Ranjeeta Mallick

Effect of sirolimus on malignancy and survival after kidney transplantation: systematic review and meta-analysis of individual patient data.

Objective To examine risk of malignancy and death in patients with kidney transplant who receive the immunosuppressive drug sirolimus. Design Systematic review and meta-analysis of individual patient data. Data sources Medline, Embase, and the Cochrane Central Register of Controlled Trials from inception to March 2013. Eligibility Randomized controlled trials comparing immunosuppressive regimens with and without sirolimus in recipients of kidney or combined pancreatic and renal transplant for which the author was willing to provide individual patient level data. Two reviewers independently screened titles/abstracts and full text reports of potentially eligible trials to identify studies for inclusion. All eligible trials reported data on malignancy or survival. Results The search yielded 2365 unique citations. Patient level data were available from 5876 patients from 21 randomized trials. Sirolimus was associated with a 40% reduction in the risk of malignancy (adjusted hazard ratio 0.60, 95% confidence interval 0.39 to 0.93) and a 56% reduction in the risk of non-melanoma skin cancer (0.44, 0.30 to 0.63) compared with controls. The most pronounced effect was seen in patients who converted to sirolimus from an established immunosuppressive regimen, resulting in a reduction in risk of malignancy (0.34, 0.28 to 0.41), non-melanoma skin cancer (0.32, 0.24 to 0.42), and other cancers (0.52, 0.38 to 0.69). Sirolimus was associated with an increased risk of death (1.43, 1.21 to 1.71) compared with controls. Conclusions Sirolimus was associated with a reduction in the risk of malignancy and non-melanoma skin cancer in transplant recipients. The benefit was most pronounced in patients who converted from an established immunosuppressive regimen to sirolimus. Given the risk of mortality, however, the use of this drug does not seem warranted for most patients with kidney transplant. Further research is needed to determine if different populations, such as those at high risk of cancer, might benefit from sirolimus.

Prevalence, risk factors, and outcomes of delirium in mechanically ventilated adults.

Objective:Delirium is common during critical illness and associated with adverse outcomes. We compared characteristics and outcomes of delirious and nondelirious patients enrolled in a multicenter trial comparing protocolized sedation with protocolized sedation plus daily sedation interruption. Design:Randomized trial. Setting:Sixteen North American medical and surgical ICUs. Patients:Four hundred thirty critically ill, mechanically ventilated adults. Interventions:All patients had hourly titration of opioid and benzodiazepine infusions using a validated sedation scale. For patients in the interruption group, infusions were resumed, if indicated, at half of previous doses. Delirium screening occurred daily; positive screening was defined as an Intensive Care Delirium Screening Checklist score of 4 or more at any time. Measurements and Main Results:Delirium was diagnosed in 226 of 420 assessed patients (53.8%). Coma was identified in 32.7% of delirious compared with 22.7% of nondelirious patients (p = 0.03). The median time to onset of delirium was 3.5 days (interquartile range, 2–7), and the median duration of delirium was 2 days (interquartile range, 1–4). Delirious patients were more likely to be male (61.1% vs 46.6%; p = 0.005), have a surgical/trauma diagnosis (21.2% vs 11.0%; p = 0.030), and history of tobacco (31.5% vs 16.2%; p = 0.002) or alcohol use (34.6% vs 20.9%; p = 0.009). Patients with positive delirium screening had longer duration of ventilation (13 vs 7 d; p < 0.001), ICU stay (12 vs 8 d; p < 0.0001), and hospital stay (24 vs 15 d; p < 0.0001). Delirious patients were more likely to be physically restrained (86.3% vs 76.7%; p = 0.014) and undergo tracheostomy (34.6% vs 15.5%; p < 0.0001). Antecedent factors independently associated with delirium onset were restraint use (hazard ratio, 1.87; 95% CI, 1.33–2.63; p = 0.0003), antipsychotic administration (hazard ratio, 1.67; 95% CI, 1.005–2.767; p = 0.047), and midazolam dose (hazard ratio, 0.998; 95% CI, 0.997–1.0; p = 0.049). There was no difference in delirium prevalence or duration between the interruption and control groups. Conclusion:In mechanically ventilated adults, delirium was common and associated with longer duration of ventilation and hospitalization. Physical restraint was most strongly associated with delirium.

