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1.  Unravelling the extent of inequalities in health across urban and rural areas: Evidence from a national sample in England☆ 
Social science & medicine (1982)  2008;68(4):654-663.
Studies of inequalities in health between rural and urban settings have produced mixed and sometimes conflicting results, depending on the national setting of the study, the level of geographic detail used to define rural areas and the health indicators studied. By focusing on morbidity data from a national sample of individuals, this study aims to examine the extent of inequalities in health between urban and rural areas, as well as inequalities in health across rural areas of England. Multilevel analyses for poor self-rated health, overweight and obesity, and common mental disorders are reported for a sample of 30,776 individuals aged 18 years and older (obtained from the Health Survey for England years 2000–2003 combined) and distributed across 3645 small areas classed in four categories: two groups of urban areas (Greater London area or ‘other cities’) and two types of rural settings (semi-rural areas or villages). Results show that rural dwellers were significantly less likely than residents of urban areas to report their health as being fair or poor and to report common mental disorders, independent of their socio-demographic characteristics. However, as for urban settlements, there were significant variations in health across semi-rural areas and across villages, indicating the presence of health inequalities within rural settings in England. These inequalities were not fully explained by the individual composition of the areas or by the available measures of area socioeconomic conditions, indicating that in rural contexts more specific factors may have significance for health. Different policies and services for health promotion and care may need to be targeted to different types of rural areas.
PMCID: PMC5148618  PMID: 19108940 CAMSID: cams738
Rural health; Small area analysis; United Kingdom; Multilevel modelling; Health inequalities
2.  Evaluation of CD46 re-targeted adenoviral vectors for clinical ovarian cancer intraperitoneal therapy 
Cancer gene therapy  2016;23(7):229-234.
Ovarian cancer accounts for over 140 000 deaths globally each year. Typically disease is asymptomatic until an advanced, incurable stage. Although response to cytotoxic chemotherapy is frequently observed, resistance to conventional platinum-based therapies develop rapidly. Improved treatments are therefore urgently required. Virotherapy offers great potential for ovarian cancer, where the application of local, intraperitoneal delivery circumvents some of the limitations of intravenous strategies. To develop effective, adenovirus (Ad)-based platforms for ovarian cancer, we profiled the fluid and cellular components of patient ascites for factors known to influence adenoviral transduction. Levels of factor X (FX) and neutralising antibodies (nAbs) in ascitic fluid were quantified and tumour cells were assessed for expression of coxsackie virus and adenovirus receptor (CAR) and CD46. We show that clinical ascites contains significant levels of FX but consistently high CD46 expression. We therefore evaluated in vitro the relative transduction of EOCs by Ad5 (via CAR) and Ad5 pseudotyped with the fiber of Ad35 (Ad5T*F35++) via CD46. Ad5T*F35++ achieved significantly increased transduction in comparison to Ad5 (P<0.001), independent of FX and nAb levels. We therefore propose selective transduction of CD46 over-expressing EOCs using re-targeted, CD35-pseudotyped Ad vectors may represent a promising virotherapy for ovarian cancer.
PMCID: PMC4947523  PMID: 27229159
3.  Making needles less prickly 
PMCID: PMC4577351  PMID: 26392339
4.  Associations between adherence and outcomes among older, type 2 diabetes patients: evidence from a Medicare Supplemental database 
Patient preference and adherence  2016;10:1573-1581.
To examine the association between adherence to glucose-lowering agents and patient outcomes, including costs, acute-care resource utilization, and complications, in an older, type 2 diabetic population.
Data and methods
The study used Truven’s Medicare Supplemental database from July 1, 2009 to June 30, 2014. Patients aged 65 years or older were included if they had at least two type 2 diabetes diagnoses and received a glucose-lowering agent from July 1, 2010 through June 30, 2011. Multivariable analyses examined the relationships among 3-year patient outcomes and levels of adherence, proxied by the proportion of days covered. Outcomes included all-cause medical costs, diabetes-related medical costs, acute-care resource utilization, and acute complications.
In this study (N=123,235), higher adherence was linked to reduced costs and improved health outcomes. For example, comparing an individual with adherence of proportion of days covered <20% to one with proportion of days covered ≥80% illustrates an average saving of $28,824 in total 3-year costs. Furthermore, a 1% increase in adherence among 1,000 patients was associated with all-cause savings of $65,464 over 3 years. The probability of a hospitalization, an emergency room (ER) visit, or an acute complication decreased monotonically as adherence levels got higher, as did the number of hospitalizations, ER visits, and days hospitalized (P<0.005).
Higher adherence was associated with substantially less need for acute care, as indicated by a lowered probability of hospitalization or ER use, a reduced risk of an acute complication, and a decreased number of hospitalizations, ER visits, and days hospitalized. Higher adherence was also generally associated with lower all-cause and diabetes-related total costs, despite higher drug costs. These lower total costs were driven by the diminished acute care and outpatient costs. Results suggest that higher glucose-lowering agent adherence is associated with significant benefits for payers and older patients with type 2 diabetes.
PMCID: PMC4993402  PMID: 27574406
proportion of days covered; complications; costs; resource utilization; retrospective study
5.  Preference for pharmaceutical formulation and treatment process attributes 
Patient preference and adherence  2016;10:1385-1399.
Pharmaceutical formulation and treatment process attributes, such as dose frequency and route of administration, can have an impact on quality of life, treatment adherence, and disease outcomes. The aim of this literature review was to examine studies on preferences for pharmaceutical treatment process attributes, focusing on research in diabetes, oncology, osteoporosis, and autoimmune disorders.
