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OBJECTIVE To determine the predictors of postoperative acute kidney injury (AKI) following nonemergent cardiac surgery among patients with variable preoperative estimated glomerular filtration rate (eGFR) levels. METHODS A retrospective study of patients who underwent elective or in-hospital cardiac surgical procedures was performed between January 2006 and November 2015. The procedures included isolated coronary artery bypass grafting (CABG), isolated aortic valve replacement (AVR), or combined CABG and AVR. The primary outcome AKI (any stage) following nonemergent cardiac surgery utilizing the 2012 Kidney Disease-Improving Global Outcomes (KDIGO) criteria. Patients were categorized based on the following renal outcomes: mild AKI, severe AKI (KDIGO stage 2 or 3), and postoperative dialysis. Patients with G5 preoperative kidney function (including dialysis patients) were excluded. RESULTS A total of 6675 patients were included in our study. The mean age was 66.8 years (SD ± 10.4), with 76.3% being males. A total of 4487 patients had normal or mildly decreased eGFR (G1 or G2) preoperatively (67.2%), while 1960 patients were in the G3 category (29.4%). Only 228 patients (3.4%) had G4 renal function. A total of 1453 (21.7%) patients experienced postoperative AKI. The need for postoperative dialysis occurred in 3.2% of the AKI subgroup. In-hospital mortality was higher among the AKI subgroup (7.2% vs. 0.5%; p

BACKGROUND The Carpentier-Edwards Perimount valves have a proven track record in aortic valve replacement: good durability, hemodynamic performance, rates of survival, and low rates of valve-related complications and prosthesis-patient mismatch. The St. Jude Medical Trifecta is a newer valve that has shown comparable early and midterm outcomes. Studies show reoperation rates of Trifecta are comparable with Perimount valves, with a few recent studies bringing into focus early structural valve deterioration (SVD), and increased midterm SVD in younger patients. Given that midterm data for Trifecta is still sparse, we wanted to confirm the early low reoperation rates of Trifecta persist over time compared with Perimount. METHODS The Maritime Heart Centre Database was searched for AVR between 2011 and 2016, inclusive. The primary endpoint of the study was all-cause reoperation rate. RESULTS In total, 711 Perimount and 453 Trifecta implantations were included. The reoperation hazards were determined for age: 0.96 (0.92-0.99; p = .02), female (vs. male): 0.35 (0.08-1.53; p = .16), smoker (vs. nonsmoker): 2.44 (0.85-7.02; p = .1), and Trifecta (vs. Perimount): 2.68 (0.97-7.39; p = .06). Kaplan-Meier survival analysis in subgroups-age

Patients with sellar masses (SM) frequently have secondary hormonal deficiency (SHD) at initial presentation. While larger SM are more likely to present with SHD, it is unclear whether SHD at presentation is influenced by the type of SM.We conducted a retrospective analysis of patients with SM prospectively enrolled in our comprehensive provincial neuropituitary registry between November 2005 and December 2018. SM were subdivided based on size: 1 cm, 1-1.9 cm, 2-2.9 cm, and 3 cm.A total of 914 patients met the inclusion criteria, including: 346 nonfunctioning adenomas (NFA), 261 prolactinomas (PRLoma), 51 growth hormone adenomas, 36 adrenocorticotropic adenomas, 93 Rathke's cleft cysts, 70 craniopharyngiomas and 57 meningiomas. The overall rate of SHD at presentation was highest in PRLoma (62.8%) and craniopharyngiomas (64.3%) and lowest in meningiomas (14%). While larger SM were significantly more likely to have SHD, the rate of SHD within each group was significantly different despite similar size (p 0.001). Of the two largest groups of SM (NFA and PRLoma), NFA had significantly higher odds ratio (3.34, CI 1.89-5.89) of having multiple SHDs when compare with PRLoma, even when corrected for age, gender and size of tumor (p 0.001).Our study shows that the rate and distribution of SHD in SM vary dependent upon the size of the tumor and specific pathology; in particular, NFA are more likely to present with multiple SHDs. Our data will help clinicians in determining adequate hormonal testing strategy for different SM.

The study's objective was to examine Canadian and Australian community pharmacists' experiences with people at risk of suicide.A survey was developed and administered online. Countries were compared by Fisher's exact and t tests. Multivariable logistic-regression analysis was used to identify variables associated with preparedness to help someone in a suicidal crisis.The survey was completed by 235 Canadian and 161 Australian pharmacists. Most (85%) interacted with someone at risk of suicide at least once, and 66% experienced voluntary patient disclosure of suicidal thoughts. More Australians than Canadians had mental health crisis training (p0.001). Preparedness to help in a suicidal crisis was negatively associated with being Canadian, having a patient who died by suicide, lacking training and confidence, and permissive attitudes toward suicide.Several perceived barriers impede pharmacists' abilities to help patients who voluntarily disclose suicidal thoughts. Gatekeeper and related suicide prevention strategy training for community pharmacists is warranted.

This study investigated the impact of exercise training on interindividual variability and response rates in body composition and cardiometabolic outcomes in adolescents with obesity. Postpubertal males and females (n = 143) were randomly assigned to 6 months of a diet-only control or aerobic, resistance, or combined exercise training. Body composition indices were percentages of body fat mass and lean body mass and waist circumference. Biomarkers of cardiometabolic health were systolic blood pressure and plasma fasting glucose, triglycerides, and high-density lipoprotein cholesterol. Interindividual variability was examined by comparing the standard deviation of individual responses (SDIR) to a smallest robust change (SRC). The typical error of measurement was used to classify responses. SDIR exceeded the SRC for percent body fat mass in all exercise groups (SRC = 1.04%; aerobic SDIR = 1.50%; resistance SDIR = 1.22%; combined SDIR = 2.29%), percent lean body mass (SRC = 1.38%; SDIR = 3.2%,), systolic blood pressure (SRC = 2.06 mm Hg; SDIR = 4.92 mm Hg) in the resistance group, and waist circumference (SRC = 2.33 cm; SDIR = 4.09 cm), and fasting glucose (SRC = 0.08 mmol/L; SDIR = 0.28 mmol/L) in the combined group. However, half of the reported variables (11/21) did not have a positive SDIR. Importantly, adverse response rates were significantly lower in all 3 exercise groups compared with control for body composition. Although exercise had a small influence on interindividual variability for indices of body composition, the rate of adverse responses did not increase for any outcome. Novelty Interindividual variability and individual responses to exercise training have not been investigated in adolescents with obesity. Six months of exercise training does not increase interindividual variability in adolescents with obesity. Exercise created a positive, uniform shift in responses.

Vasovagal syncope (VVS) occurs in40% of individuals at least once in their lifetime. Sex-dependent differences in presentation and outcomes are not understood. We sought to determine differences in clinical presentation, treatment modalities, and outcomes of VVS between men and women.Data were collected as part of the Prevention of Syncope Trials (POST) I and II, 2 multicenter, placebo-controlled, randomized trials testing the effectiveness of metoprolol and fludrocortisone, respectively. Data regarding clinical presentation, outcomes, and time to first syncope event after randomization were compared.Of the 418 patients (280 women and 138 men), women were younger at the time of first syncope event (21 vs 26 years P = 0.002) and had a lower baseline systolic blood pressure (117 vs 124 mm Hg, P0.001). Response to heat as a trigger for syncope was more common in women (68% vs 48%, P = 0.011). Clinical presentation in women consisted more commonly of feeling warm, having seizures, and experiencing more postsyncope fatigue (68% vs 54%, P = 0.048; 10% vs 2.7%, P = 0.045; 75% vs 59%, P = 0.017, respectively). Women were more likely to experience recurrent syncope after adjustment for prerandomization syncope burden and randomization assignment (hazard ratio, 1.56; 95% confidence interval, 1.10-2.22; P = 0.012).Clinical presentation and provocative factors of VVS differ between men and women, as do recurrent events. Recognition of these differences may help target therapy specifically in men and women.

BACKGROUND Phlebotomy for diagnostic testing is among the commonest hospital procedures, but hospital-wide surveys of all inpatients characterizing blood draw volumes have not been published. The objectives were to characterize the daily blood volumes drawn for diagnostic testing from patients discharged from a Canadian tertiary care center, describe the daily distributions of phlebotomy volumes across service locations, and describe changes in hemoglobin (Hb) and transfusion across service locations. STUDY DESIGN AND METHODS Data were obtained on all patients discharged between 2012 and 2014 using linked discharge abstract and laboratory data. Cumulative daily blood volume and draw frequency were reported by service and days since admission. Changes in Hb and red blood cell (RBC) transfusion rates were reported for nontransfused and transfused patients. RESULTS Data were included on 59,715 subjects. Mean daily estimated blood loss varied from 8.5 ± 6.5 mL/day onward to 27.2 ± 20.0 mL/day in the intensive care unit (ICU; p

Background Comparisons between frailty assessment tools for waitlist candidates are a recognized priority area for kidney transplantation. We compared the prevalence of frailty using three established tools in a cohort of waitlist candidates. Methods Waitlist candidates were prospectively enrolled from 2016 to 2020 across five centers. Frailty was measured using the Frailty Phenotype (FP), a 37-variable frailty index (FI), and the Clinical Frailty Scale (CFS). The FI and CFS were dichotomized using established cutoffs. Agreement was compared using κ coefficients. Area under the receiver operating characteristic (ROC) curves were generated to compare the FI and CFS (treated as continuous measures) with the FP. Unadjusted associations between each frailty measure and time to death or waitlist withdrawal were determined using an unadjusted Cox proportional hazards model. Results Of 542 enrolled patients, 64% were male, 80% were White, and the mean age was 54±14 years. The prevalence of frailty by the FP was 16%. The mean FI score was 0.23±0.14, and the prevalence of frailty was 38% (score of ≥0.25). The median CFS score was three (IQR, 2–3), and the prevalence was 15% (score of ≥4). The κ values comparing the FP with the FI (0.44) and CFS (0.27) showed fair to moderate agreement. The area under the ROC curves for the FP and FI/CFS were 0.86 (good) and 0.69 (poor), respectively. Frailty by the CFS (HR, 2.10; 95% CI, 1.04 to 4.24) and FI (HR, 1.79; 95% CI, 1.00 to 3.21) was associated with death or permanent withdrawal. The association between frailty by the FP and death/withdrawal was not statistically significant (HR, 1.78; 95% CI, 0.79 to 3.71). Conclusion Frailty prevalence varies by the measurement tool used, and agreement between these measurements is fair to moderate. This has implications for determining the optimal frailty screening tool for use in those being evaluated for kidney transplant.

