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1.  Direct observations of active school transportation and stroller use in kindergarten children 
Preventive Medicine Reports  2016;4:558-562.
Little is known about kindergarten students' active school transportation (AST) and stroller/wagon use as sedentary travel devices. The primary objective of this cross-sectional study was to determine the prevalence of kindergarten children arriving to school by active and sedentary modes, including strollers, in Toronto elementary schools and compare to students in kindergarten to grade 6 (K–6). The secondary objective was to examine factors associated with AST in kindergarten and K–6 students. School travel mode was counted using direct observations at elementary schools in the City of Toronto in 2015. Two samples were observed: 1) Kindergarten sample: a random sample of schools with separate kindergarten entrances (n = 26 schools, 1069 children); 2) Kindergarten to grade 6 sample: observations were conducted at arrival locations at 50% of eligible elementary schools for students of all ages (n = 88 schools, 17,224 children). Proportions arriving by different travel modes were compared using Chi-square analysis. Negative binomial regression was conducted to examine the association between school characteristics and AST. AST was lower in the kindergarten compared to the K–6 sample (60% versus 74%, χ2 = 91.37, p < 0.001). The predominant sedentary mode for kindergarten students was by vehicle (38%), with < 2% using strollers/wagons. Recent immigrant status was related to higher AST in kindergarten students; higher social disadvantage, crossing guards, school population and collision rates were related to higher AST in the K–6 sample. Factors influencing AST in young students require further investigation to influence the development of healthy active lifestyles at an early age.
•Observational counts of school transportation mode and stroller use was conducted.•Active school transportation (AST) was less in kindergarten versus all age students.•< 2% of kindergarten students use strollers for transportation to school.•School proportion of recent immigrants was related to AST in kindergarten students.•Higher social disadvantage was most strongly related to AST in all age students.
PMCID: PMC5094266  PMID: 27818914
Children; Physical fitness; Schools; Walking; Strollers
3.  Discovery of MK-1421, a Potent, Selective sstr3 Antagonist, as a Development Candidate for Type 2 Diabetes 
ACS Medicinal Chemistry Letters  2015;6(5):513-517.
The imidazolyl-tetrahydro-β-carboline class of sstr3 antagonists have demonstrated efficacy in a murine model of glucose excursion and may have potential as a treatment for type 2 diabetes. The first candidate in this class caused unacceptable QTc interval prolongation in oral, telemetrized cardiovascular (CV) dogs. Herein, we describe our efforts to identify an acceptable candidate without CV effects. These efforts resulted in the identification of (1R,3R)-3-(4-(5-fluoropyridin-2-yl)-1H-imidazol-2-yl)-1-(1-ethyl-pyrazol-4-yl)-1-(3-methyl-1,3,4-oxadiazol-3H-2-one-5-yl)-2,3,4,9-tetrahydro-1H-β-carboline (17e, MK-1421).
PMCID: PMC4434471  PMID: 26005524
sstr3; antagonist; type 2 diabetes; tetrahydro-β-carboline
4.  Installation of speed humps and pedestrian-motor vehicle collisions in Toronto, Canada: a quasi-experimental study 
BMC Public Health  2015;15:774.
Evidence related to the effectiveness of speed humps on reducing pedestrian-motor vehicle collisions (PMVC) has been conflicting. The purpose of this study was to determine the association between speed hump installation and changes in PMVC rates in Toronto, Canada.
Speed humps were mapped along with police-reported pedestrian collisions from 2000–2011 and built environment roadway characteristics. A quasi-experimental study identified collision counts before and after speed hump installation, modeled using repeated measures Poisson regression adjusted for season and roadway characteristics. Stratified analyses were conducted by age group and injury severity.
There were 27,827 PMVC, with 1344 collisions along 409 roadways with speed humps. PMVC incidence rates/meters of road/month decreased after installation of speed humps (IRR 0.78 95 % CI 0.66, 0.91). Winter, collector roads (versus local), pre-amalgamated city centre and increased land use mix were associated with more collisions. The association between speed humps and PMVC rates decreased more for children (IRR 0.57, 95 % CI 0.41, 0.79) than for adults (IRR 0.80, 95 % CI 0.68, 0.95).
