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Background: In-hospital medication review has been linked to improved outcomes after discharge, yet there is little evidence to support the use of community pharmacy-based interventions as part of transitional care., Objective: To determine whether receipt of a postdischarge community pharmacy-based medication reconciliation and adherence review is associated with a reduced risk of death or re-admission., Design: Propensity score-matched cohort study., Setting: Ontario, Canada PARTICIPANTS: Patients over age 66 years discharged home from an acute care hospital from 1 April 2007 to 16 September 2016., Exposure: MedsCheck, a publicly funded medication reconciliation and adherence review provided by community pharmacists., Main Outcome: The primary outcome was time to death or re-admission (defined as an emergency department visit or urgent rehospitalisation) up to 30 days. Secondary outcomes were the 30-day count of outpatient physician visits and time to adverse drug event., Results: MedsCheck recipients had a lower risk of 30-day death or re-admission (23.4% vs 23.9%, HR 0.97, 95% CI 0.95 to 1.00, p=0.02), driven by a decreased risk of death (1.7% vs 2.1%, HR 0.79, 95% CI 0.73 to 0.86) and rehospitalisation (11.0% vs 11.4%, HR 0.96, 95% 0.93-0.99). In a post hoc sensitivity analysis with pharmacy random effects added to the propensity score model, these results were substantially attenuated. There was no significant difference in 30-day return to the emergency department (22.5% vs 22.8%, HR 0.99, 95% CI 0.96 to 1.01) or adverse drug events (1.5% vs 1.5%, HR 1.03, 95% CI 0.94 to 1.12). MedsCheck recipients had more outpatient visits (mean 2.11 vs 2.09, RR 1.01, 95% CI 1.00 to 1.02, p=0.02)., Conclusions and Relevance: Among older adults, receipt of a community pharmacy-based medication reconciliation and adherence review was associated with a small reduced risk of short-term death or re-admission. Due to the possibility of unmeasured confounding, experimental studies are needed to clarify the relationship between postdischarge community pharmacy-based medication review and patient outcomes., Competing Interests: Competing interests: LL-S reports support from a CIHR Fellowship Award (FRN 146714), and the Philipson Scholar program at the University of Toronto. PCA is supported by a Mid-Career Investigator award from the Heart and Stroke Foundation. NMI reports support from CIHR and the Ontario Ministry of Health and Long-Term Care. DAR reports support from a Canada Research Chair in Medical Decision Science. CMB reports support from the Department of Medicine at the University of Toronto and Sinai Health System. None of these organisations had any involvement in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication. Parts of this material are based on data and information compiled and provided by the Canadian Institute for Health Information (CIHI) and Immigration, Refugees and Citizenship Canada (IRCC). However, the analyses, conclusions, opinions and statements expressed herein are those of the authors, and not necessarily those of ICES, MOHLTC, CIHI or the IRCC. No endorsement by ICES, MOHLTC, CIHI or the IRCC is intended or should be inferred. The named organisations and funding bodies had no involvement in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Chronic hepatitis C (CHC) is among the most burdensome infectious diseases in the world. Health utilities are a valuable tool for quantifying this burden and conducting cost-utility analysis., Objective: Our study summarizes the available data on utilities in CHC patients. This will facilitate analyses of CHC treatment and elimination strategies., Methods: We searched MEDLINE, Embase, and the Cochrane Library for studies measuring utilities in CHC patients. Utilities were pooled by health state and utility instrument using meta-analysis. A further analysis used meta-regression to adjust for the effects of clinical status and methodological variation., Results: Fifty-one clinical studies comprising 15 053 patients were included. Based on the meta-regression, patients' utilities were lower for more severe health states (predicted mean EuroQol-5D-3L utility for mild/moderate CHC: 0.751; compensated cirrhosis: 0.671; hepatocellular carcinoma: 0.662; decompensated cirrhosis: 0.602). Patients receiving interferon-based treatment had lower utilities than those on interferon-free treatment (0.647 vs 0.733). Patients who achieved sustained virologic response (0.786) had higher utilities than those with mild to moderate CHC. Utilities were substantially higher for patients in experimental studies compared to observational studies (coefficient: +0.074, P < .05). The time tradeoff instrument was associated with the highest utilities, and the Health Utilities Index 3 was associated with the lowest utilities., Conclusion: Chronic hepatitis C is associated with a significant impairment in global health status, as measured by health utility instruments. Impairment is greater in advanced disease. Experimental study designs yield higher utilities-an effect not previously documented. Curative therapy can alleviate the burden of CHC, although further research is needed in certain areas, such as the long-term impacts of treatment on utilities., (Copyright © 2019 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Extrinsic camera calibration is essential for any computer vision task in a camera network. Typically, researchers place a calibration object in the scene to calibrate all the cameras in a camera network. However, when installing cameras in the field, this approach can be costly and impractical, especially when recalibration is needed. This paper proposes a novel, accurate and fully automatic extrinsic calibration framework for camera networks with partially overlapping views. The proposed method considers the pedestrians in the observed scene as the calibration objects and analyzes the pedestrian tracks to obtain extrinsic parameters. Compared to the state of the art, the new method is fully automatic and robust in various environments. Our method detect human poses in the camera images and then models walking persons as vertical sticks. We apply a brute-force method to determines the correspondence between persons in multiple camera images. This information along with 3D estimated locations of the top and the bottom of the pedestrians are then used to compute the extrinsic calibration matrices. We also propose a novel method to calibrate the camera network by only using the top and centerline of the person when the bottom of the person is not available in heavily occluded scenes. We verified the robustness of the method in different camera setups and for both single and multiple walking people. The results show that the triangulation error of a few centimeters can be obtained. Typically, it requires less than one minute of observing the walking people to reach this accuracy in controlled environments. It also just takes a few minutes to collect enough data for the calibration in uncontrolled environments. Our proposed method can perform well in various situations such as multi-person, occlusions, or even at real intersections on the street.

An onset of respiratory disease in a captive bachelor group ( n = 3) of western lowland gorillas ( Gorilla gorilla gorilla ) was concomitant with peak attendance of visitors at the institution and with unwanted occurrences of food items being thrown in the gorillas' enclosure. While the condition of two individuals improved with supportive therapy and antibiotics, the third gorilla died three days following initiation of treatment. A fatal bacterial pneumonia, secondary to an infection by a human parainfluenza virus 2 (HIPV-2), was considered to be the cause of death based on histopathology, lung cultures, and reverse transcription PCR. HPIV-2 activity in the human population of the province was detected for that period, including the same viral strain. This report confirms a HPIV-2 respiratory illness and associated death in a gorilla. Clinical presentation and context suggest conspecifics were also affected and that contaminated food thrown by visitors may have been the source of infection.

Background: Previous studies have shown that obstructive sleep apnea (OSA) is associated with a higher risk of cognitive impairment or dementia in the elderly, leading to deleterious health effects and decreasing quality of life. This systematic review aims to determine the prevalence of OSA in patients with mild cognitive impairment (MCI) and examine whether an association between OSA and MCI exists., Methods: We searched Medline, PubMed, Embase, Cochrane Central, Cochrane Database of Systematic Reviews, PsychINFO, Scopus, the Web of Science, ClinicalTrials.gov and the International Clinical Trials Registry Platform for published and unpublished studies. We included studies in adults with a diagnosis of MCI that reported on the prevalence of OSA. Two independent reviewers performed the abstract and full-text screening, data extraction and the study quality critical appraisal., Results: Five studies were included in the systematic review. Overall, OSA prevalence rates in patients with MCI varied between 11 and 71% and were influenced by OSA diagnostic methods and patient recruitment locations (community or clinic based). Among studies using the following OSA diagnostic measures- self-report, Home Sleep Apnea Testing, Berlin Questionnaire and polysomnography- the OSA prevalence rates in MCI were 11, 27, 59 and 71%, respectively. In a community-based sample, the prevalence of OSA in patients with and without MCI was 27 and 26%, respectively., Conclusions: Based on limited evidence, the prevalence of OSA in patients with MCI is 27% and varies based upon OSA diagnostic methods and patient recruitment locations. Our findings provide an important framework for future studies to prospectively investigate the association between OSA and MCI among larger community-based cohorts and implement a standardized approach to diagnose OSA in memory clinics., Prospero Registration: CRD42018096577.

