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1.  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.
doi:10.1371/journal.pone.0085370
PMCID: PMC3885698  PMID: 24416396
2.  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.
doi:10.1016/j.yebeh.2012.05.010
PMCID: PMC3483041  PMID: 22749607
Epilepsy; seizures; Antiepileptic drugs; Pregnancy; Neonatal; microcephaly; Small for Gestational Age (SGA); Apgar; Observational cohort study
3.  Adverse events among Ontario home care clients associated with emergency room visit or hospitalization: a retrospective cohort study 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1472-6963-13-227
PMCID: PMC3751652  PMID: 23800280
4.  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.
Objective:
To examine outcomes at age 4.5 years and compare to earlier ages in children with fetal antiepileptic drug (AED) exposure.
Methods:
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).
Results:
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.
Conclusions:
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.
doi:10.1212/WNL.0b013e318250d824
PMCID: PMC3324322  PMID: 22491865
5.  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.
doi:10.1259/bjr/77657029
PMCID: PMC3473830  PMID: 22101590
6.  Adverse events among children in Canadian hospitals: the Canadian Paediatric Adverse Events Study 
Background:
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.
Methods:
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.
Results:
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).
Interpretation:
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.
doi:10.1503/cmaj.112153
PMCID: PMC3447037  PMID: 22847964
7.  Child development following in utero exposure 
Neurology  2011;76(4):383-389.
Objective:
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).
Methods:
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.
Results:
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).
Conclusion:
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.
doi:10.1212/WNL.0b013e3182088297
PMCID: PMC3271390  PMID: 21263139
8.  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.
doi:10.1259/dmfr/85668294
PMCID: PMC3611462  PMID: 21159917
granuloma; giant cell; giant cell granuloma; jaw diseases
9.  Effects of breastfeeding in children of women taking antiepileptic drugs(e–Pub ahead of print)(Patient Page) 
Neurology  2010;75(22):1954-1960.
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
GLOSSARY
= antiepileptic drug;
= National Adult Reading Test;
= Neurodevelopmental Effects of Antiepileptic Drugs;
= Test of Nonverbal Intelligence;
= Wechsler Abbreviated Scale of Intelligence.
doi:10.1212/WNL.0b013e3181ffe4a9
PMCID: PMC3014232  PMID: 21106960
10.  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.
doi:10.1038/cddis.2011.76
PMCID: PMC3181421  PMID: 21866174
ototoxicity; hair cell; celastrol; heat shock protein; utricle; cochlea; hearing loss
11.  Adverse antiepileptic drug effects in new-onset seizures 
Neurology  2011;76(3):273-279.
Objective:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
doi:10.1212/WNL.0b013e318207b073
PMCID: PMC3034391  PMID: 21242496
12.  The contribution of case study research to knowledge of how to improve quality of care 
BMJ quality & safety  2011;20(Suppl_1):i30-i35.
Background
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.
Methods
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.
Conclusion
Advances in methods for coding and analysing these data are improving the quality of reports from these studies.
doi:10.1136/bmjqs.2010.046490
PMCID: PMC3066793  PMID: 21450767
Quality improvement; case study; qualitative research; healthcare quality improvement; research
13.  Pregnancy with epilepsy: obstetric and neonatal outcome of a controlled study 
Purpose
to determine the influence of epilepsy and its treatment on pregnancy and its outcome.
Design
controlled, observational study.
Setting
National Health Service maternity hospitals in Liverpool and Manchester regions.
Population
277 women with epilepsy (WWE) and 315 control women.
Methods
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.
Results
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.
Conclusion
MCM were more prevalent in the babies of WWTE particularly amongst those receiving sodium valproate.
doi:10.1016/j.seizure.2009.11.008
PMCID: PMC2823982  PMID: 20036166
Epilepsy; Antiepileptic drugs; Pregnancy outcome; Teratogenicity
14.  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.
doi:10.1111/j.1601-183X.2009.00529.x
PMCID: PMC2824030  PMID: 19751394
NMDA receptor; D-serine; D-amino acid oxidase; genetic mouse model; schizophrenia; social behaviors; latent inhibition; spatial memory
15.  Description of the development and validation of the Canadian Paediatric Trigger Tool 
BMJ quality & safety  2011;20(5):416-423.