Introduction The Diabetes Aerobic and Resistance Exercise trial found that aerobic training and resistance training alone each reduced hemoglobin A1c (HbA1c) compared with nonexercising controls, and combined aerobic and resistance training caused greater HbA1c reduction than either training type alone. Our objective was to determine whether a dose-response relationship existed between frequency of exercise training and HbA1c change, and whether this varied by exercise modality or participant characteristics. Methods Post hoc analysis of data from 185 Diabetes Aerobic and Resistance Exercise trial participants with type 2 diabetes randomized to aerobic, resistance or combined training thrice weekly. Dose-response relationships between adherence (percent of prescribed training sessions completed) and HbA1c change were assessed with linear regression. Results Median overall adherence was 84.9% (interquartile range, 74.4%-93.6%). Higher exercise adherence was associated with greater HbA1c reduction; a 20% increase in adherence (e.g., an additional two sessions per month) was associated with a 0.15% (2 mmol·mol) decrease in HbA1c (β = -0.0076, R = -0.170, P = 0.021). Significant dose-response relationships were identified for aerobic (β = -0.0142, R = -0.313, P = 0.016) and combined training (β = -0.0109, R = -0.259, P = 0.041), but not resistance training (β = 0.0068, R = 0.153, P = 0.233). Dose-response relationships in all training groups combined were significant in subgroups younger than 55 yr (β = -0.0113, R = -0.286, P = 0.005), males (β = -0.0123, R = -0.234, P = 0.010), and baseline HbA1c ≥7.5% (58 mmol·mol) (β = -0.013, R = -0.263, P = 0.011). Conclusions There was a dose-response relationship between adherence to prescribed exercise and HbA1c reduction suggesting that glycemic control is improved more in individuals with type 2 diabetes with a higher training volume. Dose-response relationships existed for aerobic and combined training but not resistance training. These findings support aerobic and combined exercise prescriptions outlined in clinical practice guidelines.

Background The combined effect of a low-carbohydrate, high-protein (LCHP) diet and omega-3 (n-3) polyunsaturated fatty acid (PUFA) supplementation on patients with type 2 diabetes (T2D) is not known. Objective The aim of this study was to evaluate the effect of an LCHP diet combined with ω-3 (LCHP+ω-3) on glycemic control in patients with T2D. Design In this randomized, double-blind, parallel-controlled trial, 122 newly diagnosed participants with T2D were randomly assigned to receive a high-carbohydrate, low-protein diet with low ω-3 PUFAs [control (CON)], an LCHP, ω-3, or LCHP+ω-3 diet for 12 wk. The ratio of carbohydrate to protein was 42:28 in the LCHP and LCHP+ω-3 diet and 54:17 in the CON and ω-3 diet. The participants were given 6 g fish oil/d (containing 3.65 g docosahexaenoic acid, eicosapentaenoic acid, and docosapentaenoic acid/d) in the ω-3 and LCHP+ω-3 diet groups or 6 g corn oil/d (placebo) in the CON and LCHP diet groups. Results Compared with the CON diet group, greater decreases in glycated hemoglobin (HbA1c) and fasting glucose were observed in all of the other 3 diet groups at 12 wk. Of note, HbA1c reduction in the LCHP+ω-3 diet group (-0.51%; 95% CI: -0.64%, -0.37%) was greater than that in the LCHP (P = 0.03) and ω-3 (P = 0.01) diet groups at 12 wk. In terms of fasting glucose, only the LCHP+ω-3 diet group showed a significant decrease at 4 wk (P = 0.03 compared with CON). Moreover, the reduction in fasting glucose in the LCHP+ω-3 diet group (-1.32 mmol/L; 95% CI: -1.72, -0.93 mmol/L) was greater than that in the LCHP (P = 0.04) and ω-3 (P = 0.03) diet groups at 12 wk. Conclusions The LCHP+ω-3 diet provided greater effects on HbA1c and fasting glucose and faster effects on fasting glucose than both the LCHP and ω-3 diets, indicating the potential necessity of combining an LCHP diet with ω-3 PUFAs in T2D control. This trial was registered at chictr.org.cn/ as ChiCTR-TRC-14004704.

Brain derived neurotrophic factor (BDNF) is a protein that plays a critical role in modulating cognition in animals and humans. Aerobic exercise often increases BDNF in adults, but effects of this exercise modality and others among adolescents remain uncertain. This study examined the effects of aerobic training, resistance training, and combined training on resting serum BDNF levels in adolescents with overweight and obesity. After a 4-week pre-randomization treatment, 304 post-pubertal, adolescents with overweight or obesity (70% females) aged 14–18 years were randomized to one of four groups for 22 weeks: aerobic training (N = 75), resistance training (N = 78), combined aerobic and resistance training (N = 75), or non-exercising control (N = 76). All participants received dietary counseling targeting a daily energy deficit of 250 kcal. The exercise prescription was 4 times per week, progressing to 45 min/session for the aerobic and resistance groups and 90 min/session for the combined group. Resting serum BDNF levels were measured at baseline and 6-months. Results showed that in both intention-to-treat (ITT) and per protocol (≥70% adherence to prescribed sessions) analyses, there were no significant within- or between-group changes in BDNF. Findings indicate that aerobic training, resistance training or their combination did change serum BDNF levels in adolescents with overweight and obesity. Trial Registration: ClinicalTrials.Gov NCT00195858 http://clinicaltrials.gov/show/NCT00195858, September 12, 2005 (Funded by the Canadian Institutes of Health Research).

Contact force-sensing technology has become a widely used addition to catheter ablation procedures. Neither the optimal contact force required to achieve adequate lesion formation in the ventricle, nor the impact of left ventricular access route on contact force has been fully clarified. Consecutive patients (n = 24) with ischemic cardiomyopathy who underwent ablation for scar-related ventricular tachycardia were included in the study. All ablations (n = 25) were performed using irrigated contact force-sensing catheters (Smart Touch, Biosense Webster). Effective lesion formation was defined as electrical unexcitability post ablation at sites which were electrically excitable prior to ablation (unipolar pacing at 10 mA, 2 ms pulse width). We explored the contact force which achieved effective lesion formation and the impact of left ventricular access route (retrograde aortic or transseptal) on the contact force achieved in various segments of the left ventricle. Scar zone was defined as bipolar signal amplitude

BACKGROUND Patients with ventricular tachycardia (VT) postmyocardial infarction (MI) are a higher risk group with significant morbidity and mortality. We examined the impact of prior coronary revascularization on clinical outcomes in patients with ischemic cardiomyopathy and VT. METHODS The VANISH trial randomized 259 patients with prior MI and antiarrhythmic drug-refractory VT to receive escalated medical therapy or catheter ablation. Clinical outcomes were compared according to whether patients have undergone prior revascularization procedures. The primary outcome was a composite of death, appropriate implantable cardiac defibrillator (ICD) shock, or VT storm. The secondary outcomes included elements of the primary outcome, hospitalization, and any ventricular arrhythmia. RESULTS 190 patients (73%) had prior coronary revascularization. Revascularization group had more men (97% vs 83%; P = 0.0003) and patients in that group were older (mean age 69.3 ± 7.6 vs 66.7 ± 9.2; P = 0.04), had more renal insufficiency (22.6% vs 8.7%; P = 0.01), and were more likely to have an implanted cardiac resynchronization device (23% vs 10%, P = 0.03) as compared with the nonrevascularized patients. There were no significant differences in baseline medication use. There was a trend toward fewer hospitalizations in the revascularization group (64% vs 77%; P = 0.07); there were no differences in the individual outcomes of mortality, VT storm, ICD shocks, recurrent MI, or cardiac failure. CONCLUSIONS In this cohort of patients with an ischemic cause for VT, a history of prior coronary revascularization was not associated with a reduction in ventricular arrhythmia or mortality.