In the surgical setting, OSA is associated with an increased risk of postoperative complications. At present, risk stratification using OSA-associated parameters derived from polysomnography (PSG) or overnight oximetry to predict postoperative complications has not been established. The objective of this narrative review is to evaluate the literature to determine the association between parameters extracted from in-laboratory PSG, portable PSG, or overnight oximetry and postoperative adverse events. We obtained pertinent articles from Ovid MEDLINE, Ovid MEDLINE In-Process & Other Non-Indexed Citations, and Embase (2008 to December 2017). The search included studies with adult patients undergoing surgery who had OSA diagnosed with portable PSG, in-laboratory PSG, or overnight oximetry that reported on specific sleep parameters and at least one adverse outcome. The search was restricted to English-language articles. The search yielded 1,810 articles, of which 21 were included in the review. Preoperative apnea-hypopnea index (AHI) and measurements of nocturnal hypoxemia such as oxygen desaturation index (ODI), cumulative sleep time percentage with oxyhemoglobin saturation (Spo 2 ) < 90% (CT90), minimum Spo 2 , mean Spo 2 , and longest apnea duration were associated with postoperative complications. OSA is associated with postoperative complications in the population undergoing surgery. Clinically and statistically significant associations between AHI and postoperative adverse events exists. Complications may be more likely to occur in the category of moderate to severe OSA (AHI ≥ 15). Other parameters from PSG or overnight oximetry such as ODI, CT90, mean and minimal Spo 2 , and longest apnea duration can be associated with postoperative complications and may provide additional value in risk stratification and minimization., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Heart failure (HF) is a complex chronic condition, leading to frequent hospitalization, decreased quality of life, and increased mortality. Current guidelines recommend that multidisciplinary care be provided in specialized HF clinics. A number of studies have demonstrated the effectiveness of these clinics; however, there is a wide range in the services provided across different clinics. This network meta-analysis will aim to identify the aspects of HF clinic care that are associated with the best outcomes: a reduction in mortality, hospitalization, and visits to emergency department (ED) and improvements to quality of life., Methods: Relevant electronic databases will be systematically searched to identify eligible studies. Controlled trials and observational cohort studies of adult (≥ 18 years of age) patients will be eligible for inclusion if they evaluate at least one component of guideline-based HF clinic care and report all-cause or HF-related mortality, hospitalizations, or ED visits or health-related quality of life assessed after a minimum follow-up of 30 days. Both controlled trials and observational studies will be included to allow us to compare the efficacy of the interventions in an ideal context versus their effectiveness in the real world. Two reviewers will independently perform both title and abstract full-text screenings and data abstraction. Study quality will be assessed through a modified Cochrane risk of bias tool for randomized controlled trials (RCTs) or the ROBINS-I tool for observational studies. The strength of evidence will be assessed using a modified Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) system. Network meta-analysis methods will be applied to synthesize the evidence across included studies. To contrast findings between study designs, data from RCTs will be analyzed separately from non-randomized controlled trials and cohort studies. We will estimate both the probability that a particular component of care is the most effective and treatment effects for specified combinations of care., Discussion: To our knowledge, this will be the first study to evaluate the comparative effectiveness of the different components of care offered in HF clinics. The findings from this systematic review will provide valuable insight about which components of HF clinic care are associated with improved outcomes, potentially informing clinical guidelines as well as the design of future care interventions in dedicated HF clinics., Systematic Review Registration: PROSPERO CRD42017058003.

Background: A broad literature base exists for measuring medication adherence to monotherapeutic regimens, but publications are less extensive for measuring adherence to multiple medications., Objectives: To identify and characterize the multiple medication adherence (MMA) methods used in the literature., Methods: A literature search was conducted using PubMed, PsycINFO, the International Pharmaceutical Abstracts, the Cumulative Index to Nursing and Allied Health Literature and the Cochrane Library databases on methods used to measure MMA published between January 1973 and May 2015. A two-step screening process was used; all abstracts were screened by pairs of researchers independently, followed by a full-text review identifying the method for calculating MMA. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed to conduct this systematic review. For studies that met the eligibility criteria, general study and adherence-specific characteristics and the number and type of MMA measurement methods were summarized., Results: The 147 studies that were included originated from 32 countries, in 13 disease states. Of these studies, 26 used proportion of days covered, 23 used medication possession ratio, and 72 used self-reported questionnaires (e.g., the Morisky Scale) to assess MMA. About 50% of the studies included more than one method for measuring MMA, and different variations of medication possession ratio and proportion of days covered were used for measuring MMA., Conclusions: There appears to be no standardized method to measure MMA. With an increasing prevalence of polypharmacy, more efforts should be directed toward constructing robust measures suitable to evaluate adherence to complex regimens. Future research to understand the validity and reliability of MMA measures and their effects on objective clinical outcomes is also needed., (Copyright © 2019 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

The epidemiology of prostate cancer (PC) continues to change. We evaluated the changes in incidence, in average age at diagnosis, and in survival from 1992 to 2015 in Ontario. We compared the cumulative incidence of PC-specific and non PC-specific mortality using two algorithms for cause of death: Method 1 assigned deaths from "other cancers" to non PC-specific causes, and Method 2 assigned these cases to PC-specific mortality. There were 188,714 cases diagnosed with PC between 1992 and 2015 in Ontario. The average age at diagnosis declined from 1992 to 2008 by 0.26 year (3.1 months) annually ( p  < 0.001) and increased by 0.15 year (1.8 months) thereafter ( p  > 0.05). Between 2010 and 2015, the proportion of patients diagnosed at stage IV increased, and the proportion diagnosed at stage I decreased ( p -values for trends <0.001). Overall survival significantly improved over the years. The cumulative incidence of PC-specific mortality at 5 and 10 years was 6.8 and 9.8% using Method 1, and 10.2 and 16.8% using Method 2. We observed trends toward older age and more advanced stage at PC diagnosis in Ontario. Further studies are needed to validate algorithms for estimating PC-specific mortality from administrative databases.