Objective
To describe the process of developing and validating the Canadian Association of Paediatric Health Centres Trigger Tool (CPTT).
Methods
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.
Results
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.
Conclusions
The CPTT is the first validated, comprehensive trigger tool available to detect AEs in children hospitalised in acute care facilities.
doi:10.1136/bmjqs.2010.041152
PMCID: PMC3088437  PMID: 21242527
Trigger; adverse event; harm; patient safety; research
16.  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
17.  Consumers of natural health products: natural-born pharmacovigilantes? 
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/1472-6882-10-8
PMCID: PMC2847952  PMID: 20184759
18.  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
doi:10.1136/qshc.2005.017103
PMCID: PMC2464846  PMID: 16751459
quality improvement; evidence; guidelines; research methods
19.  Persistence of unsafe practice in everyday work: an exploration of organizational and psychological factors constraining safety in the operating room 
Quality & Safety in Health Care  2006;15(3):165-170.
This paper explores the factors that influence the persistence of unsafe practice in an interprofessional team setting in health care, towards the development of a descriptive theoretical model for analyzing problematic practice routines. Using data collected during a mixed method interview study of 28 members of an operating room team, participants' approaches to unsafe practice were analyzed using the following three theoretical models from organizational and cognitive psychology: Reason's theory of “vulnerable system syndrome”, Tucker and Edmondson's concept of first and second order problem solving, and Amalberti's model of practice migration. These three theoretical approaches provide a critical insight into key trends in the interview data, including team members' definition of error as the breaching of standards of practice, nurses' sense of scope of practice as a constraint on their reporting behaviours, and participants' reports of the forces influencing tacit agreements to work around safety regulations. However, the relational factors underlying unsafe practice routines are poorly accounted for in these theoretical approaches. Incorporating an additional theoretical construct such as “relational coordination” to account for the emotional human features of team practice would provide a more comprehensive theoretical approach for use in exploring unsafe practice routines and the forces that sustain them in healthcare team settings.
doi:10.1136/qshc.2005.017475
PMCID: PMC2464856  PMID: 16751464
patient safety; organisational factors; teamwork
20.  Preserving professional credibility: grounded theory study of medical trainees’ requests for clinical support 
Objective To develop a conceptual framework of the influences on medical trainees’ decisions regarding requests for clinical support from a supervisor.
Design Phase 1: members of teaching teams in internal and emergency medicine were observed during regular clinical activities (216 hours) and subsequently completed brief interviews. Phase 2: 36 in depth interviews were conducted using videotaped vignettes to probe tacit influences on decisions to request support. Data collection and analysis used grounded theory methods.
Setting Three teaching hospitals in an urban setting in Canada.
Participants 124 members of teaching teams on general internal medicine wards and in the emergency department, comprising 31 attending physicians, 57 junior and senior residents, 28 medical students, and eight nurses. Purposeful sampling to saturation was conducted.
Results Trainees’ decisions about whether or not to seek clinical support were influenced by three issues: the clinical question (clinical importance, scope of practice), supervisor factors (availability, approachability), and trainee factors (skill, desire for independence, evaluation). Trainees perceived that requesting frequent/inappropriate support threatened their credibility and used rhetorical strategies to preserve credibility. These strategies included building a case for the importance of requests, saving requests for opportune moments, making a plan before requesting support, and targeting requests to specific team members.
Conclusions Trainees consider not only clinical implications but also professional credibility when requesting support from clinical supervisors. Exposing the complexity of this process provides the opportunity to make changes to training programmes to promote timely supervision and provides a framework for further exploration of the impact of clinical training on quality of care of patients.
doi:10.1136/bmj.b128
PMCID: PMC2640114  PMID: 19204035
21.  Emergency Planning in Ontario's Acute Care Hospitals: A Survey of Board Chairs 
Healthcare Policy  2008;3(3):64-74.