Reevaluation of Diagnosis in Adults With Physician-Diagnosed Asthma.

Importance Although asthma is a chronic disease, the expected rate of spontaneous remissions of adult asthma and the stability of diagnosis are unknown. Objective To determine whether a diagnosis of current asthma could be ruled out and asthma medications safely stopped in randomly selected adults with physician-diagnosed asthma. Design, Setting, and Participants A prospective, multicenter cohort study was conducted in 10 Canadian cities from January 2012 to February 2016. Random digit dialing was used to recruit adult participants who reported a history of physician-diagnosed asthma established within the past 5 years. Participants using long-term oral steroids and participants unable to be tested using spirometry were excluded. Information from the diagnosing physician was obtained to determine how the diagnosis of asthma was originally made in the community. Of 1026 potential participants who fulfilled eligibility criteria during telephone screening, 701 (68.3%) agreed to enter into the study. All participants were assessed with home peak flow and symptom monitoring, spirometry, and serial bronchial challenge tests, and those participants using daily asthma medications had their medications gradually tapered off over 4 study visits. Participants in whom a diagnosis of current asthma was ultimately ruled out were followed up clinically with repeated bronchial challenge tests over 1 year. Exposure Physician-diagnosed asthma established within the past 5 years. Main Outcomes and Measures The primary outcome was the proportion of participants in whom a diagnosis of current asthma was ruled out, defined as participants who exhibited no evidence of acute worsening of asthma symptoms, reversible airflow obstruction, or bronchial hyperresponsiveness after having all asthma medications tapered off and after a study pulmonologist established an alternative diagnosis. Secondary outcomes included the proportion with asthma ruled out after 12 months and the proportion who underwent an appropriate initial diagnostic workup for asthma in the community. Results Of 701 participants (mean [SD] age, 51 [16] years; 467 women [67%]), 613 completed the study and could be conclusively evaluated for a diagnosis of current asthma. Current asthma was ruled out in 203 of 613 study participants (33.1%; 95% CI, 29.4%-36.8%). Twelve participants (2.0%) were found to have serious cardiorespiratory conditions that had been previously misdiagnosed as asthma in the community. After an additional 12 months of follow-up, 181 participants (29.5%; 95% CI, 25.9%-33.1%) continued to exhibit no clinical or laboratory evidence of asthma. Participants in whom current asthma was ruled out, compared with those in whom it was confirmed, were less likely to have undergone testing for airflow limitation in the community at the time of initial diagnosis (43.8% vs 55.6%, respectively; absolute difference, 11.8%; 95% CI, 2.1%-21.5%). Conclusions and Relevance Among adults with physician-diagnosed asthma, a current diagnosis of asthma could not be established in 33.1% who were not using daily asthma medications or had medications weaned. In patients such as these, reassessing the asthma diagnosis may be warranted.

Bisphenol A and phthalate metabolite urinary concentrations: Daily and across pregnancy variability

Phthalates and bisphenol A (BPA) are high production volume and ubiquitous chemicals that are quickly metabolized in the body. Traditionally, studies have relied on single spot urine analyses to assess exposure; ignoring variability in concentrations throughout a day or over a longer period of time. We compared BPA and phthalate metabolite results from urine samples collected at five different time points. Participants (n=80) were asked to collect all voids in a 24 h period on a weekday and then again on a weekend before 20 weeks of pregnancy. During the second and third trimesters and in the postpartum period, single spot urines were collected. Variability over time in urinary concentrations was assessed using intraclass correlation coefficients (ICCs) and the sensitivity to correctly classify a single sample as high or low versus the geometric mean (GM) of all samples was calculated. We found low reproducibility and sensitivity of BPA and all phthalate metabolites throughout pregnancy and into the postpartum period but much higher reproducibility within a day. Time of day when the urine was collected was a significant predictor of specific gravity adjusted exposure levels. We concluded that, if the interest is in average exposures across pregnancy, maternal/fetal exposure estimation may be more accurate if multiple measurements, collected across the course of the entire pregnancy, rather than a single spot measure, are performed.

Perioperative use of pregabalin for acute pain-a systematic review and meta-analysis.