Objective: This systematic review and meta-analysis aim to evaluate the risk factors associated with postoperative opioid-induced respiratory depression (OIRD)., Design: Systematic review and meta-analysis., Data Sources: PubMed-MEDLINE, MEDLINE in-process, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, PubMed and Clinicaltrials.gov (January 1946 to November 2017)., Eligibility Criteria: The inclusion criteria were: (1) adult patients 18 years or older who were administered opioids after surgery and developed postoperative OIRD (OIRD group); (2) all studies which reported both OIRD events and associated risk factors; (3) all studies with reported data for each risk factor on patients with no OIRD (control group) and (4) published articles in English language., Data Analysis: We used a random effects inverse variance analysis to evaluate the existing evidence of risk factors associated with OIRD. Newcastle-Ottawa scale scoring system was used to assess quality of study., Results: Twelve observational studies were included from 8690 citations. The incidence of postoperative OIRD was 5.0 cases per 1000 anaesthetics administered (95% CI: 4.8 to 5.1; total patients: 841 424; OIRD: 4194). Eighty-five per cent of OIRD occurred within the first 24 hours postoperatively. Increased risk for OIRD was associated with pre-existing cardiac disease (OIRD vs control: 42.8% vs 29.6%; OR: 1.7; 95% CI: 1.2 to 2.5; I 2 : 0%; p<0.002), pulmonary disease (OIRD vs control: 17.8% vs 10.3%; OR: 2.2; 95% CI: 1.3 to 3.6; I 2 : 0%; p<0.001) and obstructive sleep apnoea (OIRD vs control: 17.9% vs 16.5%; OR: 1.4; 95% CI: 1.2 to 1.7; I 2 : 31%; p=0.0003). The morphine equivalent daily dose of the postoperative opioids was higher in the OIRD group than in the control; (24.7±14 mg vs 18.9±13.0 mg; mean difference: 2.8; 95% CI: 0.4 to 5.3; I 2 : 98%; p=0.02). There was no significant association between OIRD and age, gender, body mass index or American Society of Anesthesiologists physical status., Conclusion: Patients with cardiac, respiratory disease and/or obstructive sleep apnoea were at increased risk for OIRD. Patients with postoperative OIRD received higher doses of morphine equivalent daily dose., Competing Interests: Competing interests: JW reports grants from the Ontario Ministry of Health and Long-Term Care, Anesthesia Patient Safety Foundation and Acacia Pharma outside of the submitted work. FC reports research support from the Ontario Ministry of Health and Long-Term Care, University Health Network Foundation, Acacia Pharma, Medtronic grants to institution outside of the submitted work, up-to-date royalties, STOP-Bang proprietary to University Health Network. TNW currently serves as a consultant to Medtronic in the role as chairman of the Clinical Endpoint Committee for the Prodigy Trial; has received unrestricted investigator-initiated grants from Merck (active) and Baxter (completed), and research support from Respiratory Motion (study equipment) and research support from Respiratory Motion (study equipment)., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Obstructive sleep apnea (OSA) is the most common sleep-related breathing disorder. In-laboratory, overnight type I polysomnography (PSG) is the current "gold standard" for diagnosing OSA. Home sleep apnea testing (HSAT) using portable monitors (PMs) is an alternative testing method offering better comfort and lower costs. We aimed to systematically review the evidence on diagnostic ability of type IV PMs compared to PSG in diagnosing OSA., Methods: Participants: patients ≥16 years old with symptoms suggestive of OSA;intervention: type IV PMs (devices with < 2 respiratory channels); comparator: in-laboratory PSG; outcomes: diagnostic accuracy measures;studies: cross-sectional, prospective observational/experimental/quasi-experimental studies; information sources: MEDLINE and Cochrane Library from January 1, 2010 to May 10, 2016. All stages of review were conducted independently by two investigators., Results: We screened 6054 abstracts and 117 full-text articles to select 24 full-text articles for final review. These 24 studies enrolled a total of 2068 patients with suspected OSA and evaluated 10 different PMs with one to six channels. Only seven (29%) studies tested PMs in the home setting. The mean difference (bias) between PSG-measured and PM-measured apnea-hypopnea index (AHI) ranged from - 14.8 to 10.6 events/h. At AHI ≥ 5 events/h, the sensitivity of type IV PMs ranged from 67.5-100% and specificity ranged from 25 to 100%., Conclusion: While current evidence is not very strong for the stand-alone use of level IV PMs in clinical practice, they can potentially widen access to diagnosis and treatment of OSA. Policy recommendations regarding HSAT use should also consider the health and broader social implications of false positive and false negative diagnoses.

Background The objective of this study was to investigate the changes in blood pressure among patients enrolled in the Telehomecare programme in Ontario, Canada. Methods This observational study utilised a prospective longitudinal cohort design, including patients with heart failure and chronic obstructive pulmonary disease enrolled in the Ontario Telehomecare programme from July 2012 to July 2015. The outcome of interest was change in mean (biweekly) systolic and diastolic blood pressure levels over a six-month period. Patient data were extracted from the Ontario Telemedicine Network database, and analysed using generalised linear mixed model procedures. Results Overall, we analysed data for 3513 patients. Patients were on average 74.1 ± 11.4 years of age; almost half were men, 62% had heart failure, 55% chronic obstructive pulmonary disease and 29% diabetes. At baseline, the mean systolic and diastolic blood pressure levels were 130.4 ± 19.1 mmHg and 72.2 ± 12.5 mmHg for the total sample. At six months, the adjusted reduction in systolic and diastolic blood pressure values were 4.0 mmHg (95% confidence interval: -4.5 to -3.5) and 2.7 mmHg (95% confidence interval: -3.1 to -2.4), respectively. In a subgroup of 1220 patients with uncontrolled blood pressure at baseline (systolic/diastolic blood pressure of 150.7 ± 10.2 mmHg/80.2 ± 13.5 mmHg) the adjusted reduction in systolic blood pressure was 12.5 mmHg (95% confidence interval: -13.4 to -11.6) and in diastolic blood pressure was 7.1 mmHg (95% confidence interval: -7.8 to -6.5) over the six-month period. Conclusions Blood pressure levels were significantly reduced in patients enrolled in the Telehomecare programme, with changes being more pronounced in patients with uncontrolled blood pressure. The sustainability of decreased blood pressure on other clinical outcomes needs further evaluation.

Background: Although heart failure (HF) prevalence is equally high among men and women, observed differences in the provision of care are still not fully understood. We sought to evaluate gender differences in patient profiles, diagnostic testing, medication prescription, and referrals in specialized multidisciplinary ambulatory HF clinics in Ontario., Materials and Methods: Medical chart abstraction was conducted first by randomly selecting 9 (out of 34) HF clinics in Ontario, and then by randomly selecting 100 patient records in each clinic. Data on patient demographics, comorbidities, diagnostic tests, medication use, and referrals were abstracted, covering a period from the first clinic visit up to 1 year. Descriptive statistics and regression analysis were used to assess gender differences., Results: Of the 884 patients, only 314 were women (35.5%). At the first clinic visit, women were older, had better systolic function but worse functional status, and had a lower prevalence of hyperlipidemia, diabetes, and smoking than men. There were more women with non-ischemic HF etiology than men (63.9% vs. 43.3%, p < 0.001). Adjusted analysis did not reveal gender differences in the average number of echocardiographic assessments and in the prescription rates of evidence-based medications. Men were twice more likely to be referred to electrophysiology studies than women (18.6% vs. 7.8%, p < 0.001). The rates of dietary counseling and cardiac rehabilitation referrals were similarly low in both groups., Conclusions: More men than women are treated in specialized ambulatory HF clinics. Although women differ from men in selected clinical characteristics, no major differences were observed in patient management. The reasons for low enrollment rates of women into the HF ambulatory clinics need further investigation.

The mechanism used by mouse polyomavirus (MPyV) overcomes the crowded cytosol to reach the nucleus has not been fully elucidated. Here, we investigated the involvement of importin α/β1 mediated transport in the delivery of MPyV genomes into the nucleus. Interactions of the virus with importin β1 were studied by co-immunoprecipitation and proximity ligation assay. For infectivity and nucleus delivery assays, the virus and its capsid proteins mutated in the nuclear localization signals (NLSs) were prepared and produced. We found that at early times post infection, virions bound importin β1 in a time dependent manner with a peak of interactions at 6 h post infection. Mutation analysis revealed that only when the NLSs of both VP1 and VP2/3 were disrupted, virus did not bind efficiently to importin β1 and its infectivity remarkably decreased (by 80%). Nuclear targeting of capsid proteins was improved when VP1 and VP2 were co-expressed. VP1 and VP2 were effectively delivered into the nucleus, even when one of the NLS, either VP1 or VP2, was disrupted. Altogether, our results showed that MPyV virions can use VP1 and/or VP2/VP3 NLSs in concert or individually to bind importins to deliver their genomes into the cell nucleus., Competing Interests: The authors declare no conflicts of interest.