Introduction In patients with ischemic heart disease and ventricular tachycardia (VT) refractory to high dose amiodarone, the two most common therapeutic options are adjunctive mexiletine therapy or catheter ablation. There are little existing data on the efficacy of these strategies. We examined the relative efficacy of adjunctive mexiletine and catheter ablation among patients enrolled in the VANISH trial. Methods All subjects enrolled in the VANISH trial who had VT refractory to high dose (≥ 300 mg daily) amiodarone at baseline were included. Per protocol, subjects randomized to escalated drug therapy received adjunctive mexiletine. Results Nineteen of the 259 patients were receiving high-dose amiodarone at baseline and 11 were randomized to escalated therapy with mexiletine and 8 to ablation. The adjunctive mexiletine group had a higher rate of the primary composite outcome (death, VT storm, or appropriate shock) in comparison to catheter ablation (HR 6.87 [2.08-22.8]). Over 90% of the patients in the adjunctive mexiletine/group experienced a primary endpoint during a median 9.2 months' follow-up. There was no difference in the rate of adverse events between the two groups. Conclusions Mexiletine has limited efficacy in the treatment of recurrent VT despite high-dose amiodarone therapy, in patients with ischemic heart disease. Catheter ablation is a superior strategy in this population.

Background/objective We compared health-related quality of life (HRQoL) in patients randomized to escalated therapy and those randomized to ablation for ventricular tachycardia in the VANISH trial. Methods HRQoL was assessed among VANISH patients at baseline and 3-, 6-, and 12-month follow-up visits. Four validated instruments were used: the SF-36, the implanted cardioverter defibrillator (ICD) Concerns questionnaire (ICDC), the Hospital Anxiety and Depression Scale (HADS), and the EuroQol five dimensions questionnaire (EQ-5D). Linear mixed-effects modeling was used for repeated measures with SF-36, HADS, ICDC, and EQ-5D as dependent variables. In a second model, treatment was subdivided by amiodarone use prior to enrollment. Results HRQoL did not differ significantly between those randomized to ablation or escalated therapy. On subgroup analysis, improvement in SF-36 measures was seen at 6 months in the ablation group for social functioning (63.5-69.3, P = 0.03) and energy/fatigue (43.0-47.9, P = 0.01). ICDC measures showed a reduction in ICD concern in the ablation group at 6 months (10.4-8.7, P = 0.01) and a reduction in ICD concern in the escalated therapy group at 6 months (10.9-9.4, P = 0.04). EQ-5D measures showed a significant improvement in overall health in ablation patients at 6 months (63.4-67.3, P = 0.04). Conclusion Patients in the VANISH study randomized to ablation did not have a significant change in quality of life outcomes compared to those randomized to escalated therapy. Some subgroup findings were significant, as those randomized to ablation showed persistent improvement in SF-36 energy/fatigue and ICD concern, and transient improvement in SF-36 social functioning and EQ-5D overall health.

Objectives This study investigated the benefit of an implantable cardioverter-defibrillator (ICD) generator replacement in patients who did not have an ongoing theoretical indication for ICD therapy at time of replacement. Background Primary prevention ICD therapy is known to reduce mortality in patients with cardiomyopathy and reduced left ventricular systolic function. The data describing outcomes after generator replacement are limited. Methods This was a retrospective cohort study following patients implanted with primary prevention ICD therapy from 2002 until 2015 who subsequently received a generator replacement. Patients with an ongoing theoretical indication for ICD therapy were defined as either left ventricular ejection fraction ≤35% or having had prior appropriate ICD therapy. Outcomes were mortality, appropriate ICD therapy and shock, inappropriate shock, and device and lead complications. Results A total of 614 patients were identified; 173 (28.2%) underwent a generator replacement and were followed for a mean of 2.9 years after replacement; 144 (83.2%) had an ongoing theoretical indication. Patients with no ongoing theoretical indication (n = 29, 16.7%) had lower mortality (hazard ratio [HR]: 0.39, 95% confidence interval [CI]: 0.15-1.00, p = 0.0495), appropriate shock rate (HR: 0.29, 95% CI: 0.09 to 0.96, p = 0.04), and appropriate ICD therapy rate (HR: 0.30, 95% CI: 0.12 to 0.77, p = 0.012) when compared with patients with ongoing theoretical indication. In the entire cohort, there were low rates of inappropriate shock (4.0%), device complication (5.1%), and lead complication (2.3%). Conclusions In patients with primary prevention ICD therapy who underwent generator replacement, improved left ventricular ejection fraction and lack of prior appropriate ICD therapy at time of replacement were associated with a lower risk of mortality and incident ventricular arrhythmia.

Post-hoc analyses of clinical trials and population-based studies have shown no difference in mortality between men and women, but often show that men are more likely to receive appropriate ICD therapy. We utilized a population-based registry to investigate the interaction of sex and age and the occurrence of ventricular arrhythmia in an ICD population.A total of 776 consecutive patients receiving an ICD for primary or secondary prevention in a provincial ICD registry were studied. No significant mortality difference was found between men and women (27.5% versus 23.7%, p=0.39). Overall, men were more likely to receive appropriate ICD therapy compared to women (39.3% versus 26.7%, p=0.006). The hazard ratio for appropriate therapy in men vs. women60years of age was 3.22, CI 95% (1.56-6.65), p=0.002, and the same comparison in men vs. women over the age of 60 showed no significant difference (HR 1.11, CI 95% [0.74-1.65], p=0.61). This interaction between age and sex remained significant when adjusted for New York Heart Associated Class, ejection fraction, coronary artery disease and indication for ICD (p=0.02).This study demonstrates that the risk of appropriate ICD therapy increases as women are older, reaching similar risk as men in that age group. Further study of the mechanism of the interaction of age and sex as they modulate the occurrence of ventricular arrhythmia may be warranted.

This study examined the effects of aerobic and resistance training, and their combination on health-related quality of life (HRQoL) in adolescents with overweight or obesity. After a 4-week run-in period, 304 (91 males, 213 females) post-pubertal adolescents aged 14–18 years, were randomized to 4 groups for 22 weeks of: aerobic training (n = 75), resistance training (n = 78), combined aerobic and resistance training (n = 75), or nonexercising control (n = 76). All participants received dietary counseling with a daily energy deficit of 250 kcal. Indicators of HRQoL such as overall HRQoL, and physical and psychosocial (an aggregate of emotional, social, and school functioning) HRQoL at baseline and 6 months postintervention were measured by the Pediatric Quality of Life questionnaire. The trial began in March 2005 and was completed in June 2011. In the intention-to-treat analyses, all groups showed significant improvements at 6 months on all HRQoL indicators. The aerobic group showed greater improvements than controls on physical HRQoL (mean differences of 5.5; 95% CI; 1.4–9.6, p = 0.009). In participants with ≥70% adherence, combined training produced greater improvements than control on overall HRQoL (mean differences of 4.8, 95% CI; 0.7–9.0, p = 0.02), physical HRQoL (mean differences of 5.8; 95% CI: 0.6–10.7; p = 0.03), social HRQoL (mean differences of 7.6; 95% CI: 1.0–14.2; p = 0.02), and school-based HRQoL (mean differences of 7.6; 95% CI: 1.0–14.2; p = 0.02). These findings highlight the potential importance of including resistance exercise into traditional aerobic exercise programs to maximize HRQoL in adolescents with obesity.

The literature suggests that p63 expression in Merkel cell carcinoma (MCC) is associated with a poor prognosis. p63 immunohistochemistry marks the 2 main isoforms of this transcriptional protein: TAp63 (tumor suppressor-like properties) and ∆Np63 (oncogenic properties). Little information about the isoform of relevance in MCC exists. p40 immunohistochemistry specifically marks ∆Np63, and using comparative, semiquantitative expression of p63 and p40, we sought to clarify the issue. Our cohort of 53 cases (28 men and 25 women, median age 79 years, interquartile range 71-88) was stratified by morphology and viral status. Immunohistochemistry (p63, p40, and cytokeratin 5/6) was performed, H-scores for nuclear expression of p63 and p40 were derived (2 observers; positivity ≥ 10), and interobserver agreement was evaluated. Clinical, pathological, and outcome data were documented. The results were analyzed statistically. Mortality amounted to 57% (median follow-up 686 days, interquartile range 292-1599). Positivity for Merkel cell polyomavirus was observed in 29 (55%) of cases. Expression of p63 and p40 was present in 36 (69%) and 4 (8%) of cases, respectively. Increased age (P = .0241), negative Merkel cell polyomavirus status (P = .0185), and p63 positivity (P = .0012) were significantly associated with mortality. The latter 2 variables were highly correlated (P = .004). The interclass correlation between the 2 sets of H-scores was 0.95. Our findings support an association between p63 expression and reduced overall survival in MCC and show consistency in scoring this prognostic parameter. TAp63 is the dominant isoform of the protein involved. The paradoxical tumor suppressor-like activity of this isoform in p63-positive MCCs with reduced overall survival requires further study.