Speed humps are an easily replicated method of traffic calming which have a significant protective effect on PMVC on the roadways where they are installed, particularly for children. There is a need for an area-wide analysis to determine the effects of the installation of speed humps to ensure that PMVC are not being displaced to surrounding roadways.
PMCID: PMC4534084  PMID: 26264227
5.  Do school crossing guards make crossing roads safer? A quasi-experimental study of pedestrian-motor vehicle collisions in Toronto, Canada 
BMC Public Health  2015;15:732.
The presence of school crossing guards has been associated with more walking and more pedestrian-motor vehicle collisions (PMVCs) in area-level cross-sectional analyses. The objectives of the study were to (1) Determine the effect on PMVC rates of newly implemented crossing guards in Toronto, Canada (2) Determine where collisions were located in relation to crossing guards throughout the city, and whether they occurred during school travel times.
School crossing guards with 50 m buffers were mapped along with police-reported child PMVCs from 2000–2011. (1) A quasi-experimental study identified all age collision counts near newly implemented guards before and after implementation, modeled using repeated measures Poisson regression adjusted for season and built environment variables. (2) A retrospective cohort study of all child PMVCS throughout the city to determine the proportions of child PMVCs which occurred during school travel times and at guard locations.
There were 27,827 PMVCs, with 260 PMVCs at the locations of 58 newly implemented guards. Repeated measures adjusted Poisson regression found PMVCs rates remained unchanged at guard locations after implementation (IRR 1.02, 95 % CI 0.74, 1.39). There were 568 guards citywide with 1850 child PMVCs that occurred at guard locations. The majority of child PMVCs occurred outside school travel times (n = 1155, 62 %) and of those that occurred during school travel times, only 95 (13.7 %) were at a guard location.
School crossing guards are a simple roadway modification to increase walking to school without apparent detrimental safety effects. Other more permanent interventions are necessary to address the frequency of child PMVCs occurring away from the location of crossing guards, and outside of school travel times.
PMCID: PMC4520271  PMID: 26227508
Motor vehicles; Walking; Injuries; Public health; Prevention; Schools
6.  Investigation of Cardiovascular Effects of Tetrahydro-β-carboline sstr3 antagonists 
ACS Medicinal Chemistry Letters  2014;5(7):748-753.
Antagonism of somatostatin subtype receptor 3 (sstr3) has emerged as a potential treatment of Type 2 diabetes. Unfortunately, the development of our first preclinical candidate, MK-4256, was discontinued due to a dose-dependent QTc (QT interval corrected for heart rate) prolongation observed in a conscious cardiovascular (CV) dog model. As the fate of the entire program rested on resolving this issue, it was imperative to determine whether the observed QTc prolongation was associated with hERG channel (the protein encoded by the human Ether-à-go-go-Related Gene) binding or was mechanism-based as a result of antagonizing sstr3. We investigated a structural series containing carboxylic acids to reduce the putative hERG off-target activity. A key tool compound, 3A, was identified from this SAR effort. As a potent sstr3 antagonist, 3A was shown to reduce glucose excursion in a mouse oGTT assay. Consistent with its minimal hERG activity from in vitro assays, 3A elicited little to no effect in an anesthetized, vagus-intact CV dog model at high plasma drug levels. These results afforded the critical conclusion that sstr3 antagonism is not responsible for the QTc effects and therefore cleared a path for the program to progress.
PMCID: PMC4094257  PMID: 25050159
sstr3; antagonist; Type-2 diabetes; β-tetrahydrocarboline; carboxylic acid; hERG channel; QTc prolongation; cardiovascular dog models
7.  Diamine Derivatives as Novel Small-Molecule, Potent, and Subtype-Selective Somatostatin SST3 Receptor Agonists 
ACS Medicinal Chemistry Letters  2014;5(6):690-695.
A novel class of small-molecule, highly potent, and subtype-selective somatostatin SST3 agonists was discovered through modification of a SST3 antagonist. As an example, (1R,2S)-9 demonstrated not only potent in vitro SST3 agonist activity but also in vivo SST3 agonist activity in a mouse oral glucose tolerance test (OGTT). These agonists may be useful reagents for studying the physiological roles of the SST3 receptor and may potentially be useful as therapeutic agents.