Medication reviews by community pharmacists are an increasingly common strategy to improve medication management for chronic conditions, and are part of wider efforts to make more effective use of community-based health professionals. To identify opportunities to optimize the medication review program in Ontario, Canada, we explored how providers and clients interpret and operationalize medication reviews within everyday community pharmacy practice. We conducted a qualitative ethnographic study at four pharmacies in Ontario, Canada, including non-participant observation of provider and client activities and interactions with specific attention to medication reviews, as well as brief ethnographic interviews with providers and clients, and in-depth, semi-structured interviews with providers. We report on 72h of field research, observation of 178 routine pharmacist-client interactions and 29 medication reviews, 62 brief ethnographic interviews with providers and clients, and 7 in-depth, semi-structured interviews with providers. We found that medication reviews were variably conducted across the dimensions of duration, provider type, location, and interaction style, and that local contexts and system-wide developments influence their meaning and practice. Medication reviews are exemplary of policy efforts to enhance the role of community pharmacies within health systems and the scope of practice of pharmacists as healthcare professionals. Our study highlights the importance of the local structure of community pharmacy practice and the clinical aspirations of pharmacists in the delivery of medication reviews., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose of Review: The primary objective of this review is to identify the risk factors for opioid-induced respiratory depression (OIRD) in the postoperative period., Recent Findings: In the postoperative period, OIRD has often been reported resulting in morbidity and mortality. The risk factors which predispose surgical patients to increased risk of OIRD are not clearly defined. A literature search was performed for adult surgical patients who were prescribed opioids during their hospital stay and any available reports on postoperative respiratory depression/respiratory events., Summary: Elderly, female sex, presence of obstructive sleep apnea, chronic obstructive pulmonary disease, cardiac disease, diabetes mellitus, hypertension, neurologic disease, renal disease, obesity, two or more comorbidities, opioid dependence, use of patient controlled analgesia, different routes of administration of opioids and concomitant administration of sedatives are significant risk factors for postoperative OIRD. The majority of patients with OIRD are deeply sedated and inadequately monitored. In patients with underlying risk factors, the dose of opioids should be carefully titrated. Enhanced monitoring of sedation level, respiratory rate, pulse oximetry and capnography is needed in the first 24 h after surgery.

Background/objectives Venous ulcers carry psychological and high financial burden for patients, causing depression, pain, and limitation of mobility. The study aimed to identify factors associated with an increased risk of venous ulceration in patients with varicose veins in Armenia. Methods A case-control study design was utilized enrolling 80 patients in each group, who underwent varicose treatment surgery in two specialized surgical centers in Armenia during 2013-2014 years. Cases were patients with varicose veins and venous leg ulcers. Controls included patients with varicose veins but without venous leg ulcers. Data were collected using interviewer-administered telephone interviews and medical record abstraction. Multiple logistic regression analysis was used to identify the risk factors of venous ulceration. Results There were more females than males in both groups (72.5% of cases and 85.0 % of controls). Cases were on average older than controls (53.9 vs. 39.2 years old, p ≤ 0.001). After adjusting for potential confounders, the estimated odds of developing venous ulcer was higher in patients with history of post thrombotic syndrome (odds ratio = 14.90; 95% confidence interval: 3.95-56.19; p = 0.001), with higher average sitting time (odds ratio = 1.32 per hour of sitting time; 95% confidence interval: 1.08-1.61; p = 0.006), those with reflux in deep veins (odds ratio = 3.58; 95% confidence interval: 1.23-10.31; p = 0.019) and history of leg injury (odds ratio = 3.12; 95% confidence interval: 1.18-8.23; p = 0.022). Regular exercise in form of walking (≥5 days per week) was found to be a protective factor from venous ulceration (odds ratio = 0.26; 95% confidence interval: 0.08-0.90; p = 0.034). Conclusion We found that reflux in deep veins, history of leg injury, history of post thrombotic syndrome, and physical inactivity were significant risk factors for venous ulceration in patients with varicose veins, while regular physical exercise mitigated that risk. Future studies should investigate the relationships between the duration and type of regular exercise and the risk of venous ulceration to make more specific recommendations on preventing ulcer development.

After publication of the article [1], it has been brought to our attention that an acknowledgement has been omitted from the original article. The authors would like to include the following, The authors also thank Prof. En-Min Zhou (Northwest A&F University) and his laboratory for technical support."

In order to gain insight into the role of the transcription regulatory sequences (TRSs) in the regulation of gene expression and replication of porcine reproductive and respiratory syndrome virus (PRRSV), the enhanced green fluorescent protein (EGFP) gene, under the control of the different structural gene TRSs, was inserted between the N gene and 3'-UTR of the PRRSV genome and EGFP expression was analyzed for each TRS. TRSs of all the studied structural genes of PRRSV positively modulated EGFP expression at different levels. Among the TRSs analyzed, those of GP2, GP5, M, and N genes highly enhanced EGFP expression without altering replication of PRRSV. These data indicated that structural gene TRSs could be an extremely useful tool for foreign gene expression using PRRSV as a vector.

Bovine gammaherpesvirus 4 (BoHV-4) is a herpesvirus widespread in cattle populations, and with no clear disease association. Its genome contains a long unique coding region (LUR) flanked by polyrepetitive DNA and 79 open reading frames (ORFs), with unique 17 ORFs, named Bo1 to Bo17. In 2009, a BoHV-4 strain was isolated (FMV09-1180503: BoHV-4-FMV) from cattle with respiratory disease from Quebec, Canada, and its LUR was sequenced. Despite the overall high similarity, BoHV-4-FMV had the most divergent LUR sequence compared to the two known BoHV-4 reference strain genomes; most of the divergences were in the Bo genes and in the repeat regions. Our phylogenetic analysis based on DNA polymerase and thymidine kinase genes revealed that virus isolate was BoHV-4 gammaherpesvirus and clustered it together with European BoHV-4 strains. Because BoHV-4-FMV was isolated from animals presenting respiratory signs, we have updated the BoHV-4 Canadian cattle seroprevalence data and tried to find out whether there is a link between clinical manifestation and BoHV-4 seropositivity. An indirect immunofluorescence assay (IFA) was performed with nearly 200 randomized sera of dairy cattle from two Canadian provinces, Quebec ( n  = 100) and Ontario ( n  = 91). An additional set of sera obtained from Quebec, from the healthy ( n  = 48) cows or from the animals experiencing respiratory or reproductive problems ( n  = 75), was also analyzed by IFA. BoHV-4 seroprevalence in Canadian dairy cattle was 7.9% (Quebec: 6% and Ontario: 9.9%). Among animals from the Quebec-based farms, diseased animals showed higher BoHV-4 seropositivity than healthy animals ( P  < 0.05), with a significant 2.494 odds ratio of being seropositive in sick compared to healthy animals. Although there is no established direct link between BoHV-4 and specific diseases, these seroprevalence data suggest the possible involvement of BoHV-4 in dairy cattle diseases.

Evidence-based medicine requires strong scientific evidence upon which to base treatment. In rare diseases, study populations are often small, and thus this evidence is difficult to accrue. Investigators, though, should be creative and develop a flexible toolkit of methods to deal with the problems inherent in the study of rare disease. This narrative review presents alternative clinical trial designs for studying treatments of rare diseases, including cross-over and n-of-1 trials, randomized placebo-phase design, enriched enrollment, randomized withdrawal design, and classes of adaptive designs. Examples of applications of these designs are presented along with their advantages and disadvantages. Additional analytical considerations such as Bayesian analysis, internal pilots, and use of biomarkers as surrogate outcomes are further discussed. A framework for selecting appropriate clinical trial design is proposed to guide investigators in the process of selecting alternative designs for rare diseases. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background: Medication reviews have become part of pharmacy practice across developed countries. This study aimed to identify factors affecting the likelihood of eligible Ontario seniors receiving a pharmacy-led medication review called MedsCheck annual (MCA)., Methods: We designed a cohort study using a random sample of pharmacy claims for MCA-eligible Ontario seniors using linked administrative data from April 2012 to March 2013. Guided by a conceptual framework, we constructed a generalized-estimating-equations model to estimate the effect of patient, pharmacy and community factors on the likelihood of receiving MCA., Results: Of the 2,878,958 eligible claim-dates, 65,605 included an MCA. Compared to eligible individuals who did not receive an MCA, recipients were more likely to have a prior MCA (OR = 3.03), receive a new medication on the claim-date (OR = 1.78), be hypertensive (OR = 1.18) or have a recent hospitalization (OR = 1.07). MCA recipients had fewer medications (e.g., OR = 0.44 for ≥12 medications versus 0-4 medications), and were less likely to receive an MCA in a rural (OR = 0.74) or high-volume pharmacy (OR = 0.65)., Conclusions: The most important determinant of receiving an MCA was having had a prior MCA. Overall, MCA recipients were healthier, younger, urban-dwelling, and taking fewer medications than non-recipients. Policies regarding current and future medication review programs may need to evolve to ensure that those at greatest need receive timely and comprehensive medication reviews.