This study sought to examine the adverse prognosis associated with ventricular arrhythmia clusters that falls outside the current electrical storm definition.Electrical storm is most frequently defined as a cluster of ≥3 episodes of ventricular arrhythmia (VA) in a 24-h period. This definition has been associated with adverse cardiovascular outcomes and mortality, but the effect of lesser and greater clustering of arrhythmias has not been described.Among all patients in the Resynchronization in Ambulatory Heart Failure trial, 14,515 implantable cardioverter-defibrillator-detected events with data available were rigorously adjudicated in blinded fashion. Arrhythmia incidence was examined for clustering, defined as 2 or more VA events occurring within 3 months. The prognostic importance of clustering was analyzed by varying the cluster length and number of events used to define a cluster. Mortality rates of groups with clustered arrhythmias were compared to patients with no arrhythmia or with unclustered arrhythmia.The trial included 1,764 patients, among whom 465 patients had two or more VA episodes within 3 months, whereas 406 had unclustered arrhythmias. Compared to patients with no arrhythmia, patients experiencing unclustered VA had increased risk of death (hazard ratio [HR]: 1.45; 95% confidence interval [CI]: 1.09 to 1.93; p = 0.011), whereas the risk was even higher in patients with clustered arrhythmia (HR: 2.68; 95% CI: 2.13 to 3.36; p 0.0001). Mortality risk increased with higher VA burden (number of VAs in a cluster) and shorter cluster length. This was observed in all groups tested, including the cluster with the least VA burden in the longest cluster length tested (2 VA episodes occurring within 3 months) (mortality HR: 2.85; 95% CI: 1.95 to 4.17; p 0.0001). Although clustered arrhythmias terminated with antitachycardia pacing were associated with increased mortality, clusters terminated with implantable cardioverter-defibrillator shocks were associated with still higher mortality risk.Significant adverse prognostic association of clustered VAs is observable with even 2 VA events within 3 months and increases with higher cluster density.

We evaluated the hypothesis that resistance exercise training performed alone or in combination with aerobic exercise training would increase resting metabolic rate (RMR) relative to aerobic-only and nonexercising control groups. Postpubertal adolescents (N = 304) aged 14–18 years with obesity (body mass index (BMI) ≥ 95th percentile) or overweight (BMI ≥ 85th percentile + additional diabetes risk factor(s)) were randomized to 4 groups for 22 weeks: Aerobic exercise training, Resistance exercise training, Combined aerobic and resistance exercise training, or Control. All participants received dietary counselling targeting a daily energy deficit of 250 kcal. RMR was measured by indirect calorimetry and body composition by magnetic resonance imaging. There was no significant change in RMR in any group, in spite of significant within-group increases in fat-free mass in the Aerobic, Resistance, and Combined exercise training groups. RMR at baseline and 6 months were Aerobic: 1972 ± 38 and 1990 ± 41; Resistance: 2024 ± 37 and 1992 ± 41; Combined: 2023 ± 38 and 1995 ± 38; Control: 2075 ± 38 and 2073 ± 39 kcal/day (p > 0.05). There were no between-group differences in RMR after adjustment for total body weight or fat-free mass between groups over time. Per-protocol analyses including only participants with ≥70% adherence, and analyses stratified by sex, also showed no within- or between-group differences in RMR. In conclusion, despite an increase in fat-free mass in all exercise groups, 6 months of aerobic, resistance, or combined training with modest dietary restriction did not increase RMR compared with diet only in adolescents with obesity.

The susceptibility of Merkel cell carcinoma to the host immune response has prompted a search for effective immunotherapy. CD8-positive T lymphocytes are considered key effectors of this response, but the cellular infiltrates also harbor tumor-protective agents. By developing a comprehensive morphological and immunophenotypic map of tumor-infiltrating lymphocytes (TILS) in Merkel cell carcinoma, we aimed to establish a useful template for future studies. Twenty-two cases (mean age, 79years [range, 52-95]; male-female ratio, 10:12) were studied. TILS were categorized as brisk (7), nonbrisk (9), and absent(6). Merkel cell polyomavirus (MCPyV)-positive (16) and -negative (6) cases were included, as were those with pure (18) and combined (4) morphologies. One MCPyV+ case had undergone spontaneous regression. Immunohistochemical markers included CD3, CD4, CD8, CD20, CD68, FoxP3, PD-1, and CD123. Statistical analysis used Fisher exact tests and Spearman correlations. There was a significant correlation between brisk TILs and MCPyV+ status (P=.025). CD8+ T lymphocytes predominated, were present in significantly higher proportions in brisk infiltrates (P=.003), and showed a significant predilection for the intratumoral environment (P=.003). Immune inhibitors including T regulatory cells (FOXP3+) and PD-1+ "exhausted" immunocytes were present in lower proportions. Our findings support (1) the link between a brisk immune response and MCPyV positivity, (2) the supremacy of CD8+ cells in effecting immunity, and (3) the incorporation of immune inhibitors within the global infiltrate. Efforts to therapeutically arm the "effectors" and disarm the "detractors" are well focused. These will likely have the greatest impact on MCPyV-positive cases.

There has been renewed interest in examining the relationship between specific components of energy expenditure and the overall influence on energy intake (EI). The purpose of this cross-sectional analysis was to determine the strongest metabolic and anthropometric predictors of EI. It was hypothesized that resting metabolic rate (RMR) and skeletal muscle mass would be the strongest predictors of EI in a sample of overweight and obese adolescents. 304 post-pubertal adolescents (91 boys, 213 girls) aged 16.1 (±1.4) years with body mass index at or above the 95th percentile for age and sex OR at or above the 85th percentile plus an additional diabetes risk factor were measured for body weight, RMR (kcal/day) by indirect calorimetry, body composition by magnetic resonance imaging (fat free mass (FFM), skeletal muscle mass, fat mass (FM), and percentage body fat), and EI (kcal/day) using 3 day food records. Body weight, RMR, FFM, skeletal muscle mass, and FM were all significantly correlated with EI (p < 0.005). After adjusting the model for age, sex, height, and physical activity, only FFM (β = 21.9, p = 0.007) and skeletal muscle mass (β = 25.8, p = 0.02) remained as significant predictors of EI. FFM and skeletal muscle mass also predicted dietary protein and fat intake (p < 0.05), but not carbohydrate intake. In conclusion, with skeletal muscle mass being the best predictor of EI, our results support the hypothesis that the magnitude of the body’s lean tissue is related to absolute levels of EI in a sample of inactive adolescents with obesity.

The purpose of this study was to examine the effects of aerobic, resistance, and combined exercise training on cardiorespiratory and musculoskeletal fitness in postpubertal adolescents with obesity. After a 4-week supervised moderate-intensity exercise run-in, 304 adolescents aged 14–18 years with body mass index ≥85th percentile were randomized to 4 groups for 22 weeks of aerobic training, resistance training, combined training, or a nonexercising control. All participants received dietary counselling with a maximum daily energy deficit of 250 kcal. Cardiorespiratory fitness (peak oxygen consumption) was measured by indirect calorimetry using a graded treadmill exercise test. Musculoskeletal fitness was measured using the 2003 Canadian Physical Activity Fitness and Lifestyle Appraisal tests (hand grip, push-ups, partial curl-ups, sit and reach, and vertical jump). Muscular strength was assessed using an 8-repetition maximum test on the bench press, seated row, and leg press machines. A greater increase in peak oxygen consumption in the aerobic exercise group (30.6 ± 0.6 to 33.4 ± 0.7 mLO2/kg/min) was measured relative to the control group (30.6 ± 0.5 to 30.9 ± 0.7 mLO2/kg/min) (p = 0.002). Similarly, the number of partial curl-ups increased in the aerobic group (19 ± 1 to 23 ± 1) while no differences were measured in the control group (19 ± 1 to 20 ± 1) (p = 0.015). Increases in muscular strength and number of push-ups were greatest in the resistance group versus the control and combined groups versus the aerobic group (p < 0.05). In conclusion, aerobic training had the strongest effect on cardiorespiratory fitness, while resistance and combined training improved both muscular strength and endurance more than control and aerobic training alone, respectively, in adolescents with obesity.

This study sought to evaluate the effect of cardiac resynchronization therapy with defibrillator (CRT-D) as compared with implantable cardioverter-defibrillator (ICD) on mortality, heart failure (HF) hospitalization, and ventricular arrhythmia in women versus men.CRT-D has demonstrated reduced mortality and HF hospitalizations with greater benefit observed in women compared with men. However, whether CRT-D prevented ventricular arrhythmias in women compared with men was unclear.The RAFT (Resynchronization-Defibrillation for Ambulatory Heart Failure Trial) study randomized 1,798 patients to an ICD or CRT-D. In this post hoc analysis, women and men were compared by randomized group. By using a multivariable model, the outcomes of death and HF hospitalization and incidence of ventricular arrhythmia were compared between men and women.There were 1,490 (83%) men (732, ICD; 758, CRT-D) and 308 (17%) women (172, ICD; 136, CRT-D) included in the analysis. Women with CRT-D had a significantly reduced incidence of death and HF hospitalization compared with men with CRT-D (hazard ratio: 0.52; 95% confidence interval: 0.33 to 0.81; p 0.001) on multivariable analysis. Women with a primary prevention indication and CRT-D had the lowest rate of ventricular arrhythmia compared with men (hazard ratio: 0.59; 95% confidence interval: 0.39 to 0.91; p = 0.016).Women have improved rates of death and HF hospitalization with CRT-D and were less likely to experience ventricular arrhythmia when compared with men, after adjusting for differences in baseline characteristics over a prolonged follow-up. Whether these improved outcomes reflect inherent sex differences in the underlying myocardial substrate resulting in an enhanced response to CRT-D requires further research.