The literature search focused on identifying studies reporting preferences for attributes of the pharmaceutical treatment process. Studies were required to use formal quantitative preference assessment methods, such as utility valuation, conjoint analysis, or contingent valuation. Searches were conducted using Medline, EMBASE, Cochrane Library, Health Economic Evaluation Database, and National Health Service Economic Evaluation Database (January 1993–October 2013).
A total of 42 studies met inclusion criteria: 19 diabetes, nine oncology, five osteoporosis, and nine autoimmune. Across these conditions, treatments associated with shorter treatment duration, less frequent administration, greater flexibility, and less invasive routes of administration were preferred over more burdensome or complex treatments. While efficacy and safety often had greater relative importance than treatment process, treatment process also had a quantifiable impact on preference. In some instances, particularly in diabetes and autoimmune disorders, treatment process attributes had greater relative importance than some or all efficacy and safety attributes. Some studies suggested that relative importance of treatment process depends on disease (eg, acute vs chronic) and patient (eg, injection experience) characteristics.
Despite heterogeneity in study methods and design, some general patterns of preference clearly emerged. Overall, the results of this review suggest that treatment process has a quantifiable impact on preference and willingness to pay for treatment, even in many situations where safety and efficacy were the primary concerns. Patient preferences for treatment process attributes can inform drug development decisions to better meet the needs of patients and deliver improved outcomes.
PMCID: PMC4970633  PMID: 27528802
preference; treatment process; pharmaceutical formulation; conjoint; utility; contingent valuation
6.  Magnesium nebulization utilization in management of pediatric asthma (MagNUM PA) trial: study protocol for a randomized controlled trial 
Trials  2016;17:261.
Up to 30 % of children with acute asthma are refractory to initial therapy, and 84 % of this subpopulation needs hospitalization. Finding safe, noninvasive, and effective strategies to treat this high-risk group would substantially decrease hospitalizations, healthcare costs, and the psycho-social burden of the disease.
Whereas intravenous magnesium (Mg) is effective in severe refractory asthma, its use is sporadic due to safety concerns, with the main treatment goal being to prevent intensive care unit admission. In contrast, nebulized Mg is noninvasive, allows higher pulmonary drug concentrations, and has a much higher safety potential due to the lower rate of systemic delivery. Previous studies of inhaled Mg show disparate results due to the use of unknown/inefficient delivery methods and other methodological flaws.
The study is a randomized double-blind controlled trial in seven Canadian pediatric Emergency Departments (two-center pilot 2011 to 2014, Canada-wide November 2014 to December 2017). The trial will include 816 otherwise healthy children who are 2 to 17 years old, having had at least one previous wheezing episode, have received systemic corticosteroids, and have a Pediatric Respiratory Assessment Measure (PRAM) ≥ 5 points after three salbutamol and ipratropium treatments for a current acute asthma exacerbation. Eligible consenting children will receive three experimental treatments of nebulized salbutamol with either 600 mg of Mg sulfate or placebo 20 min apart, using an Aeroneb Go nebulizer, which has been shown to maximize pulmonary delivery while maintaining safety. The primary outcome is hospitalization within 24 h of the start of the experimental therapy for persistent respiratory distress or supplemental oxygen. Secondary outcomes include all-cause hospitalization within 24 h, PRAM, vital signs, number of bronchodilator treatments by 240 min, and the association between the difference in the primary outcome between the groups, age, gender, baseline PRAM, atopy, and “viral induced wheeze” phenotype (Fig. 1).
If effective, inhaled Mg may represent an effective strategy to minimize morbidity in pediatric refractory acute asthma. Unlike previous works, this trial targets nonresponders to optimized initial therapy who are the most likely to benefit from inhaled Mg. Future dissemination of results will include knowledge translation, incorporation into a Cochrane Review, presentation at scientific meetings, and a peer-reviewed publication.
Trial registration
NCTO1429415, registered 2 September 2011.
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-015-1151-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4879727  PMID: 27220675
Randomized controlled trial; children; acute asthma; magnesium
7.  Pseudotyped αvβ6 integrin-targeted adenovirus vectors for ovarian cancer therapies 
Oncotarget  2016;7(19):27926-27937.
Encouraging results from recent clinical trials are revitalizing the field of oncolytic virotherapies. Human adenovirus type 5 (HAdV-C5/Ad5) is a common vector for its ease of manipulation, high production titers and capacity to transduce multiple cell types. However, effective clinical applications are hindered by poor tumor-selectivity and vector neutralization. We generated Ad5/kn48 by pseudotyping Ad5 with the fiber knob domain from the less seroprevalent HAdV-D48 (Ad48). The vector was shown to utilize coxsackie and adenovirus receptor (CAR) but not CD46 for cell entry. A 20-amino acid peptide NAVPNLRGDLQVLAQKVART (A20) was inserted into the Ad5. Luc HI loop (Ad5.HI.A20) and Ad5/kn48 DG loop (Ad5/kn48.DG.A20) to target a prognostic cancer cell marker, αvβ6 integrin. Relative to the Ad5.Luc parent vector, Ad5.HI.A20, Ad5.KO1.HI.A20 (KO1, ablated CAR-binding) and Ad5/kn48.DG.A20 showed ∼ 160-, 270- and 180-fold increased transduction in BT-20 breast carcinoma cells (αvβ6high). Primary human epithelial ovarian cancer (EOC) cultures derived from clinical ascites provided a useful ex vivo model for intraperitoneal virotherapy. Ad5.HI.A20, Ad5.KO1.HI.A20 and Ad5/kn48.DG.A20 transduction was ∼ 70-, 60- and 16-fold increased relative to Ad5.Luc in EOC cells (αvβ6high), respectively. A20 vectors transduced EOC cells at up to ∼ 950-fold higher efficiency in the presence of neutralizing ovarian ascites, as compared to Ad5.Luc. Efficient transduction and enhanced cancer-selectivity via a non-native αvβ6-mediated route was demonstrated, even in the presence of pre-existing anti-Ad5 immunity. Consequently, αvβ6-targeted Ad vectors may represent a promising platform for local intraperitoneal treatment of ovarian cancer metastases.
