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1.  A multiscale model for the study of cardiac biomechanics in single-ventricle surgeries: a clinical case 
Interface Focus  2015;5(2):20140079.
Complex congenital heart disease characterized by the underdevelopment of one ventricular chamber (single ventricle (SV) circulation) is normally treated with a three-stage surgical repair. This study aims at developing a multiscale computational framework able to couple a patient-specific three-dimensional finite-element model of the SV to a patient-specific lumped parameter (LP) model of the whole circulation, in a closed-loop fashion. A sequential approach was carried out: (i) cardiocirculatory parameters were estimated by using a fully LP model; (ii) ventricular material parameters and unloaded geometry were identified by means of the stand-alone, three-dimensional model of the SV; and (iii) the three-dimensional model of SV was coupled to the LP model of the circulation, thus closing the loop and creating a multiscale model. Once the patient-specific multiscale model was set using pre-operative clinical data, the virtual surgery was performed, and the post-operative conditions were simulated. This approach allows the analysis of local information on ventricular function as well as global parameters of the cardiovascular system. This methodology is generally applicable to patients suffering from SV disease for surgical planning at different stages of treatment. As an example, a clinical case from stage 1 to stage 2 is considered here.
PMCID: PMC4342947  PMID: 25844151
single ventricle heart; multiscale coupling; finite-element method; lumped parameter model; virtual surgery
2.  Improving System Integration: The Art and Science of Engaging Small Community Practices in Health System Innovation 
This paper focuses on successful engagement strategies in recruiting and retaining primary care physicians (PCPs) in a quality improvement project, as perceived by family physicians in small practices. Sustained physician engagement is critical for quality improvement (QI) aiming to enhance health system integration. Although there is ample literature on engaging physicians in hospital or team-based practice, few reports describe factors influencing engagement of community-based providers practicing with limited administrative support. The PCPs we describe participated in SCOPE: Seamless Care Optimizing the Patient Experience, a QI project designed to support their care of complex patients and reduce both emergency department (ED) visits and inpatient admissions. SCOPE outcome measures will inform subsequent papers. All the 30 participating PCPs completed surveys assessing perceptions regarding the importance of specific engagement strategies. Project team acknowledgement that primary care is challenging and new access to patient resources were the most important factors in generating initial interest in SCOPE. The opportunity to improve patient care via integration with other providers was most important in their commitment to participate, and a positive experience with project personnel was most important in their continued engagement. Our experience suggests that such providers respond well to personalized, repeated, and targeted engagement strategies.
PMCID: PMC4745601  PMID: 26904284
3.  Comparison of Echocardiographic and Pressure–volume Loop Indices of Systolic Function in Patients with Single Ventricle Physiology: A Preliminary Report 
Congenital heart disease  2014;10(1):E17-E24.
Differences in ventricular geometry and physiology of patients with single ventricle anatomy complicate the application of traditional, noninvasive measurements of systolic function. We compared noninvasive measures of ventricular systolic function in single ventricle patients with invasive measures to evaluate their validity in this population.
A secondary analysis of patients with single ventricle physiology enrolled in the multi-institutional research project, “multi-scale modeling of single ventricle hearts,” was performed. Pressure–volume loops (PVLs) were recorded using microconductance catheters. Transthoracic echocardiogram and cardiac magnetic resonance imaging were performed on the same day. PVL indices of systolic function including end-systolic elastance (Ees), maximal rate of pressure increase (dP/dTmax), and stroke work indexed to end-diastolic volume (SW/EDV) were compared with noninvasive measures, including echocardiographic myocardial performance index (MPI), rate of pressure rise (AV valve dP/dT), isovolumic acceleration, longitudinal shortening fraction (longSF), and fractional area change (FAC).
Fifteen patients had PVLs available for analysis. Eleven had a dominant right ventricle, three were status poststage 1 repair, five had superior cavopulmonary anastomosis, and seven had a total cavopulmonary anastomosis. FAC correlated with Ees (r = 0.69, P < .01), SW/EDV (r = 0.64, P = .01), and dP/dTmax (r = 0.59, P = .03). LongSF correlated with dP/dTmax (r = 0.61, P = .02) MPI, AV valve dP/dT, and isovolumic acceleration did not correlate with pressure–volume loop indices of systolic function.
Obtaining PVLs via microconductance catheters can reliably be performed in the single ventricle population and serve as a method to validate echocardiographic indices in this high-risk population. Of the echocardiographic variables, FAC showed the best correlation with PVL indices. Future studies controlling for stage of palliation should be performed to further validate echocardiographic measures of systolic function in this patient population.
PMCID: PMC4373647  PMID: 24869911
Single Ventricle; Systolic Function; Echocardiography; Pressure–volume Loop; Ventricular Mechanics
4.  Intellectual capital in the healthcare sector: a systematic review and critique of the literature 
Variations in the performance of healthcare organizations may be partly explained by differing “stocks” of intellectual capital (IC), and differing approaches and capacities for leveraging IC. This study synthesizes what is currently known about the conceptualization, management and measurement of IC in healthcare through a review of the literature.
Peer-reviewed papers on IC in healthcare published between 1990 and 2014 were identified through searches of five databases using the following key terms: intellectual capital/assets, knowledge capital/assets/resources, and intangible assets/resources. Articles deemed relevant for inclusion underwent systematic data extraction to identify overarching themes and were assessed for their methodological quality.
