scheduled for coronary artery bypass grafting or valve replacement, or both, from Feb. 8, 2005, to Sept. 1, 2009. Validated measures were used to assess (a) preoperative anxiety and depression, tendency to catastrophize in the face of pain, health-related quality of life and presence of persistent pain; (b) pain intensity and interference in the first postoperative week; and (c) presence and intensity of persistent postoperative pain at 3, 6, 12 and 24 months after surgery. The primary outcome was the presence of persistent postoperative pain during 24 months of follow-up. RESULTS: A total of 1247 patients completed the preoperative assessment. Follow-up retention rates at 3 and 24 months were 84% and 78%, respectively. The prevalence of persistent postoperative pain decreased significantly over time, from 40.1% at 3 months to 22.1% at 6 months, 16.5% at 12 months and 9.5% at 24 months; the pain was rated as moderate to severe in 3.6% at 24 months. Acute postoperative pain predicted both the presence and severity of persistent postoperative pain. The more intense the pain during the first week after surgery and the more it interfered with functioning, the more likely the patients were to report persistent postoperative pain. Pre-existing persistent pain and increased preoperative anxiety also predicted the presence of persistent postoperative pain. INTERPRETATION: Persistent postoperative pain of nonanginal origin after cardiac surgery affected a substantial proportion of the study population. Future research is needed to determine whether interventions to modify certain risk factors, such as preoperative anxiety and the severity of pain before and immediately after surgery, may help to minimize or prevent persistent postoperative pain.

Circulating levels of linoleic acid and HDL-cholesterol are major determinants of 4-hydroxynonenal protein adducts in patients with heart failure.

OBJECTIVE: Measurements of oxidative stress biomarkers in patients with heart failure (HF) have yielded controversial results. This study aimed at testing the hypothesis that circulating levels of the lipid peroxidation product 4-hydroxynonenal bound to thiol proteins (4HNE-P) are strongly associated with those of its potential precursors, namely n-6 polyunsaturated fatty acids (PUFA). METHODS AND RESULTS: Circulating levels of 4HNE-P were evaluated by gas chromatography-mass spectrometry in 71 control subjects and 61 ambulatory symptomatic HF patients along with various other clinically- and biochemically-relevant parameters, including other oxidative stress markers, and total levels of fatty acids from all classes, which reflect both free and bound to cholesterol, phospholipids and triglycerides. All HF patients had severe systolic functional impairment despite receiving optimal evidence-based therapies. Compared to controls, HF patients displayed markedly lower circulating levels of HDL- and LDL-cholesterol, which are major PUFA carriers, as well as of PUFA of the n-6 series, specifically linoleic acid (LA; P=0.001). Circulating 4HNE-P in HF patients was similar to controls, albeit multiple regression analysis revealed that LA was the only factor that was significantly associated with circulating 4HNE-P in the entire population (R (2)=0.086; P=0.02). In HF patients only, 4HNE-P was even more strongly associated with LA (P=0.003) and HDL-cholesterol (p<0.0002). Our results demonstrate that 4HNE-P levels, expressed relative to HDL-cholesterol, increase as HDL-cholesterol plasma levels decrease in the HF group only. CONCLUSION: Results from this study emphasize the importance of considering changes in lipids and lipoproteins in the interpretation of measurements of lipid peroxidation products. Further studies appear warranted to explore the possibility that HDL-cholesterol particles may be a carrier of 4HNE adducts.