PMCID: PMC4060944  PMID: 24944745
Somatostatin; GPCR; somatostin receptor subtype 3 (SST3); small-molecule SST3 agonists
8.  Crystallographic structure determination of B10 mutants of Vitreoscilla hemoglobin: role of Tyr29 (B10) in the structure of the ligand-binding site 
Acta Crystallographica Section F  2013;69(Pt 3):215-222.
The crystal structures of two mutants at position 29 of the dimeric hemoglobin from Vitreoscilla are reported, together with a discussion of the significance of these mutations.
Site-directed mutants of the gene encoding wild-type Vitreoscilla hemoglobin were made that changed Tyr29 (B10) of the wild-type Vitreoscilla hemoglobin (VHb) to either Phe or Ala. The wild-type and the two mutant hemoglobins were expressed in Escherichia coli and purified to homogeneity. The binding of the two mutants to CO was essentially identical to that of wild-type VHb as determined by CO-difference spectra. Circular-dichroism spectra also showed the two mutants to be essentially the same as wild-type VHb regarding overall helicity. All three VHbs were crystallized and their structures were determined at resolutions of 1.7–1.9 Å, which are similar to that of the original wild-type structure determination. The Tyr29Phe mutant has a structure that is essentially indistinguishable from that of the wild type. However, the structure of the Tyr29Ala mutant has significant differences from that of the wild type. In addition, for the Tyr29Ala mutant it was possible to determine the positions of most of the residues in the D region, which was disordered in the originally reported structure of wild-type VHb as well as in the wild-type VHb structure reported here. In the Tyr29Ala mutant, the five-membered ring of proline E8 (Pro54) occupies the space occupied by the aromatic ring of Tyr29 in the wild-type structure. These results are discussed in the context of the proposed role of Tyr29 in the structure of the oxygen-binding pocket.
PMCID: PMC3606562  PMID: 23519792
bacterial hemoglobin; Vitreoscilla; site-directed mutagenesis
9.  A national radiation oncology medical student clerkship survey: Didactic curricular components increase confidence in clinical competency 
Students applying to radiation oncology residency programs complete one or more radiation oncology clerkships. This study assesses student experiences and perspectives during radiation oncology clerkships. The impact of didactic components and number of clerkship experiences in relation to confidence in clinical competency and preparation to function as a first year radiation oncology resident are evaluated.
Methods and Materials
An anonymous, internet-based survey was sent via direct e-mail to all applicants to a single radiation oncology residency program during the 2012–2013 academic year. The survey was composed of three main sections including questions regarding baseline demographic information and prior radiation oncology experience, rotation experiences, and ideal clerkship curriculum content.
The survey response rate was 37% (70/188). Respondents reported 191 unique clerkship experiences. 27% of respondents (19/70) completed at least one clerkship with a didactic component geared towards their level of training. Completing a clerkship with a didactic component was significantly associated with a respondent’s confidence to function as a first- year radiation oncology resident (Wilcoxon rank-sum p = 0.03). However, the total number of clerkships completed did not correlate with confidence to pursue radiation oncology as a specialty (Spearman’s rho p = 0.48) or confidence to function as a first year resident (Spearman’s rho p = 0.43).
Based on responses to this survey, rotating students perceive that the majority of radiation oncology clerkships do not have formal didactic curricula. Survey respondents who completed a clerkship with a didactic curriculum reported feeling more prepared to function as a radiation oncology resident. However, completing an increasing number of clerkships does not appear to improve confidence in the decision to pursue radiation oncology as a career or to function as a radiation oncology resident. These results support further development of structured didactic curricula for the radiation oncology clerkship.
PMCID: PMC4262520  PMID: 24331651
10.  Origins of cancer symposium report: beyond the tumor cell 
Genes & Cancer  2014;5(11-12):375-377.
The Origins of Cancer Symposium is a meeting organized by graduate students at the Van Andel Research Institute and serves as a forum for focused discussion on factors that contribute to the etiology of cancer. The theme for the fifth annual Origins of Cancer held on July 11th, 2014 was Beyond the Tumor Cell, which focused on the complex influences coming from the environment in which the cancer cell exists. Here we report on the meeting proceedings and briefly discuss the far-reaching implications.
PMCID: PMC4279435
Cancer; extracellular matrix; immunology; symposium; review
11.  Three dimensional analysis of brace biomechanical efficacy for patients with AIS 
European Spine Journal  2013;22(11):2445-2448.