Background: MedsCheck Annual (MCA) is an Ontario government-funded medication review service for individuals taking 3 or more prescription medications for chronic conditions., Methods: This cohort study analyzed linked administrative claims data from April 1, 2007, to March 31, 2013. Trends in MCA claims and recipient characteristics were examined., Results: A total of 1,498,440 Ontarians (55% seniors, 55% female) received an MCA. One-third (36%) had 2 or more MCAs within 6 years. Service provision increased over time, with a sharper increase from 2010 onward. Almost half of Ontario pharmacies made at least 1 MCA claim in the first month of the program. Hypertension, respiratory disease, diabetes, psychiatric conditions and arthritis were common comorbidities. Recipients older than 65 years were most commonly dispensed an antihypertensive and/or antihyperlipidemic drug in the prior year and received an average of 11 unique prescription medications. Thirty-eight percent of recipients visited an emergency department or were hospitalized in the year prior to their first MCA., Discussion: Over the first 6 years of the program, approximately 1 in 9 Ontarians received an MCA. There was rapid and widespread uptake of the service. Common chronic conditions were well represented among MCA recipients. Older MCA recipients had less emergency department use compared with population-based estimates., Conclusions: Medication reviews increased over time; however, the number of persons receiving the service more than once was low. Service delivery was generally consistent with program eligibility; however, there are some findings possibly consistent with delivery to less complex patients., Competing Interests: Declaration of Conflicting Interests:The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

To estimate the surgical volume and the incidence of in-hospital complications of RC in Armenia from 2005 to 2012, and to investigate potential risk factors of complications. The study utilized a retrospective chart review in a cohort of patients who had RC followed by either continent or conduit urinary diversion in all hospitals of Armenia from 2005 to 2012. A detailed chart review was conducted abstracting information on baseline demographic and clinical characteristics, surgical procedural details, postoperative management and in-hospital complications. Multivariable logistic regression analysis was applied to estimate the independent risk factors for developing 'any postoperative complication'. The total study sample included 273 patients (mean age = 58.5 years, 93.4 % men). Overall, 28.9 % (n = 79) of patients had at least one in-hospital complication. The hospital mortality rate was 4.8 % (n = 13). The most frequent types of complications were wound-related (10.3 %), gastrointestinal (9.2 %) and infectious (7.0 %). The ischemic heart disease (OR = 3.3, 95 % CI 1.5-7.4), perioperative transfusion (OR = 2.0, 1.1-3.6), glucose level [OR = 0.71 (0.63-0.95)], and hospital type (OR = 2.3, 95 % CI 1.1-4.7) were independent predictors of postoperative complications. The rate of RC complications in Armenia was similar to those observed in other countries. Future prospective studies should evaluate the effect of RC complications on long-term outcomes and costs in Armenia. Policy recommendations should address the issues regarding surgeon training and hospital volume to decrease the risk of RC complications.

Background and Overview: In everyday practice, dentists face clinical decisions for which they need to consider both treatment consequences (that is, benefits and harms) and costs. Economic analysis is a study design in which investigators evaluate and compare the costs and consequences of different treatment alternatives within a defined period. A critical appraisal of such studies includes an assessment of the risk of bias, results, and applicability of the study. The authors provide the concepts and guidelines that dentists can apply to critically appraise economic analyses., Practical Implications: Dentists who wish to inform their clinical decisions regarding questions that involve both treatment consequences and costs can use these guidelines to understand the different types of economic analyses and to decide what type of economic analyses to search for, as well as to critically appraise any economic analyses identified., (Copyright © 2015 American Dental Association. Published by Elsevier Inc. All rights reserved.)

Multidisciplinary team approach is an essential component of evidence-based wound management in the community. The objective of this study was to identify and describe community-based multidisciplinary wound care teams in Ontario. For the study, a working definition of a multidisciplinary wound care team was developed, and a two-phase field evaluation was conducted. In phase I, a systematic survey with three search strategies (environmental scan) was conducted to identify all multidisciplinary wound care teams in Ontario. In phase II, the team leads were surveyed about the service models of the teams. We identified 49 wound care teams in Ontario. The highest ratio of Ontario seniors to wound team within each Ontario health planning region was 82,358:1; the lowest ratio was 14,151:1. Forty-four teams (90%) participated in the survey. The majority of teams existed for at least 5 years, were established as hospital outpatient clinics, and served patients with chronic wounds. Teams were heterogeneous in on-site capacity of specialized diagnostic testing and wound treatment, team size, and patient volume. Seventy-seven percent of teams had members from three or more disciplines. Several teams lacked essential disciplines. More research is needed to identify optimal service models leading to improved patient outcomes., (© 2014 by the Wound Healing Society.)

Objectives: The management of patients on anticoagulation therapy is challenging. The objective of this study was to conduct a systematic review to establish the effectiveness of hemostatic interventions to prevent postoperative bleeding following dental extractions among patients taking warfarin., Methods: A systematic review of the literature was conducted using PubMed, EMBASE and the Cochrane Central Register of Controlled Trials databases and applying relevant MeSH terms. Identified studies were screened independently by 2 reviewers using the following selection criteria: tooth extraction, patients taking warfarin as the only anticoagulant, randomized controlled trials and a hemostatic intervention., Results: Six articles were included in the final review, all evaluating different interventions. Oral or local hemostatic agents were compared in 4 studies where patients continued taking warfarin before and after the procedure; in 3 studies, there were no differences between the agents in preventing postoperative bleeding and, in 1, Histoacryl glue was superior to a gelatin sponge. Two studies compared warfarin continuation with temporary discontinuation and found that continuation did not increase the risk of bleeding in patients who had an international normalized ratio (INR) within the therapeutic range., Conclusions: Patients with an INR within the therapeutic range can safely continue taking the regular dose of warfarin before dental extractions. There is no evidence to support or reject the superiority of local hemostatic agents over warfarin discontinuation.

Background: Hemophilia A is a rare, sex-linked genetic disorder treated with intravenous administration of factor VIII (FVIII) to prevent bleeding; however, approaches vary across and within countries. Value-of-information (VOI) methods identify situations in which the cost-benefit evidence is sufficient to adopt one treatment strategy over another; when the evidence is insufficient, VOI methods provide the optimal sample size for additional research., Objective: The objective of the study was to use VOI methods in a cost-benefit decision context to evaluate the current evidence in support of using (1) alternate day prophylaxis (AP), (2) tailored prophylaxis (TP) or (3) on-demand treatment (OD) with FVIII to prevent arthropathy in children with severe hemophilia A., Methods: To apply VOI methods, several parameters such as incidence, time horizon for the decision, costs, and threshold values to avoid MRI-detected joint damage or arthropathy were defined. Two baseline threshold values of willingness to pay for avoiding arthropathy--$200,000 and $400,000--were selected for comparing the treatment strategies., Results: For threshold values < $200,000, OD had a higher expected net benefit than either prophylaxis strategy, and the evidence was sufficient for its adoption. For threshold values > $400,000 prophylaxis strategies had higher expected net benefit; however, a new trial with 38 patients per arm was needed to compare AP and TP, yielding an expected net gain of over $17 million. In sensitivity analyses, the results were robust to assumptions regarding discount rate, trial fixed and variable costs, enrollment fraction, and the time horizon., Conclusions: In rare diseases, evidence is often scarce and insufficient for decision making. In considering the funding of new research and patient reimbursement in rare diseases, VOI methodology may provide more relevant determinations of the value and costs of additional research, compared to standard frequentist methods.