Abstract Evidence supporting postoperative pain management using pregabalin as an adjunct intervention across various surgical pain models is lacking. The objective of this systematic review was to evaluate “model-specific” comparative effectiveness and harms of pregabalin following a previously published systematic review protocol. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from inception through August 2013. Data were screened and single extraction with independent verification and dual risk of bias assessment was performed. Quality of evidence (QoE) was rated using the GRADE approach. Primary outcomes were pain relief at rest and on movement and reduction in postoperative analgesic consumption. A total of 1423 records were screened, and 43 studies were included. Perioperative pregabalin resulted in: 16% (95% confidence interval [CI], 9%-21%) reduction in analgesic consumption (moderate QoE, 24 trials) and a small reduction in the magnitude of pain in surgeries associated with pronociceptive pain. Per 1000 patients, 10 more will experience blurred vision (95% CI, 5-20 more; moderate QoE, 17 trials) and 41 more sedation (95% CI, 13-77 more, 17 trials). To prevent 1 case of perioperative nausea and vomiting, the number needed to treat is 11 (95% CI: 7-28, 25 trials). Inadequate evidence addressed outcomes of enhanced recovery and serious harms. Pregabalin analgesic effectiveness is largely restricted to surgical procedures associated with pronociceptive mechanisms. The clinical significance of observed pregabalin benefits must be weighed against the uncertainties about serious harms and enhanced recovery to inform the careful selection of surgical patients. Recommendations for future research are proposed.

Peri-operative morbidity associated with radical cystectomy in a multicenter database of community and academic hospitals.

Objective To characterize the frequency and timing of complications following radical cystectomy in a cohort of patients treated at community and academic hospitals. Patients and Methods Radical cystectomy patients captured from NSQIP hospitals from January 1 2006 to December 31 2012 were included. Baseline information and complications were abstracted by study surgical clinical reviewers through a validated process of medical record review and direct patient contact. We determined the incidence and timing of each complication and calculated their associations with patient and operative characteristics. Results 2303 radical cystectomy patients met inclusion criteria. 1115 (48%) patients were over 70 years old and 1819 (79%) were male. Median hospital stay was 8 days (IQR 7–13 days). 1273 (55.3%) patients experienced at least 1 post-operative complication of which 191 (15.6%) occurred after hospital discharge. The most common complication was blood transfusion (n = 875; 38.0%), followed by infectious complications with 218 (9.5%) urinary tract infections, 193 (8.4%) surgical site infections, and 223 (9.7%) sepsis events. 73 (3.2%) patients had fascial dehiscence, 82 (4.0%) developed a deep vein thrombosis, and 67 (2.9%) died. Factors independently associated with the occurrence of any post-operative complication included: age, female gender, ASA class, pre-operative sepsis, COPD, low serum albumin concentration, pre-operative radiotherapy, pre-operative transfusion >4 units, and operative time >6 hours (all p<0.05). Conclusion Complications remain common following radical cystectomy and a considerable proportion occur after discharge from hospital. This study identifies risk factors for complications and quality improvement needs.

TNFα antagonists for acute exacerbations of COPD: a randomised double-blind controlled trial

Background The purpose of this randomised double-blind double-dummy placebo-controlled trial was to investigate whether etanercept, a tumour necrosis factor α (TNFα) antagonist, would provide more effective anti-inflammatory treatment for acute exacerbations of chronic obstructive pulmonary disease (COPD) than prednisone. Methods We enrolled 81 patients with acute exacerbations of COPD and randomly assigned them to treatment with either 40 mg oral prednisone given daily for 10 days or to 50 mg etanercept given subcutaneously at randomisation and 1 week later. Both groups received levofloxacin for 10 days plus inhaled bronchodilators. The primary endpoint was the change in the patients forced expiratory volume in 1 s (FEV1) 14 days after randomisation. Secondary endpoints included 90-day treatment failure rates and dyspnoea and quality of life. Results At 14 days the mean±SE change in FEV1 from baseline was 20.1±5.0% and 15.2±5.7% for the prednisone and etanercept groups, respectively. The mean between-treatment difference was 4.9% (95% CI −10.3% to 20.2%), p=0.52. Rates of treatment failure at 90 days were similar in the prednisone and etanercept groups (32% vs 40%, p=0.44), as were measures of dyspnoea and quality of life. Subgroup analysis revealed that patients with serum eosinophils >2% at exacerbation tended to experience fewer treatment failures if treated with prednisone compared with etanercept (22% vs 50%, p=0.08). Conclusions Etanercept was not more effective than prednisone for treatment of acute exacerbations of COPD. Efficacy of prednisone was most apparent in patients who presented with serum eosinophils >2%. Clinical Trials gov number NCT 00789997.