Background:
Effective hospital governance depends on proactive board leadership to minimize risk.
Study Aim:
To survey hospital board chairs about governance practices, particularly with respect to approval processes for oversight of management preparedness for unforeseen emergencies.
Methods:
A 2004 survey of hospital managers initially suggested greater board leadership in risk management as a desired strategic priority for Ontario's acute care hospitals. Our literature review and panel process defined 34 best practices in board governance, including two practices explicitly addressing the board's role in preparing for risk.
Results:
Our findings revealed that some boards may not be actively engaged in ensuring that adequate processes are in place to protect against risk. More than one-quarter (n=28, 26.9%) of board chairs reported that they had not approved a management plan to address emergencies. Thirty respondents (28.8%) said they had not approved a process to identify, manage and minimize risks to the hospital's sustainability. Forty-seven respondents (45.2%) said they had not approved both of these two processes. A significant association emerged between boards that had approved both risk preparation strategies and boards that had implemented six key governance practices relating to accountability for leadership and stakeholder communication.
PMCID: PMC2645143  PMID: 19305769
22.  Getting teams to talk: development and pilot implementation of a checklist to promote interprofessional communication in the OR 
Quality & safety in health care  2005;14(5):340-346.
Background: Pilot studies of complex interventions such as a team checklist are an essential precursor to evaluating how these interventions affect quality and safety of care. We conducted a pilot implementation of a preoperative team communication checklist. The objectives of the study were to assess the feasibility of the checklist (that is, team members' willingness and ability to incorporate it into their work processes); to describe how the checklist tool was used by operating room (OR) teams; and to describe perceived functions of the checklist discussions.
Methods: A checklist prototype was developed and OR team members were asked to implement it before 18 surgical procedures. A research assistant was present to prompt the participants, if necessary, to initiate each checklist discussion. Trained observers recorded ethnographic field notes and 11 brief feedback interviews were conducted. Observation and interview data were analyzed for trends.
Results: The checklist was implemented by the OR team in all 18 study cases. The rate of team participation was 100% (33 vascular surgery team members). The checklist discussions lasted 1–6 minutes (mean 3.5) and most commonly took place in the OR before the patient's arrival. Perceived functions of the checklist discussions included provision of detailed case related information, confirmation of details, articulation of concerns or ambiguities, team building, education, and decision making. Participants consistently valued the checklist discussions. The most significant barrier to undertaking the team checklist was variability in team members' preoperative workflow patterns, which sometimes presented a challenge to bringing the entire team together.
Conclusions: The preoperative team checklist shows promise as a feasible and efficient tool that promotes information exchange and team cohesion. Further research is needed to determine the sustainability and generalizability of the checklist intervention, to fully integrate the checklist routine into workflow patterns, and to measure its impact on patient safety.
doi:10.1136/qshc.2004.012377
PMCID: PMC1744073  PMID: 16195567
23.  Clinical Oversight: Conceptualizing the Relationship Between Supervision and Safety 
Journal of General Internal Medicine  2007;22(8):1080-1085.
Background
Concern about the link between clinical supervision and safe, quality health care has led to widespread increases in the supervision of medical trainees. The effects of increased supervision on patient care and trainee education are not known, primarily because the current multifacted and poorly operationalized concept of clinical supervision limits the potential for evaluation.
Objective
To develop a conceptual model of clinical supervision to inform and guide policy and research.
Design, Setting, and Participants
Observational fieldwork and interviews were conducted in the Emergency Department and General Internal Medicine in-patient teaching wards of two academic health sciences centers associated with an urban Canadian medical school. Members of 12 Internal Medicine and Emergency Medicine teaching teams (n = 88) were observed during regular clinical activities (216 hours). Sixty-five participants (12 physicians, 28 residents, 17 medical students, 8 nurses) also completed interviews about supervision. Field notes and interview transcripts were analyzed for emergent themes using grounded theory methodology.