To get access to the replication site, small non-enveloped DNA viruses have to cross the cell membrane using a limited number of capsid proteins, which also protect the viral genome in the extracellular environment. Most of DNA viruses have to reach the nucleus to replicate. The capsid proteins involved in transmembrane penetration are exposed or released during endosomal trafficking of the virus. Subsequently, the conserved domains of capsid proteins interact with cellular membranes and ensure their efficient permeabilization. This review summarizes our current knowledge concerning the role of capsid proteins of small non-enveloped DNA viruses in intracellular membrane perturbation in the early stages of infection.

Background: Although multidisciplinary heart failure (HF) clinics are efficacious, it is not known how patient factors or HF clinic structural indicators and process measures have an impact on the cumulative health care costs., Research Design: In this retrospective cohort study using administrative databases in Ontario, Canada, we identified 1216 HF patients discharged alive after an acute care hospitalization in 2006 and treated at a HF clinic. The primary outcome was the cumulative 1-year health care costs. A hierarchical generalized linear model with a logarithmic link and gamma distribution was developed to determine patient-level and clinic-level predictors of cost., Results: The mean 1-year cost was $27,809 (range, $69 to $343,743). There was a 7-fold variation in the mean costs by clinic, from $14,670 to $96,524. Delays in being seen at a HF clinic were a significant patient-level predictor of costs (rate ratio 1.0015 per day; P<0.001). Being treated at a clinic with >3 physicians was associated with lower costs (rate ratio 0.78; P=0.035). Unmeasured patient-level differences accounted for 97.4% of the between-patient variations in cost. The between-clinic variation in costs decreased by 16.3% when patient-level factors were accounted for; it decreased by a further 49.8% when clinic-level factors were added., Conclusions: From a policy perspective, the wide spectrum of HF clinic structure translates to inefficient care. Greater guidance as to the type of patient seen at a HF clinic, the timeliness of the initial visit, and the most appropriate structure of the HF clinics may potentially result in more cost-effective care.

Evidence based medicine requires strong scientific evidence upon which to base treatment. Because the available study populations for rare diseases are small, this evidence is difficult to accrue. Investigators need to consider a flexible toolkit of methods to deal with the problems inherent in the study of rare disease. We present some potential solutions in this paper.

The Canadian Heart Health Strategy and Action Plan recommended that the Canadian Cardiovascular Society (CCS) lead the development of pan-Canadian data definitions and quality indicators (QIs) for evaluating cardiovascular care in Canada. In response to this recommendation, the CCS developed and adopted a standardized QI development methodology. This report provides a brief overview of the CCS "Best Practices" for developing pan-Canadian cardiovascular QIs. A more detailed description is available in Supplemental Material. The CCS Best Practices QI development methodology consists of 3 phases: phase I, plan and organize the QI development initiative; phase II, develop and select QIs; and phase III, operationalize the QIs. Phase I includes identifying the cardiovascular focus or content area, determining the objective and/or purpose of the initiative, the target users of, and the target population for, the QIs, and selection of a QI working group. Phase II involves formulating the QIs including generating a preliminary set of QIs and draft definitions, followed by an indicator rating and ranking process based on the CCS QI rating criteria. Phase III involves finalizing technical specifications and pilot testing the QIs. It also describes the CCS QI approval process and addresses knowledge translation. Adoption of a standardized methodology for QI development will improve the quality, completeness, acceptability, and usability of pan-Canadian cardiovascular QIs developed by the CCS. Public release of the QI definitions and related performance data might help improve patient care quality and outcomes., (Copyright © 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Heart failure (HF) clinics are associated with improved outcomes in randomized trials, however, there is substantial heterogeneity in the service models of HF clinics in practice. Our objective was to evaluate the effect of this clinic level heterogeneity on HF patient management in Ontario, Canada., Methods: Charts were abstracted from 9 HF clinics, chosen at random from the 34 HF clinics in operation in Ontario in 2011. From each clinic, approximately 100 patient charts were randomly selected for detailed abstraction on patient demographic characteristics, comorbidities, diagnostic tests, medication use, and referrals, over a 1-year period from the first clinic visit., Results: Significant heterogeneity was observed in patient baseline profiles, pharmacological therapies, diagnostic testing, clinic personnel, and referrals across 9 clinics. The mean age of patients was 66.1 ± 15.7 years and was significantly different between the clinics. Most patients were male (65%), and mean left ventricular ejection fraction was 33%. There was significant variation in the utilization of echocardiography (42%-94%) and coronary angiography (19%-62%). Overall, approximately 88% of patients were prescribed angiotensin converting enzyme inhibitors and/or angiotensin receptor blockers, and 85% were prescribe β-blockers. The rates of referral to cardiac rehabilitation programs were overall low at 10.4% of patients, with substantial variation (1%-28%)., Conclusions: Specialized HF clinics have wide variation in the health personnel involved and the care provided; in addition, patients treated at these HF clinics have important differences in clinical characteristics. Strategies should be considered at the appropriate level (eg, province-wide in Ontario) to standardize HF management and provide best evidence-based care to patients., (Copyright © 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

The V1 and V2 variable regions of the primate immunodeficiency viruses contribute to the trimer association domain of the gp120 exterior envelope glycoprotein. A pair of V2 cysteine residues at 183 and 191 ("twin cysteines") is present in several simian immunodeficiency viruses, human immunodeficiency virus type 2 (HIV-2) and some SIV(cpz) lineages, but not in HIV-1. To examine the role of this potentially disulfide-bonded twin-cysteine motif, the cysteine residues in the SIVmac239 envelope glycoproteins were individually and pairwise substituted by alanine residues. All of the twin-cysteine mutants exhibited decreases in gp120 association with the Env trimer, membrane-fusing activity, and ability to support virus entry. Thus, the twin-cysteine motif plays a role in Env trimer stabilization in SIV and may do so in HIV-2 and some SIV(cpz) as well. This implies that HIV-1 lost the twin-cysteines, and may have relatively unstable Env trimers compared to SIV and HIV-2.

A better understanding of how the biological functions of the HIV-1 envelope (Env) changes during disease progression may aid the design of an efficacious anti-HIV-1 vaccine. Although studies from patient had provided some insights on this issue, the differences in the study cohorts and methodology had make it difficult to reach a consensus of the variations in the HIV-1 Env functions during disease progression. To this end, an animal model that can be infected under controlled environment and reflect the disease course of HIV-1 infection in human will be beneficial. Such an animal model was previously demonstrated by the infection of macaque with SHIV, expressing HIV-1 clade C Env V1-V5 region. By using this model, we examined the changes in biological functions of Env in the infected animal over the entire disease course. Our data showed an increase in the neutralization resistance phenotype over time and coincided with the decrease in the net charges of the V1-V5 region. Infection of PBMC with provirus expressing various Env clones, isolated from the infected animal over time, showed a surprisingly better replicative fitness for viruses expressing the Env from early time point. Biotinylation and ELISA data also indicated a decrease of cell-surface-associated Env and virion-associated gp120 content with disease progression. This decrease did not affect the CD4-binding capability of Env, but were positively correlated with the decrease of Env fusion ability. Interestingly, some of these changes in biological functions reverted to the pre-AIDS level during advance AIDS. These data suggested a dynamic relationship between the Env V1-V5 region with the host immune pressure. The observed changes of biological functions in this setting might reflect and predict those occurring during natural disease progression in human.