Temporal variability and sources of triclosan exposure in pregnancy.

BACKGROUND Triclosan (TCS) is an antibacterial agent commonly added to personal care products. Some animal research studies have associated TCS exposure with androgenic and thyroid effects, as well as endocrine disruption, contact dermatitis and skin irritation. Limited Canadian data exist on exposure levels, temporal variability and sources of exposure to TCS, especially among pregnant women. METHODS Single and serial spot urine samples (n=1249), as well as consumer product use information were collected over 5 study visits across pregnancy and post-partum from 80 healthy pregnant women in Ottawa, Canada. Urine samples were analyzed for TCS by GC-MS-MS. Summary statistics, linear mixed effects models, and surrogate category analysis were used to describe the results. RESULTS Triclosan was detected in 87% of maternal urine samples (LOD=3.0μg/L). The geometric mean TCS concentration of all urine samples was 21.6μg/L (95% CI 18.2-25.7). Triclosan concentrations were significantly higher when the urine was collected before 16:00, in the autumn, and more than 90min since last void, and in nulliparous women with household incomes greater than

Is Cytomegalovirus Testing of Blood Products Still Needed for Hematopoietic Stem Cell Transplant Recipients in the Era of Universal Leukoreduction

100,000. A significant correlation was observed between maternal urinary TCS concentrations and number of reported uses of TCS-containing products. The ability of a single spot urine sample collected at any time during or post-pregnancy to predict an individuals geometric mean urinary TCS level corresponding to low, medium, or high exposure was 86.7%. Intraclass correlation coefficients indicated high reproducibility within a week-day (0.77) and week-end day (0.79) and moderate reproducibility across the study period (0.50). CONCLUSIONS This study provided the first data on temporal variability of urinary TCS concentrations and predictors of exposure in Canadian pregnant women. These results can inform exposure assessments in pregnant women and justify collection of single spot urine samples in epidemiologic studies, especially for women with higher exposures.

The association between nerve sparing and a positive surgical margin during radical prostatectomy

Hematopoietic stem cell transplantation (HSCT) recipients are a high-risk, immunocompromised group of patients who receive frequent transfusions after transplantation. Transfusion of cytomegalovirus (CMV)-negative blood products has long been the standard of care to prevent transfusion-transmitted CMV in this patient population. Leukoreduction of blood products before transfusion has been shown to significantly reduce the risk of transfusion-transmitted CMV. In the era of universal leukoreduction in Canada, the need for CMV testing of blood products remains unclear. We sought to identify whether there is a difference in transfusion-transmitted CMV viremia in patients receiving only leukoreduced versus CMV-negative and leukoreduced blood products in HSCT recipients. Patients who were CMV negative and received an allogeneic HSCT from a CMV-negative donor between October 1, 1999 and June 30, 2012 were included in the analysis. Transfusion data were collected from The Ottawa Hospital Blood Bank and Canadian Blood Services. CMV viremia was defined as PCR positivity. One hundred sixty-six patients were identified who met the inclusion criteria. Of these, 89 patients received an HSCT before January 2007, during the time when patients received leukoreduced and CMV-negative blood products. Seventy-seven patients received an HSCT after this time, receiving only leukoreduced blood products. The 2 groups did not differ in terms of age, gender, diagnosis, graft type, graft source, conditioning regimen, or ABO compatibility (P > .05). CMV viremia was detected in 3 patients who received CMV-negative leukoreduced blood products (3.37%) and in 1 patient who received only leukoreduced blood products (1.30%, P = .6244). Of the patients who developed CMV viremia, 2 developed suspected CMV disease. Both of these patients were transfused with CMV-negative blood products. Secondary outcomes, including total length of stay in hospital, admission to the intensive care unit, acute and chronic graft versus host disease, and 100-day nonrelapse mortality, did not differ between the groups. In the era of universal leukoreduction of blood products, this study demonstrates that testing for CMV-negative blood products is not needed for HSCT recipients.