Background: Sellar masses (SM) are mostly benign growths of pituitary or nonpituitary origin that are increasingly encountered in clinical practice. To date, no comprehensive population-based study has reported the epidemiology of SM from North America. Aim: To determine the epidemiology of SM in the province of Nova Scotia, Canada. Methods: Data from all pituitary-related referrals within the province were prospectively collected in interlinked computerized registries starting in November 2005. We conducted a retrospective analysis on all patients with SM seen within the province between November 2005 and December 2013. Results: A total of 1107 patients were identified, of which 1005 were alive and residing within the province. The mean age at presentation was 44.6±18 years, with an overall female preponderance (62%) and a population prevalence rate of 0.1%. Of patients with SM, 837 (83%) had pituitary adenomas and 168 (17%) had nonpituitary lesions. The relative prevalence and standardized incidence ratio, respectively, of various SM were: nonfunctioning adenomas (38.4%; 2.34), prolactinomas (34.3%; 2.22), Rathke’s cyst (6.5%; 0.5), growth hormone–secreting adenomas (6.5%; 0.3), craniopharyngiomas (4.5%; 0.2), adrenocorticotropic hormone–secreting adenomas (3.8%; 0.2), meningiomas (1.9%), and others (3.9%; 0.21). At presentation, 526 (52.3%) had masses ≥1 cm, 318 (31.6%) at Conclusions: This is the largest North American study to date to assess the epidemiology of SM in a large stable population. Given their significant prevalence in the general population, more studies are needed to evaluate the natural history of these masses and to help allocate appropriate resources for their management.

Purpose To determine the incidence of postintubation hypotension (PIH) and associated outcomes in critically ill patients requiring endotracheal intubation. Materials and Methods Medical records were reviewed for 479 consecutive critically ill adult patients who required intubation by an intensive care unit (ICU) service at 1 of 4 academic tertiary care hospitals. The primary outcome measure was the incidence of PIH. Secondary outcome measures included mortality, ICU length of stay, requirement for renal replacement therapy, and a composite end point consisting of overall mortality, ICU length of stay greater than 14 days, duration of mechanical ventilation longer than 7 days, and renal replacement therapy requirement. Results Overall, the incidence of PIH among ICU patients requiring intubation was 46% (218/479 patients). On univariate analysis, patients who developed PIH had increased ICU mortality (37% PIH vs 28% no PIH, P = .049) and overall mortality (39% PIH vs 30% no PIH, P = .045). After adjusting for important risk factors, development of PIH was associated with the composite end point of major morbidity and mortality (odds ratio, 2.00; 95% confidence interval, 1.30-3.07; P = .0017). Conclusions The development of PIH is common in ICU patients requiring emergency airway control and is associated with poor patient outcomes.

Merkel cell polyomavirus is of oncogenic significance in approximately 80% of Merkel cell carcinomas. Morphological subcategories of the tumor differ in regard to viral status, the rare combined type being uniformly virus negative and the predominant pure type being mainly virus positive. Indications that different biological subsets of the tumor exist led us to explore this diversity. In an Eastern Canadian cohort of cases (75 patients; mean age, 76 years [range, 43-91]; male/female ratio, 43:32; 51 [68%] pure and 24 [34%] combined tumors), we semiquantitatively compared the immunohistochemical expression of 3 cellular proteins (p53, Bcl-2, and c-kit) in pure versus combined groups. Viral status was known in a subset of cases. The significant overexpression of p53 in the combined group (mean [SD], 153.8 [117.8] versus 121.6 [77.9]; P = .01) and the increased epidermal expression of this protein (p53 patches) in the same group lend credence to a primary etiologic role for sun damage in these cases. Expression of Bcl-2 and c-kit did not differ significantly between the 2 morphological groups. A relative increase in c-kit expression was significantly associated with a virus-negative status (median [interquartile range], 100 [60-115] versus 70 [0-100]; P = .03). Emerging data reveal divergent biological pathways in Merkel cell carcinoma, each with a characteristic immunohistochemical profile. Virus-positive tumors (all pure) exhibit high retinoblastoma protein and low p53 expression, whereas virus-negative cases (few pure and all combined) show high p53 and relatively high c-kit expression. The potential biological implications of this dichotomy call for consistent stratification of these tumors in future studies.

To investigate the effects of aerobic training, resistance training, or both on abdominal subcutaneous fat (subcutaneous adipose tissue (SAT)) (deep and superficial), visceral fat (visceral adipose tissue (VAT)), apolipoproteins A-1 and B (ApoA-1, ApoB), ApoB/ApoA-1 ratio and high-sensitivity C-reactive protein (HSCRP) in post-pubertal adolescents with obesity.After a 4-week supervised moderate-intensity exercise run-in period, 304 postpubertal adolescents with overweight (body mass index (BMI) ⩾85th percentile for age and sex+diabetes risk factor) or obesity (⩾95th BMI percentile) aged 14-18 years were randomized to four groups for 22 weeks (5 months): aerobic training, resistance training, combined training or a non-exercising control.This study used a randomized controlled design. All groups received dietary counseling designed to promote healthy eating with a maximum daily energy deficit of 250 kcal. Abdominal fat (SAT and VAT) at the level of the fourth and fifth lumbar vertebrae (L4-L5) was measured by magnetic resonance imaging and ApoA-1, ApoB and HSCRP were measured after a 12-h fast at baseline and after 6 months.Changes in SAT at L4-L5 were -16.2 cm(2) in aerobic (P=0.04 vs control), -22.7 cm(2) in resistance (P=0.009 vs control) and -18.7 cm(2) in combined (P=0.02 vs control). Combined training reduced ApoB levels from 0.81±0.02 to 0.78±0.02 g l(-1) (P=0.04 vs control) and ApoB/ApoA-1 ratio from 0.67±0.02 to 0.64±0.02 (P=0.02 vs control and P=0.04 vs aerobic). There were no significant differences in VAT, ApoA-1 or HSCRP levels between groups.Aerobic and resistance training and their combination decreased abdominal SAT in adolescents with obesity. Combined training caused greater improvements in ApoB/ApoA-1 ratio compared with aerobic training alone.

Clinical trials and meta-analyses have suggested that aspirin may be effective for the prevention of venous thromboembolism (proximal deep-vein thrombosis or pulmonary embolism) after total hip or total knee arthroplasty, but comparisons with direct oral anticoagulants are lacking for prophylaxis beyond hospital discharge.We performed a multicenter, double-blind, randomized, controlled trial involving patients who were undergoing total hip or knee arthroplasty. All the patients received once-daily oral rivaroxaban (10 mg) until postoperative day 5 and then were randomly assigned to continue rivaroxaban or switch to aspirin (81 mg daily) for an additional 9 days after total knee arthroplasty or for 30 days after total hip arthroplasty. Patients were followed for 90 days for symptomatic venous thromboembolism (the primary effectiveness outcome) and bleeding complications, including major or clinically relevant nonmajor bleeding (the primary safety outcome).A total of 3424 patients (1804 undergoing total hip arthroplasty and 1620 undergoing total knee arthroplasty) were enrolled in the trial. Venous thromboembolism occurred in 11 of 1707 patients (0.64%) in the aspirin group and in 12 of 1717 patients (0.70%) in the rivaroxaban group (difference, 0.06 percentage points; 95% confidence interval [CI], -0.55 to 0.66; P0.001 for noninferiority and P=0.84 for superiority). Major bleeding complications occurred in 8 patients (0.47%) in the aspirin group and in 5 (0.29%) in the rivaroxaban group (difference, 0.18 percentage points; 95% CI, -0.65 to 0.29; P=0.42). Clinically important bleeding occurred in 22 patients (1.29%) in the aspirin group and in 17 (0.99%) in the rivaroxaban group (difference, 0.30 percentage points; 95% CI, -1.07 to 0.47; P=0.43).Among patients who received 5 days of rivaroxaban prophylaxis after total hip or total knee arthroplasty, extended prophylaxis with aspirin was not significantly different from rivaroxaban in the prevention of symptomatic venous thromboembolism. (Funded by the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT01720108 .).

This study sought to evaluate the predictive value of noninducibility on long-term outcomes.The traditional endpoint for catheter ablation of ventricular tachycardia (VT) is noninducibility of VT by programmed stimulation; however, the definition of inducibility remains variable and its prognostic value limited by nonstandardized periprocedural antiarrhythmic drug therapy and implantable cardioverter-defibrillator programming in prior observational studies. The VANISH trial randomized patients with prior myocardial infarction and VT to ablation (with an endpoint of noninducibility of VT ≥300 ms after ablation) versus antiarrhythmic drug escalation.Patients enrolled in the VANISH study randomized to catheter ablation were included. The relationship between post-ablation inducibility and the primary composite endpoint (death, VT storm30 days, or appropriate implantable cardioverter-defibrillator shock30 days) was assessed using a time-to-event analysis, adjusting for other clinical and procedural characteristics.A total of 129 patients from the ablation arm were included in the primary analysis, of which 51 were noninducible post-ablation compared with 78 who had inducible VT or in whom inducibility testing was not performed. There were no significant baseline characteristic or procedural differences except for increased implantable cardioverter-defibrillator shocks before randomization in the noninducible group. In multivariate analysis, inducibility significantly increased the risk of death, appropriate shock, or VT storm after 30 days (HR: 1.87; p = 0.017).Inducibility of any VT post-ablation was associated with an increased risk of the composite endpoint in the VANISH trial. A randomized trial is required to confirm whether more aggressive ablation targeting faster induced VTs (300 ms) can improve outcomes.