Corrective three dimensional (3D) effect of different braces is debatable. We evaluated differences in in-brace radiographic correction comparing a custom thoracic-lumbo-sacral-orthosis (TLSO) (T) brace to a Chêneau type TLSO (C) brace using 3D EOS reconstruction technology. Our primary research question was the 3D effect of brace on the spine and in particularly the apical vertebra rotation (AVR).
This was a retrospective comparative analysis of patients with adolescent idiopathic scoliosis who had orthogonal AP and lateral X-rays with and without brace. A 3D image of the spine was reconstructed. Coronal, sagittal and axial spine parameters were measured before bracing and then on the first post-brace X-ray. Brace efficacy in controlling coronal, sagittal and axial parameters was evaluated.
Eighteen patients treated with the C brace and ten patients treated with the T brace were included. No difference was found regarding patients’ age, gender, magnitude of Cobb angle, sagittal parameters or AVR at inclusion. Following bracing, AVR was significantly reduced by the C brace compared to the T brace [average correction of 8.2° vs. 4.9° (P = 0.02)]. Coronal and sagittal correction did not differ significantly between the two groups.
By utilizing a novel 3D reconstruction technology, we were able to demonstrate that braces differ in their immediate effects on the spine. Although clinical relevance should be evaluated in a future trial we feel that the ability to measure treatment effects in 3D, and especially the transverse plane, is an important tool when evaluating different treatments.
PMCID: PMC3886493  PMID: 23873054
Scoliosis; 3D; Apical vertebrae rotation (AVR)
12.  Do obese children experience more severe fractures than nonobese children? A cross-sectional study from a paediatric emergency department 
Paediatrics & Child Health  2014;19(5):251-255.
To determine whether there is an association between childhood obesity and severe extremity fractures. Associations between obesity and complications related to the fracture and/or fracture management were also examined.
The present study was a retrospective, cross-sectional study conducted at a tertiary care children’s emergency department. Eligible cases for review were children (two to 17 years of age) with an extremity fracture. Severe extremity fractures were defined as those requiring manipulation under anesthesia, open operative repair and/or admission to hospital. The primary outcome was the proportion of severe extremity fractures and the secondary outcome was the proportion of complications.
A total of 1340 charts of children who presented with extremity fracture from January 2008 to December 2010 were reviewed. The mean (± SD) age of the study population was 9.1±4.0 years and 62.1% were male. Overall, 19.9% (95% CI 17.8% to 22.0%) were obese and 39.6% (95% CI 36.7% to 39.1%) sustained a severe extremity fracture. The OR of severe extremity fractures among obese versus nonobese children was 1.00 (95% CI 0.76 to 1.32), adjusted for age, sex and mechanism of injury. In addition, the OR of experiencing complications among obese relative to nonobese children was 1.12 (95% CI 0.68 to 1.85).
The results of the present study demonstrated that in children with extremity fractures, obese children were not at increased risk for sustaining more severe extremity fractures or subsequent complications compared with nonobese children.
PMCID: PMC4029229  PMID: 24855428
Child; Emergencies; Fracture; Obesity; Prevention
13.  GPR40 (FFAR1) – Combined Gs and Gq signaling in vitro is associated with robust incretin secretagogue action ex vivo and in vivo 
Molecular Metabolism  2014;4(1):3-14.
GPR40 (FFAR1), a clinically proven anti-diabetes target, is a Gq-coupled receptor for long chain fatty acids (LCFA) stimulating insulin secretion directly and mediating a major part of the dietary triglyceride-induced secretion of the incretins GLP-1 and GIP. In phase-II studies the GPR40 agonist TAK-875 decreased blood glucose but surprisingly without stimulating incretins.