Results
The term “clinical oversight” was developed to describe patient care activities performed by supervisors to ensure quality of care. “Routine oversight” (preplanned monitoring of trainees’ clinical work) can expose supervisors to concerns that trigger “responsive oversight” (a double-check or elaboration of trainees’ clinical work). Supervisors sometimes engage in “backstage oversight” (oversight of which the trainee is not directly aware). When supervisors encounter a situation that exceeds a trainee’s competence, they move beyond clinical oversight to “direct patient care”.
Conclusions
This study elaborates a typology of clinical oversight activities including routine, responsive, and backstage oversight. This new typology provides a framework for clinical supervision policy and for research to evaluate the relationship between supervision and safety.
doi:10.1007/s11606-007-0179-3
PMCID: PMC2305735  PMID: 17557190
qualitative research; grounded theory methodology; medical education; professionalism; patient safety
24.  Development and Organization of Ocular Dominance Bands in Primary Visual Cortex of the Sable Ferret 
Thalamocortical afferents in the visual cortex of the adult sable ferret are segregated into eye-specific ocular dominance bands. The development of ocular dominance bands was studied by transneuronal labeling of the visual cortices of ferret kits between the ages of postnatal day 28 (P28) and P81 after intravitreous injections of either tritiated proline or wheat germ agglutinin-horseradish peroxidase. Laminar specificity was evident in the youngest animals studied and was similar to that in the adult by P50. In P28 and P30 ferret kits, no modulation reminiscent of ocular dominance bands was detectable in the pattern of labeling along layer IV. By P37 a slight fluctuation in the density of labeling in layer IV was evident in serial reconstructions. By P50, the amplitude of modulation had increased considerably but the pattern of ocular dominance bands did not yet appear mature. The pattern and degree of modulation of the ocular dominance bands resembled that in adult animals by P63. Flat mounts of cortex and serial reconstructions of layer IV revealed an unusual arrangement of inputs serving the two eyes in the region rostral to the periodic ocular dominance bands. In this region, inputs serving the contralateral eye were commonly fused along a mediolateral axis, rostral to which were large and sometimes fused patches of ipsilateral input.
PMCID: PMC2453001  PMID: 10213088
area 17; transneuronal; cortical columns; thalamocortical; functional architecture; critical period
25.  The expression of p53-induced protein with death domain (Pidd) and apoptosis in oral squamous cell carcinoma 
British Journal of Cancer  2007;96(9):1425-1432.
The Pidd (p53-induced protein with death domain) gene was shown to be induced by the tumour suppressor p53 and to mediate p53-dependent apoptosis in mouse and human cells, through interactions with components of both the mitochondrial and the death receptor signalling pathways. To study the role of Pidd in clinical tumours, we measured its expression by quantitative reverse transcription-PCR in microdissected oral squamous cell carcinomas (OSCC) with and without p53 mutation. Tumour cell apoptosis was assessed by in situ terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling. Tumour proliferation was assessed by immunohistochemical staining for the Ki-67 antigen. We found a wide range of Pidd expression among OSCC. Statistical analysis revealed an association between Pidd expression and apoptotic index (Mann–Whitney test, P<0.001), consistent with a role of Pidd in apoptosis in this tumour type. Furthermore, we showed a positive correlation between apoptotic index and proliferative index that has not been previously described for OSCC. There was no correlation between Pidd expression and the p53 mutation status of these tumours, suggesting that Pidd expression may be regulated by p53-independent mechanisms. Further characterisation of these molecular defects in the control of proliferation and apoptosis should help in developing treatments that target OSCC according to their biological properties.
doi:10.1038/sj.bjc.6603745
PMCID: PMC2360189  PMID: 17437012
Pidd; apoptosis; p53; oral; carcinoma

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