PMCID: PMC5053699  PMID: 27056886
adenovirus; re-targeting; neutralizing antibody; ovarian cancer; αvβ6 integrin
8.  Development and psychometric properties of the client’s assessment of treatment scale for supported accommodation (CAT-SA) 
BMC Psychiatry  2016;16:43.
Patient-Reported Outcome Measures (PROMs) are important for evaluating mental health services. Yet, no specific PROM exists for the large and diverse mental health supported accommodation sector. We aimed to produce and validate a PROM specifically for supported accommodation services, by adapting the Client’s Assessment of Treatment Scale (CAT) and assessing its psychometric properties in a large sample.
Focus groups with service users in the three main types of mental health supported accommodation services in the United Kingdom (residential care, supported housing and floating outreach) were conducted to adapt the contents of the original CAT items and assess the acceptability of the modified scale (CAT-SA). The CAT-SA was then administered in a survey to service users across England. Internal consistency was assessed using Cronbach’s alpha. Convergent validity was tested through correlations with subjective quality of life and satisfaction with accommodation, as measured by the Manchester Short Assessment of Quality of Life (MANSA).
All seven original items of the CAT were regarded as relevant to appraisals of mental health supported accommodation services, with only slight modifications to the wording required. In the survey, data were obtained from 618 clients. The internal consistency of the CAT-SA items was 0.89. Mean CAT-SA scores were correlated with the specific accommodation item on the MANSA (rs = 0.37, p˂.001).
The content of the CAT-SA has relevance to service users living in mental health supported accommodation. The findings from our large survey show that the CAT-SA is acceptable across different types of supported accommodation and suggest good psychometric properties. The CAT-SA appears a valid and easy to use PROM for service users in mental health supported accommodation services.
Electronic supplementary material
The online version of this article (doi:10.1186/s12888-016-0755-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4766675  PMID: 26911904
Patient Reported Outcome; Supported Accommodation; Treatment Satisfaction; Mental Health
9.  Increasing Access to Mental Health Care With Breathe, an Internet-Based Program for Anxious Adolescents: Study Protocol for a Pilot Randomized Controlled Trial 
JMIR Research Protocols  2016;5(1):e18.
There is a demand to make first-line treatments, including cognitive behavioural therapy (CBT) for adolescent anxiety disorders, more widely available. Internet-based CBT is proposed to circumvent access and availability barriers and reduce health care system costs. Recent reviews suggest more evidence is needed to establish the treatment effects of Internet-based CBT in children and adolescents and to determine related economic impacts.
This pilot trial aims to collect the necessary data to inform the planning of a full-scale RCT to test the effectiveness of the Internet-based CBT program Breathe (Being Real, Easing Anxiety: Tools Helping Electronically).
We are conducting a 27-month, 2-arm parallel-group, pilot randomized controlled trial (RCT). Outcomes will inform the planning of a full-scale RCT aimed to test the effectiveness of Internet-based CBT with a population of adolescents with moderate to mild anxiety problems. In the pilot RCT we will: (1) define a minimal clinically important difference (MCID) for the primary outcome measure (total anxiety score using the Multidimensional Anxiety Scale for Children); (2) determine a sample size for the full-scale RCT; (3) estimate recruitment and retention rates; (4) measure intervention acceptability to inform critical intervention changes; (5) determine the use of co-interventions; and (6) conduct a cost-consequence analysis to inform a cost-effectiveness analysis in the full-scale RCT. Adolescents aged 13-17 years seeking care for an anxiety complaint from a participating emergency department, mobile or school-based crisis team, or primary care clinic are being screened for interest and eligibility. Enrolled adolescents are being randomly allocated to either 8 weeks of Internet-based CBT with limited telephone and e-mail support, or a control group with access to a static webpage listing anxiety resources. Adolescents are randomly assigned using a computer generated allocation sequence. Data are being collected at baseline, treatment completion, and at a 3-month follow-up.
Currently, adolescents are being enrolled in the study. Enrolment is taking place between March 2014 and February 2016; data collection will conclude May 2016. We expect that analysis and results will be available by August 2016.
In many communities, the resources available for front-line anxiety treatment are outweighed by the need for care. This pilot RCT is an essential step to designing a robust RCT to evaluate the effectiveness of an Internet-based CBT program for adolescents with moderate to mild anxiety problems.
Trial Registration NCT02059226; (Archived by WebCite at
PMCID: PMC4752691  PMID: 26825111
anxiety; etherapy; cognitive behavioral therapy; adolescents; mental health; Internet; intervention; pilot; randomized controlled trial
10.  Clustered randomised controlled trial of two education interventions designed to increase physical activity and well-being of secondary school students: the MOVE Project 
BMJ Open  2016;6(1):e009318.
To assess the effectiveness of 2 interventions in improving the physical activity and well-being of secondary school children.
A clustered randomised controlled trial; classes, 1 per school, were assigned to 1 of 3 intervention arms or a control group based on a 2×2 factorial design. The interventions were peer-mentoring and participative learning. Year 7 children (aged 11–12) in the peer-mentoring intervention were paired with year 9 children for 6 weekly mentoring meetings. Year 7 children in the participative learning arm took part in 6 weekly geography lessons using personalised physical activity and Global Positioning System (GPS) data. Year 7 children in the combined intervention received both interventions, with the year 9 children only participating in the mentoring sessions.