Thirty-seven papers were included in the review. The primary research method used was cross-sectional questionnaires focused on hospital managers’ perceptions of IC, followed by semi-structured interviews and analysis of administrative data. Empirical studies suggest that IC is linked to subjective process and performance indicators in healthcare organizations. Although the literature on IC in healthcare is growing, it is not advanced. In this paper, we identify and examine the conceptual, theoretical and methodological limitations of the literature.
The concept and framework of IC offer a means to study the value of intangible resources in healthcare organizations, how to manage systematically these resources together, and their mutually enhancing interactions on performance. We offer several recommendations for future research.
Electronic supplementary material
The online version of this article (doi:10.1186/s12913-015-1234-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4678586  PMID: 26670123
Intellectual capital; Organizational knowledge; Intangible assets; Knowledge management; Health system performance
5.  Role of context in care transition interventions for medically complex older adults: a realist synthesis protocol 
BMJ Open  2015;5(11):e008686.
Approximately 30–50% of older adults have two or more conditions and are referred to as multimorbid or complex patients. These patients often require visits to various healthcare providers in a number of settings and are therefore susceptible to fragmented healthcare delivery while transitioning to receive care. Care transition interventions have been implemented to improve continuity of care, however, current evidence suggests that some interventions or components of interventions are only effective within certain contexts. There is therefore a need to unpack the mechanisms of how and within which contexts care transition interventions and their components are effective. Realist review is a synthesis method that explains how complex programmes work within various contexts. The purpose of this study is to explain the effect of context on the activities and mechanisms of care transition interventions in medically complex older adults using a realist review approach.
Methods and analysis
This synthesis will be guided by Pawson and colleagues’ 2004 and 2005 protocols for conducting realist reviews. The underlying theories of care transition interventions were determined based on an initial literature search using relevant databases. English language peer-reviewed studies published after 1993 will be included. Several relevant databases will be searched using medical subject headings and text terms. A screening form will be piloted and titles, abstracts and full text of potentially relevant articles will be screened in duplicate. Abstracted data will include study characteristics, intervention type, contextual factors, intervention activities and underlying mechanisms. Patterns in Context-Activity-Mechanism-Outcome (CAMO) configurations will be reported.
Ethics and dissemination
Internal knowledge translation activities will occur throughout the review and existing partnerships will be leveraged to disseminate findings to frontline staff, hospital administrators and policymakers. Finalised results will be presented at local, national and international conferences, and disseminated via peer-reviewed publications in relevant journals.
PMCID: PMC4654392  PMID: 26586323
health care delivery; knowledge synthesis; continuity of care; aged
6.  Acute Care Hospitals' Accountability to Provincial Funders 
Healthcare Policy  2014;10(SP):25-35.
Ontario's acute care hospitals are subject to a number of tools, including legislation and performance measurement for fiscal accountability and accountability for quality. Examination of accountability documents used in Ontario at the government, regional and acute care hospital levels reveals three trends: (a) the number of performance measures being used in the acute care hospital sector has increased significantly; (b) the focus of the health system has expanded from accountability for funding and service volumes to include accountability for quality and patient safety; and (c) the accountability requirements are misaligned at the different levels. These trends may affect the success of the accountability approach currently being used.
PMCID: PMC4255572  PMID: 25305386
7.  Comparison of Pressure-Volume Loop and Echocardiographic Measures of Diastolic Function in Patients with Single Ventricle Physiology 
Pediatric cardiology  2014;35(6):998-1006.
Echocardiographic measurements of diastolic function have not been validated against invasive pressure-volume loop (PVL) analysis in the single ventricle population. We hypothesized that echocardiographic measures of diastolic function would correlate with PVL indices of diastolic function in patients with single ventricle physiology.
Materials and Methods
Conductance-derived PVL measures of diastolic function included the isovolumic relaxation time constant (tau), maximum rate of ventricular pressure decline (peak -dP/dt), and a measure of passive diastolic stiffness, μ. Echocardiographic measures included Doppler inflow patterns of the dominant atrioventricular valve (DAVV), tissue Doppler velocities (TDI) at the lateral (ventricular free wall) component of the DAVV annulus, and TDI-derived isovolumic relaxation time (IVRT′). The correlation between PVL and echocardiographic measures was examined.
Thirteen patients were enrolled at various stages of surgical palliation. Median age was 3yr (range 3mo to 19yr). Tau correlated well with Doppler E:A (r = 0.832, p = 0.005), lateral E:E′ (r = 0.747, p = 0.033), and IVRT′ (r = 0.831, p = 0.001). There was also correlation between peak -dP/dt and IVRT′ (r = 0.609, p = 0.036) while μ also correlated with IVRT′ (r = 0.884, p = 0.001).
This study represents the first-ever comparison of diastolic echocardiographic and PVL indices in a single ventricle population. We found that Doppler E:A, lateral E:E′, and IVRT′ correlate well with PVL measures of diastolic function. This study supports the further validation of echocardiographic measures of diastolic function vs. PVL measures of diastolic function in the single ventricle population..
