Repurposing of the Cardiovascular Drug Statin for the Treatment of Cancers: Efficacy of Statin-Dipyridamole Combination Treatment in Melanoma Cell Lines.

Metastatic melanoma has a very poor prognosis. Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) inhibitors, are cholesterol-lowering agents with a potential for cancer treatment. The inhibition of HMGCR by statins, however, induces feedback, which paradoxically upregulates HMGCR expression via sterol regulatory element-binding protein-2 (SREBP2). Dipyridamole, an antiplatelet agent, is known to inhibit SREBP2 upregulation. We aimed to demonstrate the efficacy of statin-dipyridamole combination treatment in both human and spontaneously occurring canine melanoma cell lines. The half maximal inhibitory concentration (IC50) of atorvastatin showed a 68-92% reduction when combined with dipyridamole, compared with that of atorvastatin alone. In some melanoma cell lines, cell proliferation was suppressed to almost zero by the combination treatment (≥3 µM atorvastatin). Finally, the BRAF inhibitor, vemurafenib, further potentiated the effects of the combined statin-dipyridamole treatment in BRAF V600E mutation-bearing human melanoma cell lines. In conclusion, the inexpensive and frequently prescribed statin-dipyridamole combination therapy may lead to new developments in the treatment of melanoma and may potentiate the effects of vemurafenib for the targeted therapy of BRAF V600E-mutation bearing melanoma patients. The concordance between the data from canine and human melanoma cell lines reinforces this possibility.

Biomechanical assessment of gastrocnemii and Achilles tendon using MyotonPRO: in vivo measurements, and preliminary in situ measurements using formalin-fixed tissues.

PURPOSE: This study aims to evaluate the reliability and validity of using MyotonPRO to quantify the mechanical properties of the muscle-tendon unit through in vivo measurements and preliminary in situ measurements using formalin-fixed tissues. MATERIALS AND METHODS: The mechanical properties of gastrocnemii and the Achilles tendon of 12 healthy adults (six males and six females, 34.9 ± 5.8 years) were examined for in vivo test twice within a day and once post-24 hours using MyotonPRO, while nine human cadavers (formalin-fixed, 3 males and 6 females, 89.9 ± 5.1 years) were assessed for preliminary in situ test with identical time schedule to evaluate the within-day and inter-day reliability and validity. RESULTS: In vivo tests had very high within-day (ICC: 0.96-0.99) and inter-day reliability (ICC: 0.83-0.96), while in situ tests (formalin-fixed tissues) showed high within-day (ICC: 0.87-0.99) and inter-day reliability (ICC: 0.76-0.98) for the results of tone and stiffness. There was no significant difference in the stiffness of the free part of the Achilles tendon between in vivo and in situ conditions. The stiffness of the lateral gastrocnemius (r = 0.55, p = 0.018), proximal part of the Achilles tendon (r = 0.56, p = 0.015), and free part of the Achilles tendon (r = 0.47, p = 0.048) before removing the skin was significantly correlated with that after removing the skin condition. CONCLUSIONS: The findings of the current study suggest that MyotonPRO is reliable and valid for evaluating tendon stiffness both in vivo and in situ (formalin-fixed tissues).

Comparison of the anticancer effects of various statins on canine oral melanoma cells.

Canine oral melanoma is a highly malignant cancer with a poor prognosis. Statins, commonly used drugs for treating dyslipidemia, exhibit pleiotropic anticancer effects and marked anti-proliferative effects against melanoma cells. The anticancer effects among statins vary; in human cancers, lipophilic statins have shown stronger anticancer effects compared with hydrophilic statins. However, data on the differences in the effects of various statins on canine cancer cells are lacking, hence the optimal statins for treating canine melanoma remain unknown. Therefore, this study aimed to clarify the most effective statin by comparing the anticancer effects of hydrophilic rosuvastatin and lipophilic atorvastatin, simvastatin, fluvastatin and pitavastatin on three canine oral melanoma cell lines. Time-dependent measurement of cell confluence showed that lipophilic statins had a stronger anti-proliferative effect on all cell lines than hydrophilic rosuvastatin. Quantification of lactate dehydrogenase release, an indicator of cytotoxicity, showed that lipophilic statins more effectively induced cell death than hydrophilic rosuvastatin. Lipophilic statins affected both inhibition of cell proliferation and induction of cell death. The anticancer effects of statins on canine oral melanoma cells differed in the following ascending order of IC50 values: pitavastatin < fluvastatin = simvastatin < atorvastatin < rosuvastatin. The required concentration of pitavastatin was approximately 1/20th that of rosuvastatin. Among the statins used in this study, pitavastatin had the highest anticancer effect. Our results suggest lipophilic pitavastatin as the optimal statin for treating canine oral melanoma.