1494 year 7 students from 60 schools in the North of England took part in the trial. Of these, 43 students opted out of taking part in the evaluation measurements, 2 moved teaching group and 58 changed school. Valid accelerometry outcome data were collected for 892 students from 53 schools; and well-being outcome data were available for 927 students from 52 schools.
Main outcome measures
The primary outcomes were mean minutes of accelerometer-measured moderate-to-vigorous intensity physical activity per day, and well-being as evaluated by the KIDSCREEN-27 questionnaire. These data were collected 6 weeks after the intervention; a 12-month follow-up is planned.
No significant effects (main or interaction) were observed for the outcomes. However, small positive differences were found for both outcomes for the participative learning intervention.
These findings suggest that the 2 school-based interventions did not modify levels of physical activity or well-being within the period monitored. Change in physical activity may require more comprehensive individual behavioural intervention, and/or more system-based efforts to address wider environmental influences such as family, peers, physical environment, transport and educational policy.
Trial registration number
PMCID: PMC4716156  PMID: 26739729
11.  Evaluating preferences for profiles of GLP-1 receptor agonists among injection-naïve type 2 diabetes patients in the UK 
To use a discrete choice experiment (DCE) to evaluate preferences for the actual treatment features and overall profiles of two injectable glucagon-like peptide-1 receptor agonists (dulaglutide and liraglutide) among patients with type 2 diabetes mellitus (T2DM) in the UK.
In-person interviews were conducted in the UK to administer a DCE to patients with self-reported T2DM, naïve to treatment with injectable medications. The DCE examined six attributes of T2DM treatment each described by two levels: “dosing frequency,” “hemoglobin A1c change,” “weight change,” “type of delivery system,” “frequency of nausea,” and “frequency of hypoglycemia.” Part-worth utilities were estimated using random effects logit models and were used to calculate relative importance (RI) values for each attribute. A chi-square test was used to determine differences in preferences for dulaglutide versus liraglutide profiles.
A total of 243 participants [mean age: 60.5 (standard deviation 10.9) years; 76.1% male; mean body mass index: 29.8 (standard deviation 5.4) kg/m2] completed the study. RI values for the attributes in rank order were: “dosing frequency” (41.6%), “type of delivery system” (35.5%), “frequency of nausea” (10.4%), “weight change” (5.9%), “hemoglobin A1c change” (3.6%), and “frequency of hypoglycemia” (3.0%). Significantly more participants preferred the dulaglutide profile (83.1%) compared with the liraglutide profile (16.9%; P<0.0001).
This study elicited patients’ preferences for attributes and levels representing the actual characteristics of two specific glucagon-like peptide-1 medications. In this context, dosing frequency and type of delivery system were most important, accounting for over 75% of the RI. While previous studies have identified efficacy as highly important in T2DM medication decisions, this study suggests that when differences in efficacy between medications are small, other treatment features (eg, dosing frequency and delivery system) are of much greater importance to patients.
PMCID: PMC4646588  PMID: 26635470
discrete choice experiment; patient preference; type 2 diabetes; GLP-1 receptor agonist
12.  A literature review on the representativeness of randomized controlled trial samples and implications for the external validity of trial results 
Trials  2015;16:495.
Randomized controlled trials (RCTs) are conducted under idealized and rigorously controlled conditions that may compromise their external validity. A literature review was conducted of published English language articles that reported the findings of studies assessing external validity by a comparison of the patient sample included in RCTs reporting on pharmaceutical interventions with patients from everyday clinical practice. The review focused on publications in the fields of cardiology, mental health, and oncology. A range of databases were interrogated (MEDLINE; EMBASE; Science Citation Index; Cochrane Methodology Register). Double-abstract review and data extraction were performed as per protocol specifications. Out of 5,456 de-duplicated abstracts, 52 studies met the inclusion criteria (cardiology, n = 20; mental health, n = 17; oncology, n = 15). Studies either performed an analysis of the baseline characteristics (demographic, socioeconomic, and clinical parameters) of RCT-enrolled patients compared with a real-world population, or assessed the proportion of real-world patients who would have been eligible for RCT inclusion following the application of RCT inclusion/exclusion criteria. Many of the included studies concluded that RCT samples are highly selected and have a lower risk profile than real-world populations, with the frequent exclusion of elderly patients and patients with co-morbidities. Calculation of ineligibility rates in individual studies showed that a high proportion of the general disease population was often excluded from trials. The majority of studies (n = 37 [71.2 %]) explicitly concluded that RCT samples were not broadly representative of real-world patients and that this may limit the external validity of the RCT. Authors made a number of recommendations to improve external validity. Findings from this review indicate that there is a need to improve the external validity of RCTs such that physicians treating patients in real-world settings have the appropriate evidence on which to base their clinical decisions. This goal could be achieved by trial design modification to include a more representative patient sample and by supplementing RCT evidence with data generated from observational studies. In general, a thoughtful approach to clinical evidence generation is required in which the trade-offs between internal and external validity are considered in a holistic and balanced manner.
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-015-1023-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4632358  PMID: 26530985
Randomized controlled trial; External validity; Generalizability; Real-world patients; Cardiology; Mental health; Oncology; Literature review
13.  Oncolytic Adenovirus: Strategies and Insights for Vector Design and Immuno-Oncolytic Applications 
Viruses  2015;7(11):6009-6042.