PMCID: PMC4082737  PMID: 24584211
Pressure-volume loop; single ventricle; echocardiography; diastolic function
8.  Application of a trigger tool in near real time to inform quality improvement activities: a prospective study in a general medicine ward 
BMJ Quality & Safety  2015;24(4):272-281.
Retrospective record review using trigger tools remains the most widely used method for measuring adverse events (AEs) to identify targets for improvement and measure temporal trends. However, medical records often contain limited information about factors contributing to AEs. We implemented an augmented trigger tool that supplemented record review with debriefing front-line staff to obtain details not included in the medical record. We hypothesised that this would foster the identification of factors contributing to AEs that could inform improvement initiatives.
A trained observer prospectively identified events in consecutive patients admitted to a general medical ward in a tertiary care academic medical centre (November 2010 to February 2011 inclusive), gathering information from record review and debriefing front-line staff in near real time. An interprofessional team reviewed events to identify preventable and potential AEs and characterised contributing factors using a previously published taxonomy.
Among 141 patients, 14 (10%; 95% CI 5% to 15%) experienced at least one preventable AE; 32 patients (23%; 95% CI 16% to 30%) experienced at least one potential AE. The most common contributing factors included policy and procedural problems (eg, routine protocol violations, conflicting policies; 37%), communication and teamwork problems (34%), and medication process problems (23%). However, these broad categories each included distinct subcategories that seemed to require different interventions. For instance, the 32 identified communication and teamwork problems comprised 7 distinct subcategories (eg, ineffective intraprofessional handovers, poor interprofessional communication, lacking a shared patient care, paging problems). Thus, even the major categories of contributing factors consisted of subcategories that individually related to a much smaller subset of AEs.
Prospective application of an augmented trigger tool identified a wide range of factors contributing to AEs. However, the majority of contributing factors accounted for a small number of AEs, and more general categories were too heterogeneous to inform specific interventions. Successfully using trigger tools to stimulate quality improvement activities may require development of a framework that better classifies events that share contributing factors amenable to the same intervention.
PMCID: PMC4387453  PMID: 25749028
Trigger tools; Adverse events, epidemiology and detection; Hospital medicine
9.  Patient safety, resident well-being and continuity of care with different resident duty schedules in the intensive care unit: a randomized trial 
Shorter resident duty periods are increasingly mandated to improve patient safety and physician well-being. However, increases in continuity-related errors may counteract the purported benefits of reducing fatigue. We evaluated the effects of 3 resident schedules in the intensive care unit (ICU) on patient safety, resident well-being and continuity of care.
Residents in 2 university-affiliated ICUs were randomly assigned (in 2-month rotation-blocks from January to June 2009) to in-house overnight schedules of 24, 16 or 12 hours. The primary patient outcome was adverse events. The primary resident outcome was sleepiness, measured by the 7-point Stanford Sleepiness Scale. Secondary outcomes were patient deaths, preventable adverse events, and residents’ physical symptoms and burnout. Continuity of care and perceptions of ICU staff were also assessed.
We evaluated 47 (96%) of 49 residents, all 971 admissions, 5894 patient-days and 452 staff surveys. We found no effect of schedule (24-, 16- or 12-h shifts) on adverse events (81.3, 76.3 and 78.2 events per 1000 patient-days, respectively; p = 0.7) or on residents’ sleepiness in the daytime (mean rating 2.33, 2.61 and 2.30, respectively; p = 0.3) or at night (mean rating 3.06, 2.73 and 2.42, respectively; p = 0.2). Seven of 8 preventable adverse events occurred with the 12-hour schedule (p = 0.1). Mortality rates were similar for the 3 schedules. Residents’ somatic symptoms were more severe and more frequent with the 24-hour schedule (p = 0.04); however, burnout was similar across the groups. ICU staff rated residents’ knowledge and decision-making worst with the 16-hour schedule.
Our findings do not support the purported advantages of shorter duty schedules. They also highlight the trade-offs between residents’ symptoms and multiple secondary measures of patient safety. Further delineation of this emerging signal is required before widespread system change. Trial registration:, no. NCT00679809.
PMCID: PMC4361104  PMID: 25667258
10.  One size does not fit all: a qualitative content analysis of the importance of existing quality improvement capacity in the implementation of Releasing Time to Care: the Productive Ward™ in Saskatchewan, Canada 
Releasing Time to Care: The Productive Ward™ (RTC) is a method for conducting continuous quality improvement (QI). The Saskatchewan Ministry of Health mandated its implementation in Saskatchewan, Canada between 2008 and 2012. Subsequently, a research team was developed to evaluate its impact on the nursing unit environment. We sought to explore the influence of the unit’s existing QI capacity on their ability to engage with RTC as a program for continuous QI.
We conducted interviews with staff from 8 nursing units and asked them to speak about their experience doing RTC. Using qualitative content analysis, and guided by the Organizing for Quality framework, we describe the existing QI capacity and impact of RTC on the unit environment.
The results focus on 2 units chosen to highlight extreme variation in existing QI capacity. Unit B was characterized by a strong existing environment. RTC was implemented in an environment with a motivated manager and collaborative culture. Aided by the structural support provided by the organization, the QI capacity on this unit was strengthened through RTC. Staff recognized the potential of using the RTC processes to support QI work. Staff on unit E did not have the same experience with RTC. Like unit B, they had similar structural supports provided by their organization but they did not have the same existing cultural or political environment to facilitate the implementation of RTC. They did not have internal motivation and felt they were only doing RTC because they had to. Though they had some success with RTC activities, the staff did not have the same understanding of the methods that RTC could provide for continuous QI work.