Objectives: This study evaluated the relationship between medication noncompliance and patient satisfaction in patients with drug-eluting stent revascularization in Armenia., Background: Reasons for medication noncompliance are multifactorial--often related to health system, patient, condition, therapy, and socioeconomic factors., Methods: The analytical cross-sectional survey used a simple random sample of patients aged 18 and over who had undergone percutaneous coronary artery intervention with drug-eluting stent from 2006 to 2008 (n = 271) at Nork Marash Medical Center, Yerevan, Armenia. Medication noncompliance was assessed using the Morisky Adherence Scale. Patient satisfaction items were selected from the Patient Satisfaction Questionnaire (PSQ-18)., Results: Respondents' mean age was 57.5 ± 9.8 years. Most (87.8%) were male. Nearly one-third of patients (31.0%) were noncompliant. Most reported good health (91.9%). Respondents most often cited out-of-pocket costs as a reason for noncompliance (19.2%). Age, gender, health status, smoking status, and cost were associated with medication noncompliance (P < 0.05). Noncompliance was not associated with elapsed time after the intervention or satisfaction (P > 0.05). Medication noncompliance was positively related to cost (odds ratio [OR]= 2.57, 95% CI = 1.33-4.97) and inversely related to health status (OR = 0.46, 95% CI = 0.25-0.85) and age (OR = 0.94, 95% CI = 0.91-0.97)., Conclusion: Medication noncompliance is a multifactorial problem. Strategies reducing the economic burden on patients should improve compliance and, thus, treatment outcomes. These findings further efforts to benchmark performance in Armenia and other post-Soviet countries against western standards and experiences., (©2012, Wiley Periodicals, Inc.)

Background: Multi-disciplinary heart failure (HF) clinics have been shown to improve outcomes for HF patients in randomized clinical trials. However, it is unclear how widely available specialized HF clinics are in Ontario. Also, the service models of current clinics have not been described. It is therefore uncertain whether the efficacy of HF clinics in trials is generalizable to the HF clinics currently operating in the province., Methods: As part of a comprehensive evaluation of HF clinics in Ontario, we performed an environmental scan to identify all HF clinics operating in 2010. A semi-structured interview was conducted to understand the scope of practice. The intensity and complexity of care offered were quantified through the use of a validated instrument, and clinics were categorized as high, medium or low intensity clinics., Results: We identified 34 clinics with 143 HF physicians. We found substantial regional disparity in access to care across the province. The majority of HF physicians were cardiologists (81%), with 81% of the clinics physically based in hospitals, of which 26% were academic centers. There was a substantial range in the complexity of services offered, most notably in the intensity of education and medication management services offered. All the clinics focused on ambulatory care, with only one having an in-patient focus. None of the HF clinics had a home-based component to care., Conclusions: Multiple HF clinics are currently operating in Ontario with a wide spectrum of care models. Further work is necessary to understand which components lead to improved patient outcomes.

Quality indicators (QIs) are increasingly being used to measure and improve the quality of cardiac care. We conducted an international environmental scan to identify and critically appraise published QI development initiatives addressing cardiovascular disease (CVD). A review of the peer-reviewed and grey English-language literature was conducted to identify published CVD QI development initiatives. The quality of identified studies was assessed using a modified version of the Appraisal of Guidelines for Research and Evaluation (AGREE) II QI tool-an instrument originally developed for the assessment of the quality of clinical practice guidelines. An initial literature search identified 2314 potentially relevant abstracts of peer-reviewed articles. After a review of the abstracts, 120 full text articles were retrieved and reviewed. Of these, 20 articles and 1 peer-reviewed monograph were selected for critical appraisal (n = 21). Most of the initiatives were conducted in North America (76%) and were published after 2005 (62%). The majority (5 of 6) of the AGREE II QI domain scores were skewed toward higher values, including the median score for the 'overall quality' rating (83.3%). Of the CVD categories addressed within the 21 initiatives, heart failure was the most common (n = 10 QI indicator sets), followed by acute coronary syndromes (n = 8). Considerable variation was observed in the methods utilized and the degree of scientific rigour applied in the published international CVD QI development initiatives. Adoption of standardized methods could help improve the quality of QI development initiatives., (Copyright © 2012 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Objectives: The study evaluated the power of the randomized placebo-phase design (RPPD)-a new design of randomized clinical trials (RCTs), compared with the traditional parallel groups design, assuming various response time distributions. In the RPPD, at some point, all subjects receive the experimental therapy, and the exposure to placebo is for only a short fixed period of time., Study Design and Setting: For the study, an object-oriented simulation program was written in R. The power of the simulated trials was evaluated using six scenarios, where the treatment response times followed the exponential, Weibull, or lognormal distributions. The median response time was assumed to be 355 days for the placebo and 42 days for the experimental drug., Results: Based on the simulation results, the sample size requirements to achieve the same level of power were different under different response time to treatment distributions. The scenario where the response times followed the exponential distribution had the highest sample size requirement. In most scenarios, the parallel groups RCT had higher power compared with the RPPD., Conclusion: The sample size requirement varies depending on the underlying hazard distribution. The RPPD requires more subjects to achieve a similar power to the parallel groups design., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: This study evaluated the statistical distribution of time to treatment response in patients with rheumatic diseases., Study Design and Setting: The study used a secondary data analysis design. Data from the trial of etanercept and methotrexate with radiographic patient outcomes were used to model the response times for etanercept (ETN), methotrexate (MTX), and combined ETN+MTX in patients with rheumatoid arthritis. The German etanercept registry was used to evaluate the response time distributions in patients with juvenile idiopathic arthritis., Results: For MTX, the lognormal distribution was considered to be the best model for the outcome American College of Rheumatology (ACR20), lognormal, generalized gamma, and log-logistic distributions for ACR50, and lognormal and generalized gamma for ACR70. For ETN, the lognormal model was best for ACR20, the generalized gamma for ACR50, and both lognormal and generalized gamma distributions for ACR70. For combined treatment, the best model was the log-logistic distribution for ACR20, generalized gamma for ACR50, and both lognormal and generalized gamma distributions for ACR70. For the German etanercept registry, the lognormal distribution was the best model for all three outcomes of pediatric ACR30, ACR50, and ACR70 without interval censoring., Conclusion: Study designs might be more efficient if the response distributions are taken into consideration during planning., (Crown Copyright © 2010. Published by Elsevier Inc. All rights reserved.)

Our earlier work indicated that the human immunodeficiency virus type 1 (HIV-1) genomic RNA (vRNA) is trafficked to the microtubule-organizing center (MTOC) when heterogeneous nuclear ribonucleoprotein A2/B1 is depleted from cells. Also, Rab7-interacting lysosomal protein promoted dynein motor complex, late endosome and vRNA clustering at the MTOC suggesting that the dynein motor and late endosomes were involved in vRNA trafficking. To investigate the role of the dynein motor in vRNA trafficking, dynein motor function was disrupted by small interference RNA-mediated depletion of the dynein heavy chain or by p50/dynamitin overexpression. These treatments led to a marked relocalization of vRNA and viral structural protein Gag to the cell periphery with late endosomes and a severalfold increase in HIV-1 production. In contrast, rerouting vRNA to the MTOC reduced virus production. vRNA localization depended on Gag membrane association as shown using both myristoylation and Gag nucleocapsid domain proviral mutants. Furthermore, the cytoplasmic localization of vRNA and Gag was not attributable to intracellular or internalized endocytosed virus particles. Our results demonstrate that dynein motor function is important for regulating Gag and vRNA egress on endosomal membranes in the cytoplasm to directly impact on viral production.

Retroviral genomic RNA (gRNA) dimerization appears essential for viral infectivity, and the nucleocapsid protein (NC) of human immunodeficiency virus type 1 (HIV-1) facilitates HIV-1 gRNA dimerization. To identify the relevant and dispensable positions of NC, 34 of its 55 residues were mutated, individually or in small groups, in a panel of 40 HIV-1 mutants prepared by site-directed mutagenesis. It was found that the amino-terminus, the proximal zinc finger, the linker, and the distal zinc finger of NC each contributed roughly equally to efficient HIV-1 gRNA dimerization. The N-terminal and linker segments appeared to play predominantly electrostatic and steric roles, respectively. Mutating the hydrophobic patch of either zinc finger, or substituting alanines for their glycine doublet, was as disabling as deleting the corresponding finger. Replacing the CysX(2)CysX(4)HisX(4)Cys motif of either finger by CysX(2)CysX(4)CysX(4)Cys or CysX(2)CysX(4)HisX(4)His, interchanging the zinc fingers or, replacing one zinc finger by a copy of the other one, had generally intermediate effects; among these mutations, the His23-->Cys substitution in the N-terminal zinc finger had the mildest effect. The charge of NC could be increased or decreased by up to 18%, that of the linker could be reduced by 75% or increased by 50%, and one or two electric charges could be added or subtracted from either zinc finger, without affecting gRNA dimerization. Shortening, lengthening, or making hydrophobic the linker was as disabling as deleting the N-terminal or the C-terminal zinc finger, but a neutral and polar linker was innocuous. The present work multiplies by 4 and by 33 the number of retroviral and lentiviral NC mutations known to inhibit gRNA dimerization, respectively. It shows the first evidence that gRNA dimerization can be inhibited by: 1) mutations in the N-terminus or the linker of retroviral NC; 2) mutations in the proximal zinc finger of lentiviral NC; 3) mutations in the hydrophobic patch or the conserved glycines of the proximal or the distal retroviral zinc finger. Some NC mutations impaired gRNA dimerization more than mutations inactivating the viral protease, indicating that gRNA dimerization may be stimulated by the NC component of the Gag polyprotein. Most, but not all, mutations inhibited gRNA packaging; some had a strong effect on virus assembly or stability.