Obesity in youth increases the risk of type 2 diabetes (T2D), and both are risk factors for neurocognitive deficits. Exercise attenuates the risk of obesity and T2D while improving cognitive function. In adults, these benefits are associated with the actions of the brain-derived neurotrophic factor (BDNF), a protein critical in modulating neuroplasticity, glucose regulation, fat oxidation, and appetite regulation in adults. However, little research exists in youth. This study examined the associations between changes in diabetes risk factors and changes in BDNF levels after 6 months of exercise training in adolescents with obesity. The sample consisted of 202 postpubertal adolescents with obesity (70% females) aged 14–18 years who were randomized to 6 months of aerobic and/or resistance training or nonexercise control. All participants received a healthy eating plan designed to induce a 250/kcal deficit per day. Resting serum BDNF levels and diabetes risk factors, such as fasting glucose, insulin, homeostasis model assessment (HOMA-B—beta cell insulin secretory capacity) and (HOMA-IS—insulin sensitivity), and hemoglobin A1c (HbA1c), were measured after an overnight fast at baseline and 6 months. There were no significant intergroup differences on changes in BDNF or diabetes risk factors. In the exercise group, increases in BDNF were associated with reductions in fasting glucose (β = −6.57, SE = 3.37, p=0.05) and increases in HOMA-B (β = 0.093, SE = 0.03, p=0.004) after controlling for confounders. No associations were found between changes in diabetes risk factors and BDNF in controls. In conclusion, exercise-induced reductions in some diabetes risk factors were associated with increases in BDNF in adolescents with obesity, suggesting that exercise training may be an effective strategy to promote metabolic health and increases in BDNF, a protein favoring neuroplasticity. This trial is registered with ClinicalTrials.gov NCT00195858, September 12, 2005 (funded by the Canadian Institutes of Health Research).

Background The VANISH trial (Ventricular Tachycardia Ablation Versus Escalated Antiarrhythmic Drug Therapy in Ischemic Heart Disease) compared the effectiveness of escalated antiarrhythmic drug therapy to catheter ablation in patients with prior myocardial infarction, an implanted defibrillator, and ventricular tachycardia (VT). The effectiveness of these interventions in patients on sotalol versus amiodarone was compared. Methods and Results Analysis was conducted based on whether patients had recurrent VT, despite amiodarone (amio-refractory) or nonamiodarone drugs (sotalol-refractory). Outcomes included death, VT storm, appropriate implantable cardioverter defibrillator shock, and any ventricular arrhythmia. At baseline, 169 (65.2%) were amio-refractory, and 90 (34.7%) were sotalol-refractory (1 patient on procainamide rather than sotalol). Amio-refractory patients had more renal insufficiency (23.7% versus 10%; P =0.0008), worse New York Heart Association class (82.3% II/III versus 65.5%; P =0.0003), and lower ejection fraction (29±9.7% versus 35.2±11%; P P =0.020). Sotalol-refractory patients had trends toward higher mortality and VT storm with ablation, with no effect on implantable cardioverter defibrillator shocks. Within the escalated drug therapy arm, amio-refractory patients had a higher rate of the composite outcome (hazard ratio, 1.94; 95% confidence interval, 1.14–3.29; P =0.0144) and a trend to higher mortality (hazard ratio, 2.40; 95% confidence interval, 0.93–6.22; P =0.07), whereas mortality was not different between amio- and sotalol-refractory patients within the ablation treatment group. Conclusions Patients with amio-refractory VT have a higher rate of ventricular arrhythmia and mortality than those with sotalol-refractory VT and derive greater benefit of catheter ablation than for patients with sotalol-refractory VT who are switched to amiodarone. CLINICAL TRIAL REGISTRATION URL: https://clinicaltrials.gov . Unique identifier: NCT00905853.

Background Despite widespread use of the 250-mcg Cosyntropin test (ACTH test) for the diagnosis of adrenal insufficiency (AI), the effect of time of day and the utility of performing both 30- and 60-min serum cortisol values remains unclear. Methods We conducted a retrospective cohort study of all ACTH testing at the Halifax Neuropituitary Program, Nova Scotia, Canada between January 2006 and April 2016. Data were collected on age, gender, medication history, serum cortisol levels at 0, 30 and 60 min after ACTH administration, as well as time of and indication for testing. Results There were 336 tests performed, divided by time of day (0800–1000 h, 1001–1200 h, and after 1200 h). There were no differences in mean cortisol levels at 30 (574.5, 559, 534 nmol/L, respectively; p = 0.25) and 60 min (642, 623, 619 nmol/L, respectively; p = 0.63) between groups. When comparing 30- vs. 60-min values using a cut-off of ≥500 nmol/L, 45 patients (13.4%) failed to reach the cut-off at 30 min but met the cut-off at 60 min. Conversely, only 2 patients (0.6%) who met the cut-off at 30 min failed to reach it at 60 min. Conclusion We found that outcomes from ACTH testing are not affected by time of day. Furthermore, using a 30-min cortisol level in isolation results in more than one in seven patients having a false positive diagnosis of AI; a 60-min value of ≥500 nmol/L alone may be sufficient to diagnose AI in >99% of cases.

Recent evidence has invoked immunohistochemical expression of p63 in Merkel cell carcinoma as an adverse prognostic factor. Conflicting data led us to evaluate this. An Eastern Canadian cohort diagnosed between 1990 and 2012 was studied. Demographic and clinical data were obtained from pathology records and Provincial Cancer Registries. Pathological features were evaluated by the investigators. Merkel cell polyomavirus status was known in a subset of cases. Clinicopathological features were correlated with overall survival. The cohort consisted of 83 patients (mean age, 75.8 ± 11.7 years) with a male/female ratio of 1.24:1. In a mean follow-up period of 175 weeks (±177), 51 patients died (61.4%). Of several parameters examined, 6 showed significant adverse associations with survival on univariate analysis: age (hazard ratio [HR], 1.05 [1.02-1.08]), clinical stage (III/IV versus I/II; HR, 2.24 [1.18-4.27]), tumor size (HR, 1.16 [1.05-1.28]), combined versus pure morphology (HR, 1.82 [1.04-3.18]), minimal tumor-infiltrating lymphocytes (HR, 2.23 [1.04-4.78]), and expression of p63 (positive in 49.4%; HR, 1.93 [1.09-3.43]). In the stage I/II subgroup, p63 expression was associated with a trend toward poor survival. On multivariate analysis, p63 expression was not significantly associated with reduced survival. Our data support existing evidence that p63 expression in Merkel cell carcinoma carries adverse implications for survival. That it was not an independent prognostic factor may be due to study size and/or its potential as a confounding variable with clinical stage. Of clinical importance is its association with a trend toward a poor outcome in early stage disease.

To explore the relationships between wheelchair services received during wheelchair provision and positive outcomes for users of wheelchairs.Secondary analysis of cross-sectional data.Urban and periurban communities in Kenya and the Philippines.Adult basic manual wheelchair users (N=852), about half of whom reported having received some wheelchair services with the provision of their current wheelchairs.Not applicable.Participants completed a survey that included questions related to demographic, clinical, and wheelchair characteristics. The survey also included questions about the past receipt of 13 wheelchair services and 4 positive outcomes for users of wheelchairs. The relationships between individual services received and positive outcomes were assessed using logistic regression analyses. In addition to assessing individual services and outcomes, we analyzed a composite service score (the total number of services received) and a composite outcome score (≥3 positive outcomes).The top 3 individual services from the perspective of relationships with the composite outcome score were "provider did training" (P=.0009), "provider assessed wheelchair fit while user propelled the wheelchair" (P=.002), and "peer group training received" (P=.033). The composite service score was significantly related to "daily wheelchair use" (P.0001), "outdoor unassisted wheelchair use" (P.0001), "high performance of activities of daily living" (P=.046) and the composite outcome score (P=.005), but not to the "absence of serious falls" (P=.73).The receipt of wheelchair services is associated with positive outcomes for users of wheelchairs, but such relationships do not exist for all services and outcomes. These findings are highly relevant to ongoing efforts to optimize wheelchair service delivery.

Determine the role of cardiac output and central venous pressure (CVP) measurements in the clinical decisions that were based on the algorithm used in a randomized trial that compared a colloid to a crystalloid solution in the management of patients early after cardiac surgery (FACS trial, NCT00337805, Crit Care Med 2010; 38:2117).We analyzed the changes in CVP and cardiac index (CI) in 729 fluid challenges from the FACS trial in which 119 patients were randomized to colloid and 118 to crystalloid boluses in a flow-based protocol. A fluid challenge was defined as being positive if CI increased by ≥ 0.3 L/min(-1)m(-2) and negative if CI increased by0.3 L/min(-1)m(-2) but CVP increased by ≥ 2 mmHg.As defined in the protocol, 26% of boluses were given for a low CI (2.2 L/min(-1)m(-2)). CI did not increase in 20% of boluses despite an adequate increase in CVP; in the protocol this meant that further volume boluses were not given. In another 34% of boluses in which CI did not increase, CVP increased by2 mmHg, which meant that volume responsiveness could not be ruled out and another bolus was indicated. 43% of the boluses were given for hypotension, but surprisingly in 90% of these instances, CI was in the acceptable range indicating that the low arterial pressure was due to decreased systemic vascular resistance.Measurement of cardiac output and CVP significantly influenced clinical decisions in the FACS algorithm.