Methods and results
Here we find that GPR40 can signal through not only Gq and IP3 but also Gs and cAMP when stimulated with certain agonists such as AM-1638 and AM-5262 in contrast to the endogenous LCFA ligands and agonists such as TAK-875 and AM-837, which only signal through Gq. In competition binding against [3H]AM-1638 and [3H]L358 the Gq + Gs and the Gq-only agonists either competed for or showed positive cooperativity by increasing the binding of the two different radio-ligands, in opposite ways. Nevertheless, both the Gq-only and the Gq + Gs agonists all docked surprisingly well into the binding site for TAK-875 in the X-ray structure of GPR40. In murine intestinal primary cell-cultures the endogenous LCFAs and the Gq-only agonists stimulated GLP-1 secretion with rather poor efficacy as compared with the high efficacy Gq + Gs GPR40 agonists and a prototype GPR119 agonist. Similarly, in fasting both male and female mice the Gq + Gs agonists showed significantly higher efficacy than the Gq-only agonists in respect of increasing plasma GLP-1 and plasma GIP in a GPR40-dependent manner.
It is concluded that stimulation of GPR40 by endogenous LCFAs or by Gq-only synthetic agonists result in a rather limited incretin response, whereas Gq + Gs GPR40 agonists stimulate incretin secretion robustly.
PMCID: PMC4314522  PMID: 25685685
G protein-coupled receptor; Glucagon like peptide 1 (GLP-1); Biased signaling; Ago-allosteric agonist; Long chain fatty acids (LCFAs)
14.  Improved survival time trends for glioblastoma using the SEER 17 population-based registries 
Journal of neuro-oncology  2011;107(1):207-212.
The EORTC/NCIC 22981/26981 study demonstrated an improvement in median overall survival (OS) from 12.1 to 14.6 months in patients with glioblastoma (GBM) who received temozolomide with post-operative radiotherapy (RT). The current study was performed to determine if those results translated into a survival benefit in a population-based cohort. Patients diagnosed between 2000 and 2006 with a GBM who underwent surgery and post-operative RT were selected from the Surveillance, Epidemiology and End Results database. Patients were grouped into time periods: 2000–2001, 2002–2003, 2004 and 2005–2006 (which represented those treated after the EORTC/NCIC trial presentation in 2004). Relative survival (RS) was estimated by the Kaplan–Meier method, and Cox multivariable regression modeling was used to estimate proportional hazard ratios (HR). Over time, there was improvement in the median and 2-year RS of 12 months and 15% for 2000–2001, 13 months and 19% for 2002–2003, 14 months and 24% for 2004, and 15 months and 26% for 2005–2006 (P < 0.0001 compared to 2000–2001 and 2002–2003; P = 0.07 compared to 2004). The estimated adjusted HR showed that patients diagnosed in 2005–2006 had significantly improved survival when compared to patients diagnosed in 2000–2001 (HR = 0.648, 95% CI 0.604–0.696). The median and 2 year RS of 15 months and 26% in 2005–2006 was similar to the median and 2 year OS of 14.6 months and 26% seen in the EORTC/NCIC phase III study. These results are encouraging and suggest that the current treatment of glioblastoma nationwide is now associated with an improved survival compared to previous time cohorts.
PMCID: PMC4077033  PMID: 21984115
Glioblastoma; Radiation; Temozolomide; SEER
15.  A Catalytic Mechanism for d-Tyr-tRNATyr Deacylase Based on the Crystal Structure of Hemophilus influenzae HI0670* 
The Journal of biological chemistry  2003;278(15):13496-13502.
d-Tyr-tRNATyr deacylase is an editing enzyme that removes d-tyrosine and other d-amino acids from charged tRNAs, thereby preventing incorrect incorporation of d-amino acids into proteins. A model for the catalytic mechanism of this enzyme is proposed based on the crystal structure of the enzyme from Haemophilus influenzae determined at a 1.64-Å resolution. Structural comparison of this dimeric enzyme with the very similar structure of the enzyme from Escherichia coli together with sequence analyses indicate that the active site is located in the dimer interface within a depression that includes an invariant threonine residue, Thr-80. The active site contains an oxyanion hole formed by the main chain nitrogen atoms of Thr-80 and Phe-79 and the side chain amide group of the invariant Gln-78. The Michaelis complex between the enzyme and d-Tyr-tRNA was modeled assuming a nucleophilic attack on the carbonyl carbon of d-Tyr by the Thr-80 Oγ atom and a role for the oxyanion hole in stabilizing the negatively charged tetrahedral transition states. The model is consistent with all of the available data on substrate specificity. Based on this model, we propose a substrate-assisted acylation/deacylation-catalytic mechanism in which the amino group of the d-Tyr is deprotonated and serves as the general base.