The purpose of this study was to determine predictors and evaluate outcomes of emergency conversion to cardiopulmonary bypass during planned off-pump coronary artery bypass grafting. From January 2001 to November 2005, of 467 consecutive patients aged >or= 60 years who underwent off-pump coronary surgery, 17 (3.6%) were converted to cardiopulmonary bypass. Those converted to an on-pump technique had significantly higher rates of postoperative cerebrovascular accident (17.6% vs 1.1%), intraaortic balloon pumping (5.9% vs 0%), and red blood cell transfusion (82.4% vs 57.3%), as well as prolonged intensive care unit stay (52.9% vs 25.2%), ventilation time (25% vs 5.3%) and hospital stay (64.7% vs 31.3%) compared to patients whose operation was completed off-pump. Multivariable logistic regression identified left ventricular ejection and left main stenosis as significantly associated with conversion. The rate of emergency conversion to cardiopulmonary bypass during planned off-pump coronary surgery was acceptable, but patients who required conversion had less favorable early outcomes than those who remained off-pump.

RNA helicases play important roles in RNA metabolism. Human immunodeficiency virus type 1 (HIV-1) does not carry its own RNA helicase, the virus thus needs to exploit cellular RNA helicases to promote the replication of its RNA at various steps such as transcription, folding and transport. In this study, we report that knockdown of a DEAD-box protein named DDX24 inhibits the packaging of HIV-1 RNA and thus diminishes viral infectivity. The decreased viral RNA packaging as a result of DDX24-knockdown is observed only in the context of the Rev/RRE (Rev response element)-dependent but not the CTE (constitutive transport element)-mediated nuclear export of viral RNA, which is explained by the specific interaction of DDX24 with the Rev protein. We propose that DDX24 acts at the early phase of HIV-1 RNA metabolism prior to nuclear export and the consequence of this action extends to the viral RNA packaging stage during virus assembly.

The HIV-1 ribonucleoprotein (RNP) contains the major structural protein, pr55(Gag), viral genomic RNA, as well as the host protein, Staufen1. In this report, we show that the nonsense-mediated decay (NMD) factor UPF1 is also a component of the HIV-1 RNP. We investigated the role of UPF1 in HIV-1-expressing cells. Depletion of UPF1 by siRNA resulted in a dramatic reduction in steady-state HIV-1 RNA and pr55(Gag). Pr55(Gag) synthesis, but not the cognate genomic RNA, was efficiently rescued by expression of an siRNA-insensitive UPF1, demonstrating that UPF1 positively influences HIV-1 RNA translatability. Conversely, overexpression of UPF1 led to a dramatic up-regulation of HIV-1 expression at the RNA and protein synthesis levels. The effects of UPF1 on HIV-1 RNA stability were observed in the nucleus and cytoplasm and required ongoing translation. We also demonstrate that the effects exerted by UPF1 on HIV-1 expression were dependent on its ATPase activity, but were separable from its role in NMD and did not require interaction with UPF2.

Human immunodeficiency virus type 1 (HIV-1) requires the sequential activities of virus-encoded proteins during replication. The activities of several host cell proteins and machineries are also critical to the completion of virus assembly and the release of infectious virus particles from cells. One of these proteins, the double-stranded RNA-binding protein Staufen1 (Stau1), selectively associates with the HIV-1 genomic RNA and the viral precursor Gag protein, pr55Gag. In this report, we tested whether Stau1 modulates pr55Gag assembly using a new and specific pr55Gag oligomerization assay based on bioluminescence resonance energy transfer (BRET) in both live cells and extracts after cell fractionation. Our results show that both the overexpression and knockdown of Stau1 increase the pr55Gag-pr55Gag BRET levels, suggesting a role for Stau1 in regulating pr55Gag oligomerization during assembly. This effect of Stau1 on pr55Gag oligomerization was observed only in membranes, a cellular compartment in which pr55Gag assembly primarily occurs. Consistently, expression of Stau1 harboring a vSrc myristylation signal led to a 6.5-fold enrichment of Stau1 in membranes and a corresponding enhancement in the Stau1-mediated effect on pr55Gag-pr55Gag BRET, demonstrating that Stau1 acts on assembly when targeted to membranes. A role for Stau1 in the formation of particles is further supported by the detection of membrane-associated detergent-resistant pr55Gag complexes and the increase of virus-like particle release when Stau1 expression levels are modulated. Our results indicate that Stau1 influences HIV-1 assembly by modulating pr55Gag-pr55Gag interactions, as shown in a live cell interaction assay. This likely occurs when Stau1 interacts with membrane-associated assembly intermediates.

Few details are known about how the human immunodeficiency virus type 1 (HIV-1) genomic RNA is trafficked in the cytoplasm. Part of this process is controlled by the activity of heterogeneous nuclear ribonucleoprotein A2 (hnRNP A2). The role of hnRNP A2 during the expression of a bona fide provirus in HeLa cells is investigated in this study. Using immunofluorescence and fluorescence in situ hybridization techniques, we show that knockdown of hnRNP A2 expression in HIV-1-expressing cells results in the rapid accumulation of HIV-1 genomic RNA in a distinct, cytoplasmic space that corresponds to the microtubule-organizing center (MTOC). The RNA exits in the nucleus and accumulates at the MTOC region as a result of hnRNP A2 knockdown even during the expression of a provirus harboring mutations in the hnRNP A2-response element (A2RE), the expression of which results in nuclear retention of genomic RNA. We also demonstrate that hnRNP A2 expression is required for downstream trafficking of genomic RNA from the MTOC in the cytoplasm. Genomic RNA localization at the MTOC that was both the result of hnRNP A2 knockdown and the overexpression of Rab7-interacting lysosomal protein had little effect on pr55Gag synthesis but negatively influenced virus production and infectivity. These data indicate that altered HIV-1 genomic RNA localization modulates viral assembly and that the MTOC serves as a central site to which HIV-1 genomic RNA converges following its exit from the nucleus, with the host protein, hnRNP A2, playing a central role in taking it to and from this site in the cell.

The study evaluated rates and determinants of hospital morbidity, serious morbid events, and prolonged intensive care unit stay associated with isolated coronary artery bypass. The medical records of 391 patients undergoing isolated coronary artery bypass at our center during 2003 were reviewed. The observed crude hospital mortality rate was 2.05%, similar to the EuroSCORE predicted mortality rate of 2.34%. Arrhythmia was the most frequent postoperative complication (17.6%). The serious hospital morbidity rate was 5.9%. The final logistic regression model of serious morbid events identified the following predictors: drug allergy, diabetes, and EuroSCORE. Prolonged intensive care unit stay (>/= 3 days) was observed in 9.5% of patients. Multivariable logistic regression analysis revealed age, preoperative rhythm disturbances, previous cardiac operation, and hypertension as independent predictors of prolonged intensive care unit stay. The rates of hospital mortality, morbidity, and prolonged intensive care unit stay were comparable to those of other major international cardiac surgery centers. These data can be used as a benchmark for further self- and peer-assessment quality improvement activities.