RTC has the potential to be a strong tool for engaging units to do QI. This occurs best when RTC is implemented in a supporting environment. One size does not fit all and administrative bodies must consider the unique context of each environment prior to implementing large-scale QI projects. Use of an established framework, like Organizing for Quality, could highlight the distinctive supports needed in particular care environments to increase the likelihood of successful engagement.
Electronic supplementary material
The online version of this article (doi:10.1186/s12913-014-0642-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4279911  PMID: 25547227
Productive ward; Releasing time to care; Organizing for quality; Nursing; Qualitative methodology; Quality improvement capacity; Change mechanisms
11.  Organizational interventions in response to duty hour reforms 
BMC Medical Education  2014;14(Suppl 1):S4.
Changes in resident duty hours in Europe and North America have had a major impact on the internal organizational dynamics of health care organizations. This paper examines, and assesses the impact of, organizational interventions that were a direct response to these duty hour reforms.
The academic literature was searched through the SCOPUS database using the search terms “resident duty hours” and “European Working Time Directive,” together with terms related to organizational factors. The search was limited to English-language literature published between January 2003 and January 2012. Studies were included if they reported an organizational intervention and measured an organizational outcome.
Twenty-five articles were included from the United States (n = 18), the United Kingdom (n = 5), Hong Kong (n = 1), and Australia (n = 1). They all described single-site projects; the majority used post-intervention surveys (n = 15) and audit techniques (n = 4). The studies assessed organizational measures, including relationships among staff, work satisfaction, continuity of care, workflow, compliance, workload, and cost. Interventions included using new technologies to improve handovers and communications, changing staff mixes, and introducing new shift structures, all of which had varying effects on the organizational measures listed previously.
Little research has assessed the organizational impact of duty hour reforms; however, the literature reviewed demonstrates that many organizations are using new technologies, new personnel, and revised and innovative shift structures to compensate for reduced resident coverage and to decrease the risk of limited continuity of care. Future research in this area should focus on both micro (e.g., use of technology, shift changes, staff mix) and macro (e.g., culture, leadership support) organizational aspects to aid in our understanding of how best to respond to these duty hour reforms.
PMCID: PMC4304281  PMID: 25558915
12.  Two Heads Are Better Than One, but How Much? 
Experimental Psychology  2014;61(5):356-367.
Many theories of causal learning and causal induction differ in their assumptions about how people combine the causal impact of several causes presented in compound. Some theories propose that when several causes are present, their joint causal impact is equal to the linear sum of the individual impact of each cause. However, some recent theories propose that the causal impact of several causes needs to be combined by means of a noisy-OR integration rule. In other words, the probability of the effect given several causes would be equal to the sum of the probability of the effect given each cause in isolation minus the overlap between those probabilities. In the present series of experiments, participants were given information about the causal impact of several causes and then they were asked what compounds of those causes they would prefer to use if they wanted to produce the effect. The results of these experiments suggest that participants actually use a variety of strategies, including not only the linear and the noisy-OR integration rules, but also averaging the impact of several causes.
PMCID: PMC4207133  PMID: 24614872
causal reasoning; integration rules; summation
13.  Intervention for Re-coarctation in the Single Ventricle Reconstruction Trial: Incidence, Risk and Outcomes 
Circulation  2013;128(9):10.1161/CIRCULATIONAHA.112.000488.
Re-coarctation after the Norwood procedure increases risk for mortality. The Single Ventricle Reconstruction (SVR) trial randomized subjects with a single right ventricle undergoing a Norwood procedure to a modified Blalock-Taussig shunt (MBTS) or right ventricle-pulmonary artery shunt (RVPAS). We sought to determine incidence of re-coarctation, risk factors and outcomes in the SVR trial.
Methods and Results
Re-coarctation was defined by intervention, either catheter-based or surgical. Univariate analysis and multivariable Cox proportional hazard models were performed adjusting for center. Of the 549 SVR subjects, 97 (18%) underwent 131 interventions (92 balloon aortoplasty; 39 surgical) for re-coarctation at median age 4.9 months (range: 1.1–10.5). Intervention typically occurred at pre-stage II catheterization (n=71, 54%) or at stage II surgery (n=38, 29%). In multivariable analysis, re-coarctation was associated with the shunt type in place at the end of the Norwood procedure (HR 2.0 for RVPAS vs. MBTS, p=0.02), and Norwood discharge peak echo-Doppler arch gradient (HR 1.07 per 1 mmHg, p<0.01). Subjects with re-coarctation demonstrated comorbidities at pre-stage II evaluation including higher pulmonary arterial pressures (15.4±3.0 vs. 14.5±3.5 mm Hg; p=0.05), higher pulmonary vascular resistance (2.6±1.6 vs. 2.0±1.0 WU × m2; p=0.04) and increased echocardiographic volumes (end-diastolic volume: 126±39 vs. 112±33 ml/BSA1.3; p=0.02). There was no difference in 12-month post-randomization transplant-free survival between those with and without re-coarctation (p=0.14).
Re-coarctation is common after Norwood and contributes to pre-stage II comorbidities. Although with intervention there is no associated increase in 1-year transplant/mortality, further evaluation is warranted to evaluate effects of associated morbidities.
PMCID: PMC3825266  PMID: 23864006
Coarctation; heart defects; congenital; angioplasty
14.  Adverse Events Associated with Hospitalization or Detected through the RAI-HC Assessment among Canadian Home Care Clients 
Healthcare Policy  2013;9(1):76-88.
The occurrence of adverse events (AEs) in care settings is a patient safety concern that has significant consequences across healthcare systems. Patient safety problems have been well documented in acute care settings; however, similar data for clients in home care (HC) settings in Canada are limited. The purpose of this Canadian study was to investigate AEs in HC, specifically those associated with hospitalization or detected through the Resident Assessment Instrument for Home Care (RAI-HC).
A retrospective cohort design was used. The cohort consisted of HC clients from the provinces of Nova Scotia, Ontario, British Columbia and the Winnipeg Regional Health Authority.
The overall incidence rate of AEs associated with hospitalization ranged from 6% to 9%. The incidence rate of AEs determined from the RAI-HC was 4%. Injurious falls, injuries from other than fall and medication-related events were the most frequent AEs associated with hospitalization, whereas new caregiver distress was the most frequent AE identified through the RAI-HC.
The incidence of AEs from all sources of data ranged from 4% to 9%. More resources are needed to target strategies for addressing safety risks in HC in a broader context. Tools such as the RAI-HC and its Clinical Assessment Protocols, already available in Canada, could be very useful in the assessment and management of HC clients who are at safety risk.
PMCID: PMC3999553  PMID: 23968676
15.  A cognitive perspective on health systems integration: results of a Canadian Delphi study 
Ongoing challenges to healthcare integration point toward the need to move beyond structural and process issues. While we know what needs to be done to achieve integrated care, there is little that informs us as to how. We need to understand how diverse organizations and professionals develop shared knowledge and beliefs – that is, we need to generate knowledge about normative integration. We present a cognitive perspective on integration, based on shared mental model theory, that may enhance our understanding and ability to measure and influence normative integration. The aim of this paper is to validate and improve the Mental Models of Integrated Care (MMIC) Framework, which outlines important knowledge and beliefs whose convergence or divergence across stakeholder groups may influence inter-professional and inter-organizational relations.
We used a two-stage web-based modified Delphi process to test the MMIC Framework against expert opinion using a random sample of participants from Canada’s National Symposium on Integrated Care. Respondents were asked to rate the framework’s clarity, comprehensiveness, usefulness, and importance using seven-point ordinal scales. Spaces for open comments were provided. Descriptive statistics were used to describe the structured responses, while open comments were coded and categorized using thematic analysis. The Kruskall-Wallis test was used to examine cross-group agreement by level of integration experience, current workplace, and current role.
In the first round, 90 individuals responded (52% response rate), representing a wide range of professional roles and organization types from across the continuum of care. In the second round, 68 individuals responded (75.6% response rate). The quantitative and qualitative feedback from experts was used to revise the framework. The re-named “Integration Mindsets Framework” consists of a Strategy Mental Model and a Relationships Mental Model, comprising a total of nineteen content areas.
The Integration Mindsets Framework draws the attention of researchers and practitioners to how various stakeholders think about and conceptualize integration. A cognitive approach to understanding and measuring normative integration complements dominant cultural approaches and allows for more fine-grained analyses. The framework can be used by managers and leaders to facilitate the interpretation, planning, implementation, management and evaluation of integration initiatives.
PMCID: PMC4066828  PMID: 24885659
Health systems integration; Integrated care; Shared mental models; Group cognition; Organizational culture; Change management
16.  Feasibility of conductance catheter-derived pressure–volume loops to investigate ventricular mechanics in shunted single ventricles 
Cardiology in the young  2013;23(5):776-779.
We present pressure–volume loops obtained from two patients with single-ventricle physiology, one with a modified Blalock–Taussig shunt and one with a right ventricle-to-pulmonary artery shunt. The dissimilarities in pressure–volume loop contour and related indices highlight potentially important differences in ventricular mechanics between the shunt types.
PMCID: PMC3997067  PMID: 23347797
Single ventricle; RV–PA shunt; Norwood procedure; pressure–volume loop; ventricular mechanics
17.  Mutability Dynamics of an Emergent Single Stranded DNA Virus in a Naïve Host 
PLoS ONE  2014;9(1):e85370.
Quasispecies variants and recombination were studied longitudinally in an emergent outbreak of beak and feather disease virus (BFDV) infection in the orange-bellied parrot (Neophema chrysogaster). Detailed health monitoring and the small population size (<300 individuals) of this critically endangered bird provided an opportunity to longitudinally track viral replication and mutation events occurring in a circular, single-stranded DNA virus over a period of four years within a novel bottleneck population. Optimized PCR was used with different combinations of primers, primer walking, direct amplicon sequencing and sequencing of cloned amplicons to analyze BFDV genome variants. Analysis of complete viral genomes (n = 16) and Rep gene sequences (n = 35) revealed that the outbreak was associated with mutations in functionally important regions of the normally conserved Rep gene and immunogenic capsid (Cap) gene with a high evolutionary rate (3.41×10−3 subs/site/year) approaching that for RNA viruses; simultaneously we observed significant evidence of recombination hotspots between two distinct progenitor genotypes within orange-bellied parrots indicating early cross-transmission of BFDV in the population. Multiple quasispecies variants were also demonstrated with at least 13 genotypic variants identified in four different individual birds, with one containing up to seven genetic variants. Preferential PCR amplification of variants was also detected. Our findings suggest that the high degree of genetic variation within the BFDV species as a whole is reflected in evolutionary dynamics within individually infected birds as quasispecies variation, particularly when BFDV jumps from one host species to another.
PMCID: PMC3885698  PMID: 24416396
18.  Differential Effects of Antiepileptic Drugs on Neonatal Outcomes 
Epilepsy & behavior : E&B  2012;24(4):449-456.
Offspring of women with epilepsy (WWE) on AEDs are at increased risks for major congenital malformations and reduced cognition. They may be at risk for other adverse neonatal outcomes. WWE on carbamazepine (CBZ), lamotrigine (LTG), phenytoin (PHT), or valproate (VPA) monotherapy were enrolled in a prospective, observational, multicenter study of the neurodevelopmental effects of AEDs. The odds ratio for small for gestational age (SGA) was higher for VPA vs. PHT, VPA vs. LTG, and CBZ vs. PHT. Microcephaly rates were elevated to 12% for all newborns and 12-months-old, but normalized by age 24-months. Reduced Apgar scores occurred more frequently in the VPA and PHT groups at 1 minute, but scores were near normal in all groups at 5 minutes. This study demonstrates increased risks for being born SGA in the VPA and CBZ groups, and transiently reduced Apgar scores in the VPA and PHT groups. Differential risks amongst the AEDs can help inform decisions about AED selection for women during childbearing years.
PMCID: PMC3483041  PMID: 22749607
Epilepsy; seizures; Antiepileptic drugs; Pregnancy; Neonatal; microcephaly; Small for Gestational Age (SGA); Apgar; Observational cohort study
19.  Adverse events among Ontario home care clients associated with emergency room visit or hospitalization: a retrospective cohort study 
Home care (HC) is a critical component of the ongoing restructuring of healthcare in Canada. It impacts three dimensions of healthcare delivery: primary healthcare, chronic disease management, and aging at home strategies. The purpose of our study is to investigate a significant safety dimension of HC, the occurrence of adverse events and their related outcomes. The study reports on the incidence of HC adverse events, the magnitude of the events, the types of events that occur, and the consequences experienced by HC clients in the province of Ontario.
A retrospective cohort design was used, utilizing comprehensive secondary databases available for Ontario HC clients from the years 2008 and 2009. The data were derived from the Canadian Home Care Reporting System, the Hospital Discharge Abstract Database, the National Ambulatory Care Reporting System, the Ontario Mental Health Reporting System, and the Continuing Care Reporting System. Descriptive analysis was used to identify the type and frequency of the adverse events recorded and the consequences of the events. Logistic regression analysis was used to examine the association between the events and their consequences.
The study found that the incident rate for adverse events for the HC clients included in the cohort was 13%. The most frequent adverse events identified in the databases were injurious falls, injuries from other than a fall, and medication-related incidents. With respect to outcomes, we determined that an injurious fall was associated with a significant increase in the odds of a client requiring long-term-care facility admission and of client death. We further determined that three types of events, delirium, sepsis, and medication-related incidents were associated directly with an increase in the odds of client death.
Our study concludes that 13% of clients in homecare experience an adverse event annually. We also determined that an injurious fall was the most frequent of the adverse events and was associated with increased admission to long-term care or death. We recommend the use of tools that are presently available in Canada, such as the Resident Assessment Instrument and its Clinical Assessment Protocols, for assessing and mitigating the risk of an adverse event occurring.
PMCID: PMC3751652  PMID: 23800280
20.  Effects of fetal antiepileptic drug exposure 
Meador, K.J. | Baker, G.A. | Browning, N. | Cohen, M.J. | Bromley, R.L. | Clayton-Smith, J. | Kalayjian, L.A. | Kanner, A. | Liporace, J.D. | Pennell, P.B. | Privitera, M. | Loring, D.W. | Labiner, David | Moon, Jennifer | Sherman, Scott | Combs Cantrell, Deborah T. | Silver, Cheryl | Goyal, Monisha | Schoenberg, Mike R. | Pack, Alison | Palmese, Christina | Echo, Joyce | Meador, Kimford J. | Loring, David | Pennell, Page | Drane, Daniel | Moore, Eugene | Denham, Megan | Epstein, Charles | Gess, Jennifer | Helmers, Sandra | Henry, Thomas | Motamedi, Gholam | Flax, Erin | Bromfield, Edward | Boyer, Katrina | Dworetzky, Barbara | Cole, Andrew | Halperin, Lucila | Shavel-Jessop, Sara | Barkley, Gregory | Moir, Barbara | Harden, Cynthia | Tamny-Young, Tara | Lee, Gregory | Cohen, Morris | Penovich, Patricia | Minter, Donna | Moore, Layne | Murdock, Kathryn | Liporace, Joyce | Wilcox, Kathryn | Kanner, Andres | Nelson, Michael N. | Rosenfeld, William | Meyer, Michelle | Clayton-Smith, Jill | Mawer, George | Kini, Usha | Martin, Roy | Privitera, Michael | Bellman, Jennifer | Ficker, David | Baade, Lyle | Liow, Kore | Baker, Gus | Booth, Alison | Bromley, Rebecca | Casswell, Miranda | Barrie, Claire | Ramsay, Eugene | Arena, Patricia | Kalayjian, Laura | Heck, Christianne | Padilla, Sonia | Miller, John | Rosenbaum, Gail | Wilensky, Alan | Constantino, Tawnya | Smith, Julien | Adab, Naghme | Veling-Warnke, Gisela | Sam, Maria | O'Donovan, Cormac | Naylor, Cecile | Nobles, Shelli | Santos, Cesar | Holmes, Gregory L. | Druzin, Maurice | Morrell, Martha | Nelson, Lorene | Finnell, Richard | Yerby, Mark | Adeli, Khosrow | Wells, Peter | Browning, Nancy | Blalock, Temperance | Crawford, Todd | Hendrickson, Linda | Jolles, Bernadette | Kunchai, Meghan Kelly | Loblein, Hayley | Ogunsola, Yinka | Russell, Steve | Winestone, Jamie | Wolff, Mark | Zaia, Phyllis | Zajdowicz, Thad
Neurology  2012;78(16):1207-1214.
To examine outcomes at age 4.5 years and compare to earlier ages in children with fetal antiepileptic drug (AED) exposure.
The NEAD Study is an ongoing prospective observational multicenter study, which enrolled pregnant women with epilepsy on AED monotherapy (1999–2004) to determine if differential long-term neurodevelopmental effects exist across 4 commonly used AEDs (carbamazepine, lamotrigine, phenytoin, or valproate). The primary outcome is IQ at 6 years of age. Planned analyses were conducted using Bayley Scales of Infant Development (BSID at age 2) and Differential Ability Scale (IQ at ages 3 and 4.5).
Multivariate intent-to-treat (n = 310) and completer (n = 209) analyses of age 4.5 IQ revealed significant effects for AED group. IQ for children exposed to valproate was lower than each other AED. Adjusted means (95% confidence intervals) were carbamazepine 106 (102–109), lamotrigine 106 (102–109), phenytoin 105 (102–109), valproate 96 (91–100). IQ was negatively associated with valproate dose, but not other AEDs. Maternal IQ correlated with child IQ for children exposed to the other AEDs, but not valproate. Age 4.5 IQ correlated with age 2 BSID and age 3 IQ. Frequency of marked intellectual impairment diminished with age except for valproate (10% with IQ <70 at 4.5 years). Verbal abilities were impaired for all 4 AED groups compared to nonverbal skills.
Adverse cognitive effects of fetal valproate exposure persist to 4.5 years and are related to performances at earlier ages. Verbal abilities may be impaired by commonly used AEDs. Additional research is needed.
PMCID: PMC3324322  PMID: 22491865
21.  Peripancreatic intranodal haemangioma mimicking pancreatic neuroendocrine tumour: imaging and pathological findings 
The British Journal of Radiology  2011;84(1008):e236-e239.
Haemangiomas are common benign tumours that are generally detected within the skin, mucosal surfaces and soft tissues. However, intranodal haemangiomas are extremely rare and are among the benign primary vascular abnormalities of the lymph nodes that include lymphangioma, haemangioendothelioma, angiomyomatous hamartoma and haemangiomas. In this case report, we present the imaging and pathological findings of an intranodal haemangioma in the pancreatic head simulating a pancreatic neuroendocrine tumour. To the best of our knowledge, this is the first report of an intranodal haemangioma in this location.
PMCID: PMC3473830  PMID: 22101590
22.  Adverse events among children in Canadian hospitals: the Canadian Paediatric Adverse Events Study 
Limited data are available on adverse events among children admitted to hospital. The Canadian Paediatric Adverse Events Study was done to describe the epidemiology of adverse events among children in hospital in Canada.
We performed a 2-stage medical record review at 8 academic pediatric centres and 14 community hospitals in Canada. We reviewed charts from patients admitted from April 2008 through March 2009, evenly distributed across 4 age groups (0 to 28 d; 29 to 365 d; > 1 to 5 yr and > 5 to 18 yr). In stage 1, nurses and health records personnel who had received training in the use of the Canadian Paediatric Trigger Tool reviewed medical records to detect triggers for possible adverse events. In stage 2, physicians reviewed the charts identified as having triggers and described the adverse events.
A total of 3669 children were admitted to hospital during the study period. The weighted rate of adverse events was 9.2%. Adverse events were more frequent in academic pediatric centres than in community hospitals (adjusted odds ratio [OR] 2.98, 95% confidence interval [CI] 1.65–5.39). The incidence of preventable adverse events was not significantly different between types of hospital, but nonpreventable adverse events were more common in academic pediatric centres (adjusted OR 4.39, 95% CI 2.08–9.27). Surgical events predominated overall and occurred more frequently in academic pediatric centres than in community hospitals (37.2% v. 21.5%, relative risk [RR] 1.7, 95% CI 1.0–3.1), whereas events associated with diagnostic errors were significantly less frequent (11.1% v. 23.1%, RR 0.5, 95% CI 0.2–0.9).
More children have adverse events in academic pediatric centres than in community hospitals; however, adverse events in the former are less likely to be preventable. There are many opportunities to reduce harm affecting children in hospital in Canada, particularly related to surgery, intensive care and diagnostic error.
PMCID: PMC3447037  PMID: 22847964
23.  Child development following in utero exposure 
Neurology  2011;76(4):383-389.
Children born to women with epilepsy (WWE), exposed in utero to levetiracetam (LEV, n = 51), were assessed for early cognitive development and compared to children exposed to sodium valproate in utero (VPA, n = 44) and a group of children representative of the general population (n = 97).
Children were recruited prospectively from 2 cohorts in the United Kingdom and assessed using the Griffiths Mental Development Scale (1996), aged <24 months. Information regarding maternal demographics were collected and controlled for. This is an observational study with researchers not involved in the clinical management of the WWE.
On overall developmental ability, children exposed to LEV obtained higher developmental scores when compared to children exposed to VPA (p < 0.001). When compared, children exposed to LEV did not differ from control children (p = 0.62) on overall development. Eight percent of children exposed to LEV in utero fell within the below average range (DQ score of <84), compared with 40% of children exposed to VPA. After controlling for maternal epilepsy and demographic factors using linear regression analysis, exposure to LEV in utero was not associated with outcome (p = 0.67). Conversely, when compared with VPA exposure, LEV exposure was associated with higher scores for the overall developmental quotient (p < 0.001).
Children exposed to LEV in utero are not at an increased risk of delayed early cognitive development under the age of 24 months. LEV may therefore be a preferable drug choice, where appropriate, for WWE prior to and of childbearing age.
PMCID: PMC3271390  PMID: 21263139
24.  Central giant cell granuloma of the mandibular condyle: a case report and review of the literature 
Dentomaxillofacial Radiology  2011;40(1):60-64.
Central giant cell granuloma (CGCG) is a benign intraosseous lesion. The true nature of this lesion is controversial and remains unknown; the three competing theories are that it could be a reactive lesion, a developmental anomaly or a benign neoplasm. Furthermore, the actual aetiology of CGCG is still unclear, although inflammation, haemorrhage and local trauma have all been suggested; it has also been hypothesized that CGCG may have a genetic aetiology. Lesions central to the mandibular condylar head are very rare, with only three documented cases in the English language literature, none of which elaborates on the CT features.
In this case report, a 31-year-old male patient complaining of a left pre-auricular mass underwent radiographic investigation. CT images revealed a lesion central to the mandibular condyle and demonstrated features that were highly suggestive of CGCG. The patient underwent surgical curettage, and the subsequent histopathological examination confirmed the diagnosis of CGCG. 3 years after the procedure the patient presented with a recurrence and underwent complete resection of the mandibular condyle with immediate reconstruction.
This report presents CT characteristics of a rare occurrence of CGCG of the mandibular condyle, compares it with other published cases and poses the question of the role of radiology in predicting the degree of aggressive behaviour of these lesions before surgery.
PMCID: PMC3611462  PMID: 21159917
granuloma; giant cell; giant cell granuloma; jaw diseases
25.  Effects of breastfeeding in children of women taking antiepileptic drugs(e–Pub ahead of print)(Patient Page) 
Neurology  2010;75(22):1954-1960.
Breastfeeding is known to have beneficial effects, but there is concern that breastfeeding during antiepileptic drug (AED) therapy may be harmful to cognitive development. Animal and human studies have demonstrated that some AEDs can adversely affect the immature brain. However, no investigation has examined effects of breastfeeding during AED therapy on subsequent cognitive abilities in children.
The Neurodevelopmental Effects of Antiepileptic Drugs Study is an ongoing prospective multicenter observational investigation of long-term effects of in utero AED exposure on cognition. Between 1999 and 2004, we enrolled pregnant women with epilepsy who were taking a single AED (carbamazepine, lamotrigine, phenytoin, or valproate). We recently reported on differential AED effects on age 3 year cognitive outcomes. In this report, we focus on the effects of breastfeeding during AED therapy on age 3 cognitive outcomes in 199 children.
A total of 42% of children were breastfed. IQs for breastfed children did not differ from nonbreastfed children for all AEDs combined and for each of the 4 individual AED groups. Mean adjusted IQ scores (95% confidence intervals) across all AEDs were breastfed = 99 (96–103) and nonbreastfed = 98 (95–101). Power was 95% to detect a half SD IQ effect in the combined AED analysis, but was inadequate within groups.
This preliminary analysis fails to demonstrate deleterious effects of breastfeeding during AED therapy on cognitive outcomes in children previously exposed in utero. However, caution is advised due to study limitations. Additional research is needed to confirm this observation and extend investigations to other AEDs and polytherapy.
= antiepileptic drug;
= National Adult Reading Test;
= Neurodevelopmental Effects of Antiepileptic Drugs;
= Test of Nonverbal Intelligence;
= Wechsler Abbreviated Scale of Intelligence.
PMCID: PMC3014232  PMID: 21106960

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