Amyotrophic lateral sclerosis (ALS) is associated with nutritional deficits. Gastrostomy tubes are often inserted in patients with ALS to supplement or replace oral intake. The aim of this study was to better understand the practices of gastrostomy tube insertion in patients with ALS. Pre-collected de-identified data were obtained from the Canadian Neuromuscular Disease Registry (CNDR). Feeding tube status was compared with markers of dysphagia, respiratory compromise, and weight status in both univariate and multivariate analysis by employing odds ratios. Results showed that abnormal ALSFRS-R dysphagia scores were associated with higher rates of feeding tube referrals. The use of non-invasive ventilation also increased the likelihood that a tube was recommended. A higher FVC was found to decrease the likelihood of recommendation. BMI and ALSFRS-R dyspnoea scores were not found to be independently associated. In conclusion, our findings demonstrate that symptoms of dysphagia and respiratory status are associated with higher rates of recommendation for feeding tubes. While not independently significant, individuals with a lower BMI had more feeding tube referrals compared to individuals with a normal or elevated BMI. A similar trend was noted for ALSFRS-R dyspnoea scores. Further research is required to determine if these represent optimal criteria for placement.

Background— Underuse of implantable defibrillators has been previously noted in patients at risk for sudden cardiac death, as well as for survivors of sudden cardiac death. We sought to determine the utilization rates in a primary prevention implantable cardioverter-defibrillator (ICD)–eligible population and mortality in this group compared with a group that had undergone implantation of this therapy. Methods and Results— A retrospective cohort of patients from April 1, 2006, to December 31, 2009, was used to define a primary prevention ICD-eligible population. Two groups were compared on the basis of ICD implantation (no-ICD versus ICD). The primary outcome measure was mortality. Of the 717 patients found to be potentially eligible for a primary prevention ICD, 116 (16%) were referred. The remaining cohort of 601 patients were compared with an existing cohort of primary prevention ICD patients (n=290). A significant survival benefit was associated with primary prevention ICD implantation (hazard ratio, 0.46; 95% CI [0.33–0.64]; P P =0.01). Appropriate ICD therapy occurred in 26% of those in the ICD group, during a mean follow-up of 2.7 years. Conclusions— A significant mortality benefit was observed for patients who underwent primary prevention ICD implantation compared with those who did not. Vigilance is required to ensure that patients eligible for primary prevention ICDs are appropriately referred and assessed to allow such patients to benefit from this life-saving therapy.

The prognostic significance of capsular incision (CapI) into tumor during radical prostatectomy (RP) with otherwise organ-confined disease remains uncertain.To evaluate the impact of CapI into tumor on oncologic outcome.A retrospective review of 8110 consecutive patients with prostate cancer treated at Ottawa Hospital and at Memorial Sloan-Kettering Cancer Center, both tertiary academic centers, between 1985 and 2008.All patients underwent an open, laparoscopic or robotic RP.Patients were divided into four pathologic categories: group 1 (CapI group), positive surgical margins (PSMs) without extraprostatic extension (EPE); group 2, negative surgical margins (NSMs) without EPE; group 3, NSM with EPE; group 4, PSMs with EPE. Estimates of recurrence-free survival were generated with the Kaplan-Meier method. Recurrence was defined as a prostate-specific antigen (PSA)0.2 ng/ml and rising. Cox proportional hazards regression was used to estimate the hazard ratio (HR) for recurrence controlling for pretreatment PSA, RP date, RP Gleason sum, seminal vesicle invasion, and lymph node involvement. Pathologic categories were defined in the model by including the variables EPE and surgical margins (SMs) as well as their interaction.Median follow-up was 37.3 mo. The 5-yr recurrence-free probability after RP for the CapI group was 77% (95% confidence interval [CI], 72-83). This was not only inferior to patients with NSMs and no EPE (log rank p0.0001) but also to those with NSMs and EPE (log rank p=0.0002). In multivariate analysis the interaction between EPE and SM was not significant (p=0.26). In the adjusted model excluding the interaction term, patients with EPE had an increased risk for recurrence (HR: 1.80; 95% CI, 1.49-2.17; p0.0001) as did those with positive margins (HR: 1.81; 95% CI, 1.51-2.15; p0.0001). This was a retrospective study.CapI into tumor has a significant impact on patient outcome following RP. Patients, who otherwise would have organ-confined disease, will now have a higher probability of recurrence than those with completely resected extraprostatic disease.

To determine whether a starch solution for volume resuscitation in a flow-based protocol improves circulatory status better than a crystalloid solution, as defined by the need for catecholamines in patients the morning after cardiac surgery, and whether this can be performed without increased morbidity.Concealed, randomized, double-blind, controlled trial.Two hundred sixty-two patients who underwent cardiac surgery at a tertiary care hospital.Based on predefined criteria indicating a need for fluids, and a nurse-delivered algorithm that used central venous pressure and cardiac index obtained from a pulmonary artery catheter, patients were allocated to receive 250-mL boluses of 0.9% saline or a 250-molecular weight 10% solution of pentastarch.Two hundred thirty-seven patients received volume boluses: 119 hydroxyethyl starches and 118 saline. Between 8:00 am and 9:00 am the morning after surgery, 13 (10.9%) of hydroxyethyl starch patients and 34 (28.8%) saline patients were using catecholamines (p = .001). Hydroxyethyl starch patients had less pneumonia and mediastinal infections (p = .03) and less cardiac pacing (p = .03). There were two deaths in each group. There was no difference in the daily creatinine, development of RIFLE risk criteria during hospital stay, or new dialysis. The numbers and volumes of packed red blood cells were similar in the two groups, but more hydroxyethyl starch patients received plasma transfusions (p = .05).Use of a colloid solution for volume resuscitation in a nurse-delivered flow-based algorithm, which included a pulmonary artery catheter, significantly improved hemodynamic status, an important factor for readiness for discharge from the intensive care unit.

Septic shock represents the major cause of infection-associated mortality in the intensive care unit. The possibility that combination antibiotic therapy of bacterial septic shock improves outcome is controversial. Current guidelines do not recommend combination therapy except for the express purpose of broadening coverage when resistant pathogens are a concern.To evaluate the therapeutic benefit of early combination therapy comprising at least two antibiotics of different mechanisms with in vitro activity for the isolated pathogen in patients with bacterial septic shock.Retrospective, propensity matched, multicenter, cohort study.Intensive care units of 28 academic and community hospitals in three countries between 1996 and 2007.A total of 4662 eligible cases of culture-positive, bacterial septic shock treated with combination or monotherapy from which 1223 propensity-matched pairs were generated.The primary outcome of study was 28-day mortality. Using a Cox proportional hazards model, combination therapy was associated with decreased 28-day mortality (444 of 1223 [36.3%] vs. 355 of 1223 [29.0%]; hazard ratio, 0.77; 95% confidence interval, 0.67-0.88; p = .0002). The beneficial impact of combination therapy applied to both Gram-positive and Gram-negative infections but was restricted to patients treated with beta-lactams in combination with aminoglycosides, fluoroquinolones, or macrolides/clindamycin. Combination therapy was also associated with significant reductions in intensive care unit (437 of 1223 [35.7%] vs. 352 of 1223 [28.8%]; odds ratio, 0.75; 95% confidence interval, 0.63-0.92; p = .0006) and hospital mortality (584 of 1223 [47.8%] vs. 457 of 1223 [37.4%]; odds ratio, 0.69; 95% confidence interval, 0.59-0.81; p.0001). The use of combination therapy was associated with increased ventilator (median and [interquartile range], 10 [0-25] vs. 17 [0-26]; p = .008) and pressor/inotrope-free days (median and [interquartile range], 23 [0-28] vs. 25 [0-28]; p = .007) up to 30 days.Early combination antibiotic therapy is associated with decreased mortality in septic shock. Prospective randomized trials are needed.

The objectives of our study were (1) to explore the link between joint contractures acquired in the ICU and the ambulatory status of patients at discharge home, to determine (2) when and how many patients received physiotherapy services in ICU and on the hospital ward, and (3) the differences in the use of hospital resources in the presence or absence of joint contractures.Data on ICU joint contractures were extracted from an existing contracture database containing information on 155 Canadian patients with a tertiary ICU stay of 14 days or more.Of 155 patients, 115 (74.2%) received a range of motion assessment in the ICU. The assessment took place a median of 7 days (IQR 0-36) after ICU admission. Significantly fewer patients with joint contractures than without joint contractures were mobilized on the hospital ward (21/38 [55.3%] vs. 27/34 [79.4%], P = 0.03). At discharge home, more patients with joint contractures had a low ambulatory status (38 [64.4%]) compared with patients without joint contractures (26 [51.0%]; P = 0.002).The median delay of 7 days before musculoskeletal assessment in the ICU together with failure to assess 26% of patients may have allowed the development of contractures, which affected the patients' ambulatory status at discharge from hospital.