CYP11A1 silencing suppresses HMGCR expression via cholesterol accumulation and sensitizes CRPC cell line DU-145 to atorvastatin.

Statins, which are cholesterol synthesis inhibitors, are well-known therapeutics for dyslipidemia; however, some studies have anticipated their use as anticancer agents. However, epithelial cancer cells show strong resistance to statins through an increased expression of HMG-CoA reductase (HMGCR), an inhibitory target of statins. Castration-resistant prostate cancer (CRPC) cells synthesize androgens from cholesterol on their own. We performed suppression of CYP11A1, a rate-limiting enzyme in androgen synthesis from cholesterol, using siRNA or inhibitors, to examine the effect of steroidogenesis inhibition on statin sensitivity in CRPC cells. Here, we suggested that CYP11A1 silencing sensitized the statin-resistant CRPC cell line DU-145 to atorvastatin via HMGCR downregulation by an increase in intracellular free cholesterol. We further demonstrated that CYP11A1 silencing induced epithelial-mesenchymal transition, which converted DU-145 cells into a statin-sensitive phenotype. This suggests that concomitant use of CYP11A1 inhibitors could be an effective approach for overcoming statin resistance in CRPC. Moreover, we showed that ketoconazole, a CYP11A1 inhibitor, sensitized DU-145 cells to atorvastatin, although not all the molecular events observed in CYP11A1 silencing were reproducible. Although further studies are necessary to clarify the detailed mechanisms, ketoconazole may be effective as a concomitant drug that potentiates the anticancer effect of atorvastatin.

HMG-CoA reductase degrader, SR-12813, counteracts statin-induced upregulation of HMG-CoA reductase and augments the anticancer effect of atorvastatin.

Statins are cholesterol-lowering drugs that have exhibited potential as cancer therapeutic agents. However, as some cancer cells are resistant to statins, broadening an anticancer spectrum of statins is desirable. The upregulated expression of the statin target enzyme, 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase (HMGCR), in statin-treated cancer cells is a well-known mechanism of statin resistance, which can be counteracted by the downregulation of HMGCR gene expression, or degradation of the HMGCR protein. However, the mechanism by which HMGCR degradation influences the anticancer effects of statins remain unreported. We tested the effect of the HMGCR degrader compound SR-12813 at a concentration that did not affect the growth of eight diverse tumor cell lines. Combined treatment with atorvastatin and a low concentration of SR-12813 led to lowering of increased HMGCR expression, and augmented the cytostatic effect of atorvastatin in both statin-resistant and -sensitive cancer cells compared with that of atorvastatin treatment alone. Dual-targeting of HMGCR using statins and SR-12813 (or similar compounds) could provide an improved anticancer therapeutic approach.

Expression of housekeeping genes varies depending on mevalonate pathway inhibition in cancer cells.

Statins have anticancer effects and may be used as anticancer agents via drug repositioning. In reverse transcription-quantitative polymerase chain reaction (RT-qPCR) assays, the internal reference gene must not be affected by any experimental conditions. As statins exert a wide range of effects on cells by inhibiting the mevalonate pathway, it is possible that statin treatment might alter the expression of housekeeping genes used as internal reference genes, thereby misleading the assessment of obtained gene expression data. Here, we evaluated the expression stability of internal reference genes in atorvastatin-treated cancer cell lines. We treated both statin-sensitive and statin-resistant cancer cell lines with atorvastatin at seven different concentrations and performed RT-qPCR on 15 housekeeping genes whose expression stability was then assessed using five different algorithms. In both statin-sensitive and statin-resistant cancer cell lines, atorvastatin affected the expression of certain internal reference genes in a dose-dependent and cancer cell line-dependent manner; therefore, caution should be exercised when comparing target gene expression between cells. Our findings emphasize the importance of the validation of internal reference genes in gene expression analyses in drug treatment-based cancer research.

Is parental propensity to risk associated with their child's medically-attended injuries? A cross-sectional study.

BACKGROUND: Societal expectations about safety influence parents' risk perceptions and children's risky play opportunities. This study examined parents' propensity to take risks themselves and their propensity to accept risks for their child, sex-related differences in parents' propensity to accept risks for their child, and the association between parents' propensity to accept risks for their child and that child's medically-attended injury history. METHODS: A total of 467 parents attending a pediatric hospital with their 6-12-year-old child completed a questionnaire about their risk propensity for themselves and for their child and reported their child's injury history. RESULTS: Parents' risk propensity for themselves was significantly higher than for their child, and fathers' risk propensity for themselves was higher than mothers'. Linear regressions showed that fathers reported significantly more propensity to accept risks for their child than mothers, but parents did not differentiate between their sons and daughters. A binary logistic regression showed that parents' propensity to accept risks for their child was a significant predictor of pediatric medically-attended injury. CONCLUSIONS: Parents were more comfortable in taking risks for themselves than for their child. While fathers were more comfortable with their children engaging in risks than mothers, child's sex was not related to parents' propensity to accept risks for their child. Pediatric injury was predicted by parents' propensity to accept risks for their child. Further research investigating injury type and severity related parent risk propensity is needed to determine how parents' attitudes toward risk might relate to severe injury.