Adenoviruses (Ad) are commonly used both experimentally and clinically, including oncolytic virotherapy applications. In the clinical area, efficacy is frequently hampered by the high rates of neutralizing immunity, estimated as high as 90% in some populations that promote vector clearance and limit bioavailability for tumor targeting following systemic delivery. Active tumor targeting is also hampered by the ubiquitous nature of the Ad5 receptor, hCAR, as well as the lack of highly tumor-selective targeting ligands and suitable targeting strategies. Furthermore, significant off-target interactions between the viral vector and cellular and proteinaceous components of the bloodstream have been documented that promote uptake into non-target cells and determine dose-limiting toxicities. Novel strategies are therefore needed to overcome the obstacles that prevent efficacious Ad deployment for wider clinical applications. The use of less seroprevalent Ad serotypes, non-human serotypes, capsid pseudotyping, chemical shielding and genetic masking by heterologous peptide incorporation are all potential strategies to achieve efficient vector escape from humoral immune recognition. Conversely, selective vector arming with immunostimulatory agents can be utilized to enhance their oncolytic potential by activation of cancer-specific immune responses against the malignant tissues. This review presents recent advantages and pitfalls occurring in the field of adenoviral oncolytic therapies.
PMCID: PMC4664994  PMID: 26610547
adenovirus; oncolytic; virotherapy; immune epitope; neutralization; genetic masking; chimeric vector; pseudotyping; cancer immunotherapy
14.  Ultrasound or near-infrared vascular imaging to guide peripheral intravenous catheterization in children: a pragmatic randomized controlled trial 
Peripheral intravenous catheterization in children is challenging, and success rates vary greatly. We conducted a pragmatic randomized controlled trial to determine whether the use of ultrasound or near-infrared vascular imaging to guide catheterization would be more effective than the standard approach in achieving successful catheter placement on the first attempt.
We enrolled a convenience sample of 418 children in a pediatric emergency department who required peripheral intravenous catheterization between June 2010 to August 2012. We stratified them by age (≤ 3 yr and > 3 yr) and randomly assigned them to undergo the procedure with the standard approach, or with the help of either ultrasound or near-infrared vascular imaging. The primary outcome was the proportion of patients who had successful placement of a catheter on the first attempt.
The rate of successful first attempts did not differ significantly between either of the 2 intervention groups and the standard approach group (differences in proportions −3.9%, 95% confidence interval [CI] −14.2% to 6.5%, for ultrasound imaging; −8.7%, 95% CI −19.4% to 1.9%, for near-infrared imaging). Among children 3 years and younger, the difference in success rates relative to standard care was also not significant for ultrasound imaging (−9.6%, 95% CI −29.8% to 10.6%), but it was significantly worse for near-infrared imaging (−20.1%, 95% CI −40.1% to −0.2%). Among children older than 3 years, the differences in success rates relative to standard care were smaller but not significant (−2.3%, 95% CI −13.6% to 9.0%, for ultrasound imaging; −4.1%, 95% CI −15.7% to 7.5%, for near-infrared imaging). None of the pairwise comparisons were statistically significant in any of the outcomes.
Neither technology improved first-attempt success rates of peripheral intravenous catheterization in children, even in the younger group. These findings do not support investment in these technologies for routine peripheral intravenous catheterization in children. Trial registration:, no. NCT01133652.
PMCID: PMC4435867  PMID: 25897047
15.  Paediatric pain management practice and policies across Alberta emergency departments 
Paediatrics & Child Health  2014;19(4):190-194.
Many children requiring acute care receive suboptimal analgesia.
To describe paediatric pain management practices and policies in emergency departments (EDs) in Alberta.
A descriptive survey was distributed to each of the EDs in Alberta.
A response rate of 67% (72 of 108) was obtained. Seventy-one percent (42 of 59) of EDs reported the use of a pain tool, 29.3% (17 of 58) reported mandatory pain documentation and 16.7% (10 of 60) had nurse-initiated pain protocols. Topical anesthetics were reported to be used for intravenous line insertion by 70.4% of respondents (38 of 54) and for lumbar puncture (LP) by 30.8% (12 of 39). According to respondents, infiltrated anesthetic was used for LP by 69.2% (27 of 39) of respondents, and oral sucrose was used infrequently for urinary catheterization (one of 46 [2.2%]), intravenous line insertion (zero of 54 [0%]) and LP (one of 39 [2.6%]).
Few Alberta EDs use policies and protocols to manage paediatric pain. Noninvasive methods to limit procedural pain are underutilized. Canadian paediatricians must advocate for improved analgesia to narrow this knowledge-to-practice gap.
PMCID: PMC4028644  PMID: 24855415
Analgesia; Emergency; Pain; Paediatrics; Survey
16.  Protein Kinase Cα (PKCα) Regulates Bone Architecture and Osteoblast Activity* 
The Journal of Biological Chemistry  2014;289(37):25509-25522.
Background: Roles of the multifunctional kinase PKCα in bone are unknown.
Results: Female Prkca−/− mice form bone in their medullary cavities associated with higher osteoblastic differentiation. Bone and spleen changes in Prkca−/− mice resemble features of Gaucher disease.
Conclusion: PKCα regulates osteoblast differentiation and bone architecture.
Significance: PKCα-targeting therapies may benefit low bone mass conditions, including Gaucher disease and osteoporosis.
Bones' strength is achieved and maintained through adaptation to load bearing. The role of the protein kinase PKCα in this process has not been previously reported. However, we observed a phenotype in the long bones of Prkca−/− female but not male mice, in which bone tissue progressively invades the medullary cavity in the mid-diaphysis. This bone deposition progresses with age and is prevented by disuse but unaffected by ovariectomy. Castration of male Prkca−/− but not WT mice results in the formation of small amounts of intramedullary bone. Osteoblast differentiation markers and Wnt target gene expression were up-regulated in osteoblast-like cells derived from cortical bone of female Prkca−/− mice compared with WT. Additionally, although osteoblastic cells derived from WT proliferate following exposure to estradiol or mechanical strain, those from Prkca−/− mice do not. Female Prkca−/− mice develop splenomegaly and reduced marrow GBA1 expression reminiscent of Gaucher disease, in which PKC involvement has been suggested previously. From these data, we infer that in female mice, PKCα normally serves to prevent endosteal bone formation stimulated by load bearing. This phenotype appears to be suppressed by testicular hormones in male Prkca−/− mice. Within osteoblastic cells, PKCα enhances proliferation and suppresses differentiation, and this regulation involves the Wnt pathway. These findings implicate PKCα as a target gene for therapeutic approaches in low bone mass conditions.
PMCID: PMC4162157  PMID: 25070889
Bone; Estrogen; Gaucher Disease; Osteoblast; Protein Kinase C (PKC); Wnt Signaling; Mechanical Loading
17.  Pathogenesis of growth failure and partial reversal with gene therapy in murine and canine Glycogen Storage Disease type Ia 
Molecular genetics and metabolism  2013;109(2):161-170.
Glycogen Storage Disease type Ia (GSD-Ia) in humans frequently causes delayed bone maturation, decrease in final adult height, and decreased growth velocity. This study evaluates the pathogenesis of growth failure and the effect of gene therapy on growth in GSD-Ia affected dogs and mice. Here we found that homozygous G6pase (−/−) mice with GSD-Ia have normal growth hormone (GH) levels in response to hypoglycemia, decreased insulin-like growth factor (IGF) 1 levels, and attenuated weight gain following administration of GH. Expression of hepatic GH receptor and IGF 1 mRNAs and hepatic STAT5 (phospho Y694) protein levels are reduced prior to and after GH administration, indicating GH resistance. However, restoration of G6Pase expression in the liver by treatment with adeno-associated virus 8 pseudotyped vector expressing G6Pase (AAV2/8-G6Pase) corrected body weight, but failed to normalize plasma IGF 1 in G6pase (−/−) mice. Untreated G6pase (−/−) mice also demonstrated severe delay of growth plate ossification at 12 days of age; those treated with AAV2/8-G6Pase at 14 days of age demonstrated skeletal dysplasia and limb shortening when analyzed radiographically at 6 months of age, in spite of apparent metabolic correction. Moreover, gene therapy with AAV2/9-G6Pase only partially corrected growth in GSD-Ia affected dogs as detected by weight and bone measurements and serum IGF 1 concentrations were persistently low in treated dogs. We also found that heterozygous GSD-Ia carrier dogs had decreased serum IGF 1, adult body weights and bone dimensions compared to wild-type littermates. In sum, these findings suggest that growth failure in GSD-Ia results, at least in part, from hepatic GH resistance. In addition, gene therapy improved growth in addition to promoting long-term survival in dogs and mice with GSD-Ia.
PMCID: PMC3764490  PMID: 23623482
Glycogen Storage Disease Ia; Growth failure; Gene therapy; Glucose-6-phosphatase; Adeno-associated virus; IGF 1
18.  An unusual cause of small bowel obstruction caused by a Richter's-type hernia into the urinary bladder 
The authors present an unusual case of small bowel obstruction in a 62-year-old man.
A 62-year-old man with a background of transitional cell carcinoma (TCC) of the bladder presented to the emergency department with abdominal pain, distension, vomiting and had not opened his bowels for three days. 3 weeks previously he had a repeat Transurtheral resection of bladder tumour (TURBT), during which there was an iatrogenic perforation of the bladder. A CT scan of the abdomen and pelvis revealed small bowel obstruction but did not identify a cause. At laparotomy the cause of the obstruction was identified as a section of the small bowel that had partially herniated into the bladder, via the perforation. The defect was repaired and the patient made an uneventful recovery.
Herniation of the bowel into a defect in the bladder wall is a rare event with only 6 previous cases reported in the literature. It can cause signs and symptoms of bowel obstruction.
In patients with known bladder perforations who present with symptoms and signs of bowel obstruction, bowel herniation into the bladder should be considered. Early surgical intervention may be necessary if the patient is clinically unwell with appropriate symptoms and signs and imaging does not provide conclusive answer.
PMCID: PMC4064428  PMID: 24858979
Bowel obstruction; Bladder perforation; Internal hernia
19.  Screening for post-traumatic stress disorder after injury in the pediatric emergency department - a systematic review protocol 
Systematic Reviews  2014;3:19.
Pediatric injury is highly prevalent and has significant impact both physically and emotionally. The majority of pediatric injuries are treated in emergency departments (EDs), where treatment of physical injuries is the main focus. In addition to physical trauma, children often experience significant psychological trauma, and the development of acute stress disorder (ASD) and post-traumatic stress disorder (PTSD) is common. The consequences of failing to recognize and treat children with ASD and PTSD are significant and extend into adulthood. Currently, screening guidelines to identify children at risk for developing these stress disorders are not evident in the pediatric emergency setting. The goal of this systematic review is to summarize evidence on the psychometric properties, diagnostic accuracy, and clinical utility of screening tools that identify or predict PTSD secondary to physical injury in children. Specific research objectives are to: (1) identify, describe, and critically evaluate instruments available to screen for PTSD in children; (2) review and synthesize the test-performance characteristics of these tools; and (3) describe the clinical utility of these tools with focus on ED suitability.
Computerized databases including MEDLINE, EMBASE, CINAHL, ISI Web of Science and PsycINFO will be searched in addition to conference proceedings, textbooks, and contact with experts. Search terms will include MeSH headings (post-traumatic stress or acute stress), (pediatric or children) and diagnosis. All articles will be screened by title/abstract and articles identified as potentially relevant will be retrieved in full text and assessed by two independent reviewers. Quality assessment will be determined using the QUADAS-2 tool. Screening tool characteristics, including type of instrument, number of items, administration time and training administrators level, will be extracted as well as gold standard diagnostic reference properties and any quantitative diagnostic data (specificity, positive and negative likelihood/odds ratios) where appropriate.
Identifying screening tools to recognize children at risk of developing stress disorders following trauma is essential in guiding early treatment and minimizing long-term sequelae of childhood stress disorders. This review aims to identify such screening tools in efforts to improve routine stress disorder screening in the pediatric ED setting.
Trials registration
PROSPERO registration: CRD42013004893
PMCID: PMC3944964  PMID: 24580806
Post-traumatic stress disorder (PTSD); Screening; Instrument; Emergency department; Pediatrics; Injury
20.  Parenteral and oral antibiotic duration for treatment of pediatric osteomyelitis: a systematic review protocol 
Systematic Reviews  2013;2:92.
Pediatric osteomyelitis is a bacterial infection of bones requiring prolonged antibiotic treatment using parenteral followed by enteral agents. Major complications of pediatric osteomyelitis include transition to chronic osteomyelitis, formation of subperiosteal abscesses, extension of infection into the joint, and permanent bony deformity or limb shortening. Historically, osteomyelitis has been treated with long durations of antibiotics to avoid these complications. However, with improvements in management and antibiotic treatment, standard of care is moving towards short durations of intravenous antibiotics prior to enteral antibiotics.
The authors will perform a systematic review based on PRISMA guidelines in order to evaluate the literature, looking for evidence to support the optimal duration of parenteral and enteral therapy. The main goals are to see if literature supports shorter durations of either parenteral antibiotics and/or enteral antibiotics.
Multiple databases will be investigated using a thorough search strategy. Databases include Medline, Cochrane, EMBASE, SCOPUS, Dissertation Abstracts, CINAHL, Web of Science, African Index Medicus and LILACS. Search stream will include medical subject heading for pediatric patients with osteomyelitis and antibiotic therapy. We will search for published or unpublished randomized and quasi-randomized controlled trials.
Two authors will independently select articles, extract data and assess risk of bias by standard Cochrane methodologies. We will analyze comparisons between dichotomous outcomes using risk ratios and continuous outcomes using mean differences. 95% confidence intervals will be computed.
One of the major dilemmas of management of this disease is the duration of parenteral therapy. Long parenteral therapy has increased risk of serious complications and the necessity for long therapy has been called into question. Our study aims to review the currently available evidence from randomized trials regarding duration of both parenteral and oral therapy for pediatric acute osteomyelitis.
Trial registration
PMCID: PMC3852824  PMID: 24099135
Social science & medicine (1982)  2009;69(12):1845-1853.
This paper considers the relationships between health status and socio-geographic mobility over time for individuals sampled in the longitudinal National Population Health Survey of Canada. The study aims to elucidate the associations between individuals’ health outcomes (assessed on various measures), and area deprivation in their place of residence. We also aimed to investigate the significance of selective residential migration as a possible contributor to area differences in health.
PMCID: PMC3762746  PMID: 19822386 CAMSID: cams3272
22.  Neighbourhood deprivation and adolescent self-esteem: Exploration of the ‘socio-economic equalisation in youth’ hypothesis in Britain and Canada 
Material deprivation is an important determinant of health inequalities in adults but there remains debate about the extent of its importance for adolescent wellbeing. Research has found limited evidence for an association between adolescent health and socio-economic status, leading authors to suggest that there is an ‘equalisation’ of health across socio-economic groups during the adolescent stage of the life-course. This paper explores this ‘equalisation’ hypothesis for adolescent psychological wellbeing from a geographical perspective by investigating associations between neighbourhood deprivation and self-esteem in Britain and Canada. Data from the British Youth Panel (BYP) and the National Longitudinal Survey of Children and Youth (NLSCY) on adolescents aged 11–15 for the time period 1994–2004 were used to estimate variations in low self-esteem between neighbourhoods using multilevel logistic regression. Models were extended to estimate associations between self-esteem and neighbourhood deprivation before and after adjustment for individual and family level covariates. Moderation by age, sex, urban/rural status, household income and family structure was investigated. There were no significant differences in self-esteem between the most deprived and most affluent neighbourhoods (Canada unadjusted OR = 1.00, 95% CI 0.76, 1.33; Britain unadjusted OR = 1.25, 95% CI 0.74, 2.13). The prevalence of low self-esteem was higher (in Canada) for boys in the least deprived neighbourhoods compared to other neighbourhoods. No other interactions were observed. The results presented here offer some (limited) support for the socio-economic equalisation in youth hypothesis from a geographical perspective: with specific reference to equalisation of the relationship between neighbourhood deprivation and self-esteem and psychological health in early adolescence. This contrasts with previous research in the United States but supports related work from Britain. The lack of interactions with key social and economic variables suggests that findings might apply across a range of family circumstances and different communities in Britain and Canada. Policy implications are discussed.
► The relationship between adolescent self-esteem and neighbourhood deprivation in Britain and Canada was studied. ► Self-esteem was not associated with neighbourhood deprivation in large, national representative British and Canadian cohorts. ► Findings contrast with previous United States studies examining adolescent self-esteem and neighbourhood deprivation.
PMCID: PMC3726937  PMID: 23518228
Neighbourhood deprivation; Britain; Canada; United States; Health inequalities; Geographical inequalities; Self-esteem; Adolescent; Equalisation; Psychological health
23.  Long-Term Efficacy Following Readministration of an Adeno-Associated Virus Vector in Dogs with Glycogen Storage Disease Type Ia 
Human Gene Therapy  2011;23(4):407-418.
Glycogen storage disease type Ia (GSD-Ia) is the inherited deficiency of glucose-6-phosphatase (G6Pase), primarily found in liver and kidney, which causes life-threatening hypoglycemia. Dogs with GSD-Ia were treated with double-stranded adeno-associated virus (AAV) vectors encoding human G6Pase. Administration of an AAV9 pseudotyped (AAV2/9) vector to seven consecutive GSD-Ia neonates prevented hypoglycemia during fasting for up to 8 hr; however, efficacy eventually waned between 2 and 30 months of age, and readministration of a new pseudotype was eventually required to maintain control of hypoglycemia. Three of these dogs succumbed to acute hypoglycemia between 7 and 9 weeks of age; however, this demise could have been prevented by earlier readministration an AAV vector, as demonstrated by successful prevention of mortality of three dogs treated earlier in life. Over the course of this study, six out of nine dogs survived after readministration of an AAV vector. Of these, each dog required readministration on average every 9 months. However, two were not retreated until >34 months of age, while one with preexisting antibodies was re-treated three times in 10 months. Glycogen content was normalized in the liver following vector administration, and G6Pase activity was increased in the liver of vector-treated dogs in comparison with GSD-Ia dogs that received only with dietary treatment. G6Pase activity reached approximately 40% of normal in two female dogs following AAV2/9 vector administration. Elevated aspartate transaminase in absence of inflammation indicated that hepatocellular turnover in the liver might drive the loss of vector genomes. Survival was prolonged for up to 60 months in dogs treated by readministration, and all dogs treated by readministration continue to thrive despite the demonstrated risk for recurrent hypoglycemia and mortality from waning efficacy of the AAV2/9 vector. These preclinical data support the further translation of AAV vector–mediated gene therapy in GSD-Ia.
Demaster and colleagues report preclinical results of treating dogs with glycogen storage disease type Ia (GSD-Ia) with double-stranded adeno-associated viral vector type 9 (AAV2/9) encoding human glucose-6-phosphatase (G6Pase). Vector treatment was able to prevent hypoglycemia and led to normalized liver glycogen levels and increased G6Pase activity, but carefully timed readministration with a different pseudotype was required to prevent the therapeutic effect from waning. Survival was prolonged for up to 60 months in dogs treated by readministration, with all dogs continuing to thrive despite the demonstrated risk for recurrent hypoglycemia and mortality from waning vector efficacy.
PMCID: PMC4047999  PMID: 22185325
24.  Characterization of a canine model of glycogen storage disease type IIIa 
Disease Models & Mechanisms  2012;5(6):804-811.
Glycogen storage disease type IIIa (GSD IIIa) is an autosomal recessive disease caused by deficiency of glycogen debranching enzyme (GDE) in liver and muscle. The disorder is clinically heterogeneous and progressive, and there is no effective treatment. Previously, a naturally occurring dog model for this condition was identified in curly-coated retrievers (CCR). The affected dogs carry a frame-shift mutation in the GDE gene and have no detectable GDE activity in liver and muscle. We characterized in detail the disease expression and progression in eight dogs from age 2 to 16 months. Monthly blood biochemistry revealed elevated and gradually increasing serum alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) activities; serum creatine phosphokinase (CPK) activity exceeded normal range after 12 months. Analysis of tissue biopsy specimens at 4, 12 and 16 months revealed abnormally high glycogen contents in liver and muscle of all dogs. Fasting liver glycogen content increased from 4 months to 12 months, but dropped at 16 months possibly caused by extended fibrosis; muscle glycogen content continually increased with age. Light microscopy revealed significant glycogen accumulation in hepatocytes at all ages. Liver histology showed progressive, age-related fibrosis. In muscle, scattered cytoplasmic glycogen deposits were present in most cells at 4 months, but large, lake-like accumulation developed by 12 and 16 months. Disruption of the contractile apparatus and fraying of myofibrils was observed in muscle at 12 and 16 months by electron microscopy. In conclusion, the CCR dogs are an accurate model of GSD IIIa that will improve our understanding of the disease progression and allow opportunities to investigate treatment interventions.
PMCID: PMC3484863  PMID: 22736456
25.  Migration experiences, employment status and psychological distress among Somali immigrants: a mixed-method international study 
BMC Public Health  2012;12:749.
The discourse about mental health problems among migrants and refugees tends to focus on adverse pre-migration experiences; there is less investigation of the environmental conditions in which refugee migrants live, and the contrasts between these situations in different countries. This cross-national study of two samples of Somali refugees living in London (UK) and Minneapolis, Minnesota, (USA) helps to fill a gap in the literature, and is unusual in being able to compare information collected in the same way in two cities in different countries.
There were two parts to the study, focus groups to gather in-depth qualitative data and a survey of health status and quantifiable demographic and material factors. Three of the focus groups involved nineteen Somali professionals and five groups included twenty-eight lay Somalis who were living in London and Minneapolis. The quantitative survey was done with 189 Somali respondents, also living in London and Minneapolis. We used the MINI International Neuropsychiatric Interview (MINI) to assess ICD-10 and DSM-IV mental disorders.
The overall qualitative and quantitative results suggested that challenges to masculinity, thwarted aspirations, devalued refugee identity, unemployment, legal uncertainties and longer duration of stay in the host country account for poor psychological well-being and psychiatric disorders among this group.
The use of a mixed-methods approach in this international study was essential since the quantitative and qualitative data provide different layers and depth of meaning and complement each other to provide a fuller picture of complex and multi-faceted life situations of refugees and asylum seekers. The comparison between the UK and US suggests that greater flexibility of access to labour markets for this refugee group might help to promote opportunities for better integration and mental well-being.
PMCID: PMC3489604  PMID: 22954304

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