PMCID: PMC3762893  PMID: 12571243
16.  The Discovery of MK-4256, a Potent SSTR3 Antagonist as a Potential Treatment of Type 2 Diabetes 
ACS Medicinal Chemistry Letters  2012;3(6):484-489.
A structure–activity relationship study of the imidazolyl-β-tetrahydrocarboline series identified MK-4256 as a potent, selective SSTR3 antagonist, which demonstrated superior efficacy in a mouse oGTT model. MK-4256 reduced glucose excursion in a dose-dependent fashion with maximal efficacy achieved at doses as low as 0.03 mg/kg po. As compared with glipizide, MK-4256 showed a minimal hypoglycemia risk in mice.
PMCID: PMC4025728  PMID: 24900499
SSTR3; antagonist; type 2 diabetes; β-tetrahydrocarboline
17.  Establishing a surgical partnership between Addis Ababa, Ethiopia, and Toronto, Canada 
Canadian Journal of Surgery  2013;56(3):E19-E23.
Academic partnerships between high-and low/middle-income countries can improve the quality of surgical education and health care delivery in each setting. We report the perceived needs related to collaborative surgical education in a resource-limited setting.
We used qualitative methods to elicit the opinions of surgical faculty members and surgical residents and quantitative methods to outline surgical procedure type and volume.
Ethiopian faculty members identified the management of trauma and emergency surgical care as a priority. They identified supervision in the operating room (OR), topic-specific lectures and supervising resident assessments in the clinic as appropriate roles for partners. Residents were in agreement with faculty members, highlighting a desire for supervision in the OR and topic-specific lectures.
We present specific experiences and needs of a surgical teaching unit in a low-income country, paving the way to form a meaningful and responsive relationship between 2 surgical departments in 2 universities.
PMCID: PMC3672439  PMID: 23706853
18.  Stimulation of Glucose-Dependent Insulin Secretion by a Potent, Selective sst3 Antagonist 
ACS Medicinal Chemistry Letters  2012;3(4):289-293.
This letter provides the first pharmacological proof of principle that the sst3 receptor mediates glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. To enable these studies, we identified the selective sst3 antagonist (1R,3R)-3-(5-phenyl-1H-imidazol-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-β-carboline (5a), with improved ion channel selectivity and mouse pharmacokinetic properties as compared to previously described tetrahydro-β-carboline imidazole sst3 antagonists. We demonstrated that compound 5a enhances GSIS in pancreatic β-cells and blocks glucose excursion induced by dextrose challenge in ipGTT and OGTT models in mice. Finally, we provided strong evidence that these effects are mechanism-based in an ipGTT study, showing reduction of glucose excursion in wild-type but not sst3 knockout mice. Thus, we have shown that antagonism of sst3 represents a new mechanism with potential in treating type 2 diabetes mellitus.
PMCID: PMC4025754  PMID: 24900466
somatostatin; type 2 diabetes; sst3; glucose-stimulated insulin secretion
20.  Structural basis for the mechanism and substrate specificity of glycocyamine kinase, a phosphagen kinase family member†‡ 
Biochemistry  2010;49(9):2031-2041.