Convergent Validity of Myheartsmap: A Pediatric Psychosocial Health Screening Tool.

Recognition of pediatric mental health concerns often depends on assessment by parents, educators, and primary care professionals. Therefore, a psychosocial screening instrument suitable for routine use in schools and primary care is needed. The Pediatric Quality of Life (PedsQL) and the Strengths and Difficulties Questionnaire (SDQ) are widely used for screening but lack adolescent-specific mental health measures. MyHEARTSMAP is an instrument assessing aspects of youth psychosocial health via four domains: Psychiatry, Function, Social, and Youth Health. We evaluated MyHEARTSMAP convergent validity with PedsQL and SDQ among 122 child-parent dyads participating in a larger concussion study. Convergent validity was assessed via correlations: MyHEARTSMAP Psychiatry and Function domains correlated strongly (r ≥ 0.44) and Social domain correlated weakly (r ≤ 0.25) to corresponding PedsQL and SDQ subscales, while Youth Health domain correlated moderately (r ≥ 0.31) to the tools' total scales. In conclusion, MyHEARTSMAP converges with PedsQL and SDQ, and benefits from the inclusion of adolescent-specific psychosocial measures.

Atorvastatin preferentially inhibits the growth of high ZEB-expressing canine cancer cells.

The epithelial-to-mesenchymal transition (EMT) is fundamental in cancer progression and contributes to the acquisition of malignant properties. The statin class of cholesterol-lowering drugs exhibits pleiotropic anticancer effects in vitro and in vivo, and many epidemiologic studies have reported a correlation between statin use and reduced cancer mortality. We have shown previously that sensitivity to the anti-proliferative effect of statins varies among human cancer cells and statins are more effective against mesenchymal-like cells than epithelial-like ones in human cancers. There have only been few reports on the application of statins to cancer therapy in veterinary medicine, and differences in statin sensitivity among canine cancer cells have not been examined. In this study, we aimed to clarify the correlation between sensitivity to atorvastatin and epithelial/mesenchymal states in 11 canine cancer cell lines derived from mammary gland, squamous cell carcinoma, lung, and melanoma. Sensitivity to atorvastatin varied among canine cancer cells, with IC50 values ranging from 5.92 to 71.5 µM at 48 h, which were higher than the plasma concentrations clinically achieved with statin therapy. Atorvastatin preferentially attenuated the proliferation of mesenchymal-like cells. In particular, highly statin-sensitive cells were characterized by aberrant expression of the ZEB family of EMT-inducing transcription factors. However, ZEB2 silencing in highly sensitive cells did not induce resistance to atorvastatin. Taken together, these results suggest that high expression of ZEB is a characteristic of highly statin-sensitive cells and could be a molecular marker for predicting whether cancers are sensitive to statins, though ZEB itself does not confer statin sensitivity.

Estrogen modulates the skeletal muscle regeneration process and myotube morphogenesis: morphological analysis in mice with a low estrogen status.

The purpose of this study was to elucidate the functions of estrogen and two estrogen receptors (ERs; ERα and ERß) in the myoregeneration process and morphogenesis. Cardiotoxin (CTX) was injected into the tibialis anterior (TA) muscles of ovariectomized (OVX) mice to induce muscle injury, and subsequent myoregeneration was morphologically assessed. The diameter of regenerated myotubes in OVX mice was significantly smaller than that in intact mice at all time points of measurement. OVX mice also showed lower muscle recovery rates and slower speeds than did intact mice. ER protein levels showed a predominance of ERß over ERα in both intact and OVX states. The ERß level was increased significantly at 7 days after CTX injection in OVX mice and remained at a high level until 14 days. In addition, continuous administration of E2 to OVX mice in which muscle injury was induced resulted in a significantly larger diameter of regenerated myotubes than that in mice that did not receive estrogen. The results indicate that estrogen is an essential factor in the myoregeneration process since estrogen depletion delayed myoregeneration in injured muscles and administration of estrogen under the condition of a low estrogen status rescued delayed myoregeneration. The results strongly suggested that ERß may be a factor that promotes myoregeneration more than does ERα.

Concomitant attenuation of HMGCR expression and activity enhances the growth inhibitory effect of atorvastatin on TGF-ß-treated epithelial cancer cells.

Epithelial-mesenchymal transition (EMT) in primary tumor cells is a key prerequisite for metastasis initiation. Statins, cholesterol-lowering drugs, can delay metastasis formation in vivo and attenuate the growth and proliferation of tumor cells in vitro. The latter effect is stronger in tumor cells with a mesenchymal-like phenotype than in those with an epithelial one. However, the effect of statins on epithelial cancer cells treated with EMT-inducing growth factors such as transforming growth factor-ß (TGF-ß) remains unclear. Here, we examined the effect of atorvastatin on two epithelial cancer cell lines following TGF-ß treatment. Atorvastatin-induced growth inhibition was stronger in TGF-ß-treated cells than in cells not thusly treated. Moreover, treatment of cells with atorvastatin prior to TGF-ß treatment enhanced this effect, which was further potentiated by the simultaneous reduction in the expression of the statin target enzyme, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). Dual pharmacological targeting of HMGCR can thus strongly inhibit the growth and proliferation of epithelial cancer cells treated with TGF-ß and may also improve statin therapy-mediated attenuation of metastasis formation in vivo.

Absence of estrogen receptors delays myoregeneration and leads to intermuscular adipogenesis in a low estrogen status: Morphological comparisons in estrogen receptor alpha and beta knock out mice.

This study aimed to investigate the function of estrogen receptors (ERs) in myoregeneration and intermuscular adipogenesis. Ovariectomized (OVX) ERα knockout (KO) mice and ERß KO mice were used to assess the effect of estrogen on the myoregenerative process. Tibialis anterior muscle was collected on days 7, 10, and 14 after cardiotoxin injection to assess myotube morphology and adipogenesis area. Regenerated myotubes from OVX-ERß KO mice were consistently smaller in diameter than those from OVX-ERα KO and OVX-wild-type mice, whereas the adipogenesis area of OVX-ERß KO mice was consistently greater than that of the other types. Therefore, ERß may be an influential factor in promoting myoregeneration and adipogenesis inhibition compared to ERα.

Reducing length of stay and return visits for emergency department pediatric mental health presentations.

BACKGROUND: Variability in expertise and risk tolerance among emergency departments (ED) clinicians, when assessing and managing pediatric mental health presentations, leads to increased resource utilization. HEARTSMAP is a validated electronic tool that supports ED clinicians in psychosocial assessments and disposition decision making. METHODS: We used interrupted time series analysis (September 2016-December 2019) and multivariable regressions to measure the impact of integrating HEARTSMAP into ED practice on pediatric mental health presentations length of stay and return visits, at two pediatric EDs. The intervention site used HEARTSMAP trained ED clinicians to assess and manage mental health presentations, and reported bi-weekly ED median length of stay and 30 days-return visits for 15 months and a year, during passive and active implementation of HEARTSMAP, respectively. The control site used psychiatric nurses to assess and manage patients and was only exposed to passive implementation. RESULTS: HEARTSMAP average uptake was on average 47.4% (range 23.8-74.6%) during active implementation at the intervention site, while the control site showed no uptake throughout the study period. Incremental HEARSTMAP (each percent increase) use was associated with a reduction of 1.8 min (95% CI 0.8-2.9 in ED length of stay and 0.3% (95% CI 0.2-0.5 in 30-day return visit rate. This translates to an adjusted average reduction of 85.3 min in ED length of stay and 15.2% in 30-day return visits for youth with mental health presentations. CONCLUSION: Use of HEARTSMAP in the ED can decrease length of stay and return visits for emergency pediatric mental health visits, in a fixed-resource setting.

RéSUMé: CONTEXTE: La variabilité de l'expertise et de la tolérance au risque parmi les cliniciens des services d'urgence (SU), lors de l'évaluation et de la gestion des présentations de santé mentale pédiatrique, conduit à une utilisation accrue des ressources. HEARTSMAP est un outil électronique validé qui appuie les cliniciens du service d'urgence dans les évaluations psychosociales et la prise de décisions en matière de disposition. LES MéTHODES: Nous avons utilisé une analyse de séries chronologiques interrompues (de septembre 2016 à décembre 2019) et des régressions multivariables pour mesurer l'impact de l'intégration de HEARTSMAP dans la pratique des services d'urgence sur les présentations de santé mentale pédiatrique ; la durée du séjour et les visites de retour, dans deux services d'urgence pédiatriques. Le site d'intervention a utilisé des cliniciens formés par HEARTSMAP pour évaluer et gérer les présentations sur la santé mentale, et a fait état d'une durée médiane de séjour aux urgences toutes les deux semaines et de 30 jours de visites de retour pendant 15 mois et un an, pendant la mise en œuvre passive et active de HEARTSMAP, respectivement. Le site de contrôle a fait appel à des infirmières psychiatriques pour évaluer et gérer les patients et n'a été exposé qu'à une mise en œuvre passive. RéSULTATS: L'utilisation moyenne de HEARTSMAP était en moyenne de 47,4 % (intervalle : 23,8 