To compare the effect on renal function of partial and radical nephrectomy using creatinine clearance measurements from 24-hr urine collection.All patients with a solid enhancing renal mass suspicious for renal cell carcinoma, a normal contralateral kidney, and not dialysis dependent were enrolled in this prospective cohort study. Patients were treated with partial or radical nephrectomy by one urologist. Creatinine clearance (CrCl) measurements were prospectively obtained by 24-hr urine collection preoperatively, and at 3, 6, and 12 mo postoperatively. Mean change in creatinine clearance from baseline was compared at 3, 6, and 12 mo. Serum creatinine and Cockcroft-Gault calculations were also performed for comparison. Mixed model analysis incorporating patient and tumor characteristics and the procedure type was performed in SAS Version 9.1.Sixty-three consecutive patients were enrolled in this study. The partial nephrectomy (n=26) and radical nephrectomy (n=37) groups were similar with respect to age, sex, presence of hypertension, vascular disease, diabetes mellitus, and angiotensin converting enzyme inhibitor or receptor blocker use. The postoperative change in creatinine clearance was significantly less (p-value0.0001) in the partial nephrectomy group (-0.09mL/s, -6.1%) compared to the radical nephrectomy group (-0.56mL/s, -31.6%). Linear regression analysis showed intervention type (partial vs. radical nephrectomy) was the most significant predictor of change in creatinine clearance (p-value0.0001).There is significantly less deterioration in the overall renal function of patients who are treated with partial nephrectomy compared to radical nephrectomy. This highlights the importance of performing nephron-sparing surgery on appropriate patients.

Background. Our centre uses a modification of the Moncrief technique of embedding peritoneal dialysis (PD) catheters. We undertook this study to test the hypothesis that catheter survival on PD is a function of the time a catheter is left embedded prior to use. Methods. Data were retrospectively abstracted from review of patient records of those who received a first PD catheter over a 5-year period. Patients were divided into tertiles based on the number of days between insertion of the catheter and exteriorization to create three equal groups representingearly(group1,11–47days),mid(group2,48– 133days)andlate(group3,134–2041 days)exteriorization strategies. Results. 435 embedded PD catheters were inserted, 349 were exteriorized and total observation period was 5624 patient-months.Timetocatheterlosswasshortestingroup1 and longest in group 2 (P = 0.04). The overall rate of primarycatheterfailurewas6%andwassignificantlydifferent in the three groups (6.9% in group 1, 1.7% in group 2 and 9.4% in group 3, P = 0.04). The time to first episode of peritonitis was longest in group 3 and shortest in group 1 (group 1 versus group 3, P = 0.009; group 2 versus group 3, P = 0.03). Adjusted peritonitis rates, however, were not different between the three groups. Conclusions. Mechanical complications and catheter loss are associated with the length of time a catheter is embedded. We recommend insertion 6 weeks to 5 months ahead of the need for PD to maximize catheter survival.

Objective.To describe organ damage accrual, predictors of damage progression, and effect on health-related quality of life (HRQOL) in patients with systemic lupus erythematosus (SLE).Methods.A longitudinal database of patients who met the American College of Rheumatology (ACR) classification criteria for SLE was used. Annual assessments included the Systemic Lupus International Collaborating Clinics/ACR Damage Index (SDI) and the Medical Outcomes Study Short Form-36 (SF-36). The prognostic significance of demographic, disease-related, and treatment-related factors on damage progression was examined using multivariable Cox regression. The effect of changes in SDI scores on HRQOL, measured using the SF-36 summary and subscale scores, was assessed using linear mixed-effects modeling.Results.There were 273 patients with SLE studied over a mean (SD) duration of followup of 7.3 (4.3) years. During followup, 126 (46.2%) had an increase in SDI scores. Patients with preexisting damage at baseline were more likely to have earlier damage progression (HR 2.09, 95% CI 1.44–3.01). Older age, ≥ 8 ACR classification criteria, immunosuppressive drugs, cigarette smoking, and higher mean serum C-reactive protein levels were associated with an earlier increase in SDI scores in multivariable analysis. In general, changes in SDI scores were associated with initial declines in SF-36 scores at the time that damage occurred, with subsequent change comparable to that seen in patients without damage progression.Conclusion.This study identified multiple risk factors, some modifiable, associated with damage progression in patients with SLE. The negative effect on HRQOL emphasizes the need for treatment strategies to reduce the risk of organ damage over time.

Background Atrial fibrillation ( AF ) is the most common sustained cardiac arrhythmia resulting in mortality and morbidity. Gaps in oral anticoagulation and education of patients regarding AF have been identified as areas that require improvement. Methods and Results A before‐and‐after study of 433 patients with newly diagnosed AF in the 3 emergency departments in Nova Scotia from January 1, 2011 until January 31, 2014 was performed. The “before” phase underwent the usual‐care pathway for AF management; the “after” phase was enrolled in a nurse‐run, physician‐supervised AF clinic. The primary outcome was a composite of death, cardiovascular hospitalization, and AF ‐related emergency department visits. A propensity analysis was performed to account for differences in baseline characteristics. Results A total of 185 patients were enrolled into the usual‐care group, and 228 patients were enrolled in the AF clinic group. The mean age was 64±15 years and 44% were women. In a propensity‐matched analysis, the primary outcome occurred in 44 (26.2%) patients in the usual‐care group and 29 (17.3%) patients in the AF clinic group (odds ratio 0.71; 95% CI [0.59, 1]; P =0.049) at 12 months. Prescription of oral anticoagulation was increased in the CHADS 2 ≥2 group (88.4% in the AF clinic versus 58.5% in the usual‐care group, P Conclusions Adoption of this integrated management approach for the burgeoning population of AF may provide an overall benefit to cardiovascular morbidity and mortality.

Background: Computed tomography perfusion (CTP) is increasingly being used in the setting of acute ischemic stroke (AIS). The aim of the current study was to compare the prognostic utility of, and inter-observer variation between, baseline appearances on non-contrast CT (using Alberta Stroke Program Early CT score(ASPECTS)) and on CTP for predicting final infarct volume. We also assessed impact of training on interpretation of these images. Methods: Retrospectively, plain head computed tomography (CT) and CTP images at presentation and CT or diffusion imaging on follow up of patients with AIS were analyzed. The lesion volume on different CTP parameters was then correlated with the final infarct volume. This analysis was done by a Neuroradiologist, a stroke Neurologist and a medical student. Kappa statistics and Intra-class correlation coefficients were used for agreement between readers. Pearson correlation coefficients were used.Results: Thirty eight patients with AIS met all inclusion criteria. There was very good agreement among all readers for the CTP parameters. There was only fair agreement for ASPECT score. Correlation coefficient (r-square) between CTP parameters and final infarct volume showed that cerebral blood volume was the best parameter to predict the final infarct volume followed by cerebral blood flow and time to peak. The best reader to predict the final infarct volume on the initial CT perfusion study was the neuroradiologist followed by medical student and stroke neurologist. Conclusions: Cerebral blood volume defect correlated the best with the final infarct volume. There was a very good inter-observer agreement for all the CTP maps in predicting the final infarct volume despite the wide variation in the experience of the readers.

SummaryObjective Previous studies have reported recovery of secondary adrenal insufficiency (SAI) in patients with pituitary disorders, generally immediately after pituitary surgery; however, data regarding recovery of long-term SAI are lacking. We conducted a study to assess the longer term recovery rate of SAI in patients with pituitary disorders. Methods We identified all SAI patients in the Halifax Neuropituitary Database from 1 November 2005 to 30 September 2014, who had required glucocorticoid therapy for ≥3 months, and had a minimum follow-up of 6 months. Patients with ACTH-secreting adenomas, those receiving glucocorticoids only in the routine peri-operative period for pituitary surgery and those on glucocorticoids for nonpituitary conditions were excluded. SAI was defined as either basal serum cortisol < 130 nm and/or a subnormal cortisol response to ACTH-(1–24) stimulation test or insulin tolerance test response. Results Fifty-one patients fulfilled the criteria. Nine (17·6%) patients had complete recovery of SAI over a median of 20 months (range: 8–51) after initiating glucocorticoid replacement. Patients with smaller tumour size had increased likelihood of hypothalamic–pituitary–adrenal (HPA) axis recovery, whereas those with secondary hypogonadism or growth hormone deficiency were less likely to recover. Those with initial cortisol >175 nm had an almost one in two chance of recovery. Conclusion Results from our study show that approximately one in six patients with SAI recover adrenal function, even up to 5 years after diagnosis. We recommend that patients with SAI undergo regular testing to assess recovery in order to prevent unnecessary glucocorticoid therapy.

Objective:Acromegaly is frequently associated with altered facial appearance at the time of diagnosis. Furthermore, acromegaly is also associated with adverse psychological outcomes. We conducted a single-centre, cross-sectional study comparing patients with growth hormone vs non-functioning pituitary adenomas (NFA) to assess the association between morphometric changes and psychological outcomes and illness perception of patients with acromegaly.Methods:A seven-step scale was developed to grade morphometric changes based on facial photographs. In addition, all patients were asked to draw an image of their own body and an image of what they considered to be an average healthy body and complete seven psychological questionnaires. We recruited 55 consecutive patients in each of the two groups who had undergone surgery with or without radiation therapy (RT).Results:Our data showed that the clinician-rated morphometric scale was highly reliable in assessing facial changes, with 93/99 (Intraclass correlation coefficient (ICC)=0.95 (0.93–0.97)) graded as similar by independent raters. The mean (s.d.) grading for Acro and NFA patients on the clinician-rated morphometric scale were 3.5 (1.3) and 0.41 (0.35) respectively (PConclusions:Our study demonstrates a correlation between physical changes associated with acromegaly and poor psychological outcomes, whereas no such correlation existed with modes of therapy, disease control status, RT, malignancy, initial or recent GH/IGF1 or secondary hormonal deficiency. Our data support the utility of the morphometric scale as a clinical tool for grading facial changes.