Glycocyamine kinase (GK), a member of the phosphagen kinase family, catalyzes the Mg2+-dependent reversible phosphoryl group transfer of the N-phosphoryl group of phospho glycocyamine to ADP to yield glycocyamine and ATP. This reaction helps to maintain the energy homeostasis of the cell in some multicelullar organisms that encounter high and variable energy turnover. GK from the marine worm Namalycastis sp. is heterodimeric, with two homologous polypeptide chains, α and β, derived from a common pre mRNA by mutually exclusive N-terminal alternative exons. The N-terminal exon of GKβ encodes a peptide that is different in sequence and is sixteen amino acids longer than that encoded by the N-terminal exon of GKα. The crystal structures of recombinant GKαβ and GKββ from Namalycastis sp. were determined at 2.6 Å and 2.4 Å resolution, respectively. In addition, the structure of the GKββ was determined at 2.3 Å resolution in complex with a transition state analog, Mg2+-ADP-NO3--glycocyamine. Consistent with the sequence homology, the GK subunits adopt the same overall fold as that of other phosphagen kinases of known structure (the homodimeric creatine kinase (CK) and the monomeric arginine kinase (AK)). As with CK, the GK N-termini mediate the dimer interface. In both heterodimeric and homodimeric GK forms, the conformations of the two N-termini are asymmetric and the asymmetry is different than that reported previously for the homodimeric CKs from several organisms. The entire polypeptide chains of GKαβ are structurally defined and the longer N-terminus of the β subunit is anchored at the dimer interface. In GKββ the 24 N-terminal residues of one subunit and 11 N-terminal residues of the second subunit are disordered. This observation is consistent with a proposal that the GKαβ amino acids involved in the interface formation were optimized once a heterodimer emerged as the physiological form of the enzyme. As a consequence, the homodimer interface (either solely α or solely β chains) has been corrupted. In the unbound state, GK exhibits an open conformation analogous to that observed with ligand-free CK or AK. Upon binding the transition state analog, both subunits of GK undergo the same closure motion that clasps the transition state analog, in contrast to the transition state analog complexes of CK, where the corresponding transition state analog occupies only one subunit, which undergoes domain closure. The active site environments of the GK, CK and AK at the bound states reveal the structural determinants of substrate specificity. Despite the equivalent binding in both active sites of the GK heterodimer, the conformational asymmetry of the N-termini is retained. Thus, the coupling between the structural asymmetry and negative cooperativity previously proposed for CK is not supported in the case of GK.
PMCID: PMC3519428  PMID: 20121101
21.  Open reduction and internal fixation of unstable slipped capital femoral epiphysis by means of surgical dislocation does not decrease the rate of avascular necrosis: a preliminary study 
The treatment of unstable slipped capital femoral epiphysis (SCFE) remains controversial. Surgical dislocation and open reduction has the potential to significantly reduce the rate of avascular necrosis (AVN) by allowing direct preservation of the femoral head blood supply. The purpose of this study was to determine if open reduction of the unstable SCFE by means of surgical hip dislocation reduced the risk of AVN compared with closed reduction and percutaneous pinning.
We reviewed the medical records and radiographs of patients treated at our institution between the years 2000 and 2008. Sex, age, side of slip, precipitating event, pre- and post-operative anterior physeal separation (APS) and slip angle, slip severity, time between inciting event and surgical treatment, number of screws used, development of AVN, and need for subsequent surgery were evaluated. Statistical analysis was performed to compare risk factors and occurrence of AVN.
From 2004 to 2008, we treated 12 patients with unstable SCFEs: six had closed reduction and percutaneous pinning and six underwent open reduction by means of surgical hip dislocation. There were no statistically significant differences between the two groups regarding sex, age, slip angle, APS, time to surgery, and AVN rate. At follow-up, 4 (66.7 %) patients had AVN in the group which had open reduction, while 2 (33.3 %) patients had AVN in the group which underwent closed reduction. (p = 0.57).
Open reduction of the unstable SCFE by means of surgical dislocation of the hip does not decrease the rate of AVN when compared to closed reduction.
PMCID: PMC3425698  PMID: 23904893
Slipped capital femoral epiphysis; Closed reduction; Open reduction; Surgical dislocation of the hip; Percutaneous pinning; Avascular necrosis
22.  Helmet use in BIXI cyclists in Toronto, Canada: an observational study 
BMJ Open  2012;2(3):e001049.
To investigate the use of helmets for cyclists choosing to use BIXI bikes in comparison to personal bike riders in the City of Toronto.
Cross-sectional study design.
Cyclists were observed in Toronto, Canada.
Of the 6732 sample size, 306 cyclists on BIXI bikes and 6426 personal bike riders were observed.
Outcome measure
The outcome of interest was helmet use.
Overall, 50.3% of cyclists wore helmets. The proportion of BIXI bike riders using helmets was significantly lower than the proportion of helmet users on personal bikes (20.9% vs 51.7%, respectively, p<0.0001).
Although the BIXI bike programme has provided an alternate means for Torontonians to use a bicycle, cyclists using BIXI bikes are much less likely to wear a helmet. Since the prevalence of helmet use in cyclists in general is already low, helmet use should be especially promoted in BIXI bike riders in order to promote a safe and healthy environment for cyclists.
Article summary
Article focus
We investigated the use of helmets for cyclists choosing to use BIXI bikes in comparison to personal bike riders in the City of Toronto.
