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1.  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: 25523134
Productive ward; Releasing time to care; Organizing for quality; Nursing; Qualitative methodology; Quality improvement capacity; Change mechanisms
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  Celastrol inhibits aminoglycoside-induced ototoxicity via heat shock protein 32 
Cell Death & Disease  2011;2(8):e195-.
Hearing loss is often caused by death of the mechanosensory hair cells of the inner ear. Hair cells are susceptible to death caused by aging, noise trauma, and ototoxic drugs, including the aminoglycoside antibiotics and the antineoplastic agent cisplatin. Ototoxic drugs result in permanent hearing loss for over 500 000 Americans annually. We showed previously that induction of heat shock proteins (HSPs) inhibits both aminoglycoside- and cisplatin-induced hair cell death in whole-organ cultures of utricles from adult mice. In order to begin to translate these findings into a clinical therapy aimed at inhibiting ototoxic drug-induced hearing loss, we have now examined a pharmacological HSP inducer, celastrol. Celastrol induced upregulation of HSPs in utricles, and it provided significant protection against aminoglycoside-induced hair cell death in vitro and in vivo. Moreover, celastrol inhibited hearing loss in mice receiving systemic aminoglycoside treatment. Our data indicate that the major heat shock transcription factor HSF-1 is not required for celastrol-mediated protection. HSP32 (also called heme oxygenase-1, HO-1) is the primary mediator of the protective effect of celastrol. HSP32/HO-1 inhibits pro-apoptotic c-Jun N-terminal kinase (JNK) activation and hair cell death. Taken together, our data indicate that celastrol inhibits aminoglycoside ototoxicity via HSP32/HO-1 induction.
PMCID: PMC3181421  PMID: 21866174
ototoxicity; hair cell; celastrol; heat shock protein; utricle; cochlea; hearing loss
18.  Adverse antiepileptic drug effects in new-onset seizures 
Neurology  2011;76(3):273-279.
Adverse effects (AEs) are a major concern when starting antiepileptic drug (AED) treatment. This study quantified the extent to which AE reporting in people with new-onset seizures started on AEDs is attributable to the medication per se, and investigated variables contributing to AE reporting.
We pooled data from 2 large prospective studies, the Multicenter Study of Early Epilepsy and Single Seizures and the Northern Manhattan Study of incident unprovoked seizures, and compared adverse event profile (AEP) total and factor scores between adult cases prescribed AEDs for new-onset seizures and untreated controls, adjusting for several demographic and clinical variables. Differences in AEP scores were also tested across different AED monotherapies and controls, and between cases and controls grouped by number of seizures.
A total of 212 cases and 206 controls were identified. Most cases (94.2%) were taking low AED doses. AEP scores did not differ significantly between the 2 groups. Depression, female gender, symptomatic etiology, younger seizure onset age, ≥2 seizures, and history of febrile seizures were associated with higher AEP scores. There were no significant differences in AEP scores across different monotherapies and controls. AEP scores increased in both cases and controls with increasing number of seizures, the increment being more pronounced in cases.
When AED treatment is started at low doses following new-onset seizures, AE reporting does not differ from untreated individuals. Targeting specific factors affecting AE reporting could lead to improved tolerability of epilepsy treatment.
PMCID: PMC3034391  PMID: 21242496
19.  The contribution of case study research to knowledge of how to improve quality of care 
BMJ quality & safety  2011;20(Suppl_1):i30-i35.
Efforts to improve the implementation of effective practice and to speed up improvements in quality and patient safety continue to pose challenges for researchers and policy makers. Organisational research, and, in particular, case studies of quality improvement, offer methods to improve understanding of the role of organisational and microsystem contexts for improving care and the development of theories which might guide improvement strategies.
This paper reviews examples of such research and details the methodological issues in constructing and analysing case studies. Case study research typically collects a wide array of data from interviews, documents and other sources.
Advances in methods for coding and analysing these data are improving the quality of reports from these studies.
PMCID: PMC3066793  PMID: 21450767
Quality improvement; case study; qualitative research; healthcare quality improvement; research
20.  Pregnancy with epilepsy: obstetric and neonatal outcome of a controlled study 
to determine the influence of epilepsy and its treatment on pregnancy and its outcome.
controlled, observational study.
National Health Service maternity hospitals in Liverpool and Manchester regions.
277 women with epilepsy (WWE) and 315 control women.
WWE were recruited from antenatal clinics. Controls were matched for age and parity but not gestational age. Information was obtained by interview and from clinical records. Main Outcome Measures: obstetric complications, mode of delivery, condition of newborn.
Distribution of epilepsy syndromes was similar to previous surveys. Most WWE (67%) received monotherapy with carbamazepine, sodium valproate or lamotrigine. Half WWE had no seizures during pregnancy but 34% had tonic clonic seizures. Seizure related injuries were infrequent. Pregnancies with obstetric complications were increased in women with treated epilepsy (WWTE 45%, controls 33%; p = 0.01). Most had normal vaginal delivery (WWTE 63%, controls 61%; p = 0.65). Low birth weight was not increased (WWTE 6.2%, controls 5.2%; p = 0.69). There were more major congenital malformations (MCM) (WWTE 6.6%, controls 2.1%; p = 0.02) and fetal/infant deaths (WWTE 2.2%, controls 0.3%; p = 0.09). Amongst monotherapies MCM prevalence was highest with valproate (11.3%; p = 0.005). Lamotrigine (5.4%; p = 0.23) and carbamazepine (3.0%; p = 0.65) were closer to controls (2.1%). There was no association between MCM and dose of folic acid preconception.
MCM were more prevalent in the babies of WWTE particularly amongst those receiving sodium valproate.
PMCID: PMC2823982  PMID: 20036166
Epilepsy; Antiepileptic drugs; Pregnancy outcome; Teratogenicity
21.  Genetic loss of D-amino acid oxidase activity reverses schizophrenia-like phenotypes in mice 
Genes, brain, and behavior  2009;9(1):11-25.
Reduced function of the N-methyl-D-aspartate receptor (NMDAR) has been implicated in the pathophysiology of schizophrenia. The NMDAR contains a glycine binding site in its NR1 subunit that may be a useful target for the treatment of schizophrenia. In this study, we assessed the therapeutic potential of long-term increases in the brain levels of the endogenous NMDAR glycine site agonist D-serine, through the genetic inactivation of its catabolic enzyme D-amino acid oxidase (DAO) in mice. The effects of eliminating DAO function were investigated in mice that display schizophrenia-related behavioral deficits due to a mutation (Grin1D481N) in the NR1 subunit that results in a reduction in NMDAR glycine affinity. Grin1D481N mice show deficits in sociability, prolonged latent inhibition, enhanced startle reactivity, and impaired spatial memory. The hypofunctional Dao1G181R mutation elevated brain levels of D-serine, but alone it did not affect performance in the behavioral measures. Compared to animals with only the Grin1D481N mutation, mice with both the Dao1G181R and Grin1D481N mutations displayed an improvement in social approach and spatial memory retention, as well as a reversal of abnormally persistent latent inhibition and a partial normalization of startle responses. Thus, an increased level of D-serine resulting from decreased catalysis corrected the performance of mice with deficient NMDAR glycine site activation in behavioral tasks relevant to the negative and cognitive symptoms of schizophrenia. Diminished DAO activity and elevations in D-serine may serve as an effective therapeutic intervention for the treatment of psychiatric symptoms.
PMCID: PMC2824030  PMID: 19751394
NMDA receptor; D-serine; D-amino acid oxidase; genetic mouse model; schizophrenia; social behaviors; latent inhibition; spatial memory
22.  Description of the development and validation of the Canadian Paediatric Trigger Tool 
BMJ quality & safety  2011;20(5):416-423.
To describe the process of developing and validating the Canadian Association of Paediatric Health Centres Trigger Tool (CPTT).
Five existing trigger tools were consolidated with duplicate triggers eliminated. After a risk analysis and modified Delphi process, the tool was reduced from 94 to 47 triggers. Feasibility of use was tested, reviewing 40 charts in three hospitals. For validation, charts were randomly selected across four age groups, half medical/half surgical diagnoses, from six paediatric academic health sciences centres. 591 charts were reviewed by six nurses (for triggers and adverse events (AEs)) and three physicians (for AEs only). The incidence of trigger- and AE-positive charts was documented, and the sensitivity and specificity of the tool to identify charts with AEs were determined. Identification of AEs by nurses and physicians was compared. The positive predictive value (PPV) of each trigger was calculated and the ratio of false- to true-positive AE predictors analysed for each trigger.
Nurses rated the CPTT easy to use and identified triggers in 61.1% (361/591; 95% CI 57.2 to 65.0) of patient charts; physicians identified AEs in 15.1% (89/ 591, 95% CI 0.23 to 0.43). Over a third of patients with AEs were neonates. The sensitivity and specificity were 0.88 and 0.44, respectively. Nurse and physician AE assessments correlated poorly. The PPV for each trigger ranged from 0 to 88.3%. Triggers with a false/true-positive ratio of >0.7 were eliminated, resulting in the final 35-trigger CPTT.
The CPTT is the first validated, comprehensive trigger tool available to detect AEs in children hospitalised in acute care facilities.
PMCID: PMC3088437  PMID: 21242527
Trigger; adverse event; harm; patient safety; research
23.  Adverse Event Reporting for Herbal Medicines: A Result of Market Forces 
Healthcare Policy  2009;4(4):77-90.
Herbal products are readily available over the counter in health food stores and are often perceived to be without risk. The current Canadian adverse event reporting system suffers from severe underreporting, resulting in a scarcity of safety data on herbal products. Twelve health food store personnel in the Greater Toronto Area were interviewed about their responses to herbal product–related adverse reactions. They generally fostered customer loyalty by offering generous return policies, which included collecting contact information to be sent to the manufacturers with the returned product. Thus, despite the public's lack of knowledge about the formal reporting system, adverse reaction information was directed to manufacturers whenever it resulted in a product return. The relationship between health food stores, industry and Health Canada provides a new opportunity to facilitate adverse event reporting. Additional information could be collected during the return process, and educational initiatives could be implemented to augment current post-market surveillance procedures for herbal products.
PMCID: PMC2700706  PMID: 20436811
24.  Consumers of natural health products: natural-born pharmacovigilantes? 
Natural health products (NHPs), such as herbal medicines and vitamins, are widely available over-the-counter and are often purchased by consumers without advice from a healthcare provider. This study examined how consumers respond when they believe they have experienced NHP-related adverse drug reactions (ADRs) in order to determine how to improve current safety monitoring strategies.
Qualitative semi-structured interviews were conducted with twelve consumers who had experienced a self-identified NHP-related ADR. Key emergent themes were identified and coded using content analysis techniques.
Consumers were generally not comfortable enough with their conventional health care providers to discuss their NHP-related ADRs. Consumers reported being more comfortable discussing NHP-related ADRs with personnel from health food stores, friends or family with whom they had developed trusted relationships. No one reported their suspected ADR to Health Canada and most did not know this was possible.
Consumers generally did not report their suspected NHP-related ADRs to healthcare providers or to Health Canada. Passive reporting systems for collecting information on NHP-related ADRs cannot be effective if consumers who experience NHP-related ADRs do not report their experiences. Healthcare providers, health food store personnel, manufacturers and other stakeholders also need to take responsibility for reporting ADRs in order to improve current pharmacovigilance of NHPs.
PMCID: PMC2847952  PMID: 20184759
25.  Strengthening the contribution of quality improvement research to evidence based health care 
Quality & Safety in Health Care  2006;15(3):150-151.
Better reporting of quality improvement efforts could assist in the design of effectiveness research
PMCID: PMC2464846  PMID: 16751459
quality improvement; evidence; guidelines; research methods

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