We hypothesised that the proportion of helmet users using BIXI bikes would be significantly lower than those on personal bikes.
Key messages
Cyclists using BIXI bikes in Toronto are less likely to wear a helmet than cyclists riding their own bike; only 20.9% of all BIXI cyclists wear helmets compared with 51.7% of cyclists riding a personal bike.
More men than women ride bicycles in Toronto.
Women in Toronto were more likely to wear a helmet while cycling.
Strengths and limitations of this study
This is the first study (to our knowledge) investigating helmet use in a bike-sharing system. Additional strengths include the prospective study design, number of observations, randomly selected observation sites and stratified analyses by sex.
The data were collected by one of the observer not blinded to the study hypothesis; observations were limited to presumed commuter hours in the downtown core of Toronto and we were unable to account for variables previously associated with helmet use, including income, education and age.
PMCID: PMC3378939  PMID: 22710130
23.  Child automobile restraints 
PMCID: PMC3114897  PMID: 21398232
24.  Corruption in the health care sector: A barrier to access of orthopaedic care and medical devices in Uganda 
Globally, injuries cause approximately as many deaths per year as HIV/AIDS, tuberculosis and malaria combined, and 90% of injury deaths occur in low- and middle- income countries. Given not all injuries kill, the disability burden, particularly from orthopaedic injuries, is much higher but is poorly measured at present. The orthopaedic services and orthopaedic medical devices needed to manage the injury burden are frequently unavailable in these countries. Corruption is known to be a major barrier to access of health care, but its effects on access to orthopaedic services is still unknown.
A qualitative case study of 45 open-ended interviews was conducted to investigate the access to orthopaedic health services and orthopaedic medical devices in Uganda. Participants included orthopaedic surgeons, related healthcare professionals, industry and government representatives, and patients. Participants’ experiences in accessing orthopaedic medical devices were explored. Thematic analysis was used to analyze and code the transcripts.
Analysis of the interview data identified poor leadership in government and corruption as major barriers to access of orthopaedic care and orthopaedic medical devices. Corruption was perceived to occur at the worker, hospital and government levels in the forms of misappropriation of funds, theft of equipment, resale of drugs and medical devices, fraud and absenteeism. Other barriers elicited included insufficient health infrastructure and human resources, and high costs of orthopaedic equipment and poverty.
This study identified perceived corruption as a significant barrier to access of orthopaedic care and orthopaedic medical devices in Uganda. As the burden of injury continues to grow, the need to combat corruption and ensure access to orthopaedic services is imperative. Anti-corruption strategies such as transparency and accountability measures, codes of conduct, whistleblower protection, and higher wages and benefits for workers could be important and initial steps in improving access orthopaedic care and OMDs, and managing the global injury burden.
PMCID: PMC3492067  PMID: 22554349
25.  The impact of pedestrian countdown signals on pedestrian–motor vehicle collisions: a quasi-experimental study 
Injury Prevention  2011;18(4):210-215.
To determine whether pedestrian countdown signals (PCS) reduce pedestrian–motor vehicle collisions in the city of Toronto, Canada.
A quasi-experimental study design was used to evaluate the effect of PCS on the number of pedestrian–motor vehicle collisions in the city of Toronto, from January 2000 to December 2009. Each intersection acted as its own control. We compared the number of pedestrian–motor vehicle collisions per intersection-month before and after the intervention. Stratified models were used to evaluate effect modification by pedestrian age, injury severity and location (urban vs inner suburbs). Poisson regression analysis with repeated measures (generalised estimating equations) was used to estimate the RR and 95% CI.
The analysis included 9262 pedestrian–motor vehicle collisions at 1965 intersections. The RR of collisions after PCS installation was 1.014 (95% CI 0.958 to 1.073), indicating no statistically significant effect of PCS on collisions. There was no evidence to suggest effect modification between PCS and collisions by age, injury severity or location.
The installation of PCS at 1965 signalised intersections in Toronto did not reduce the number of pedestrian–motor vehicle collisions at these intersections.
PMCID: PMC3406612  PMID: 22157206
Accidents; bicycle; Canada; child; database; epidemiology; evaluation; MVTC; occupational; pedestrians; playground; public health; restraint; safety; surveillance; traffic/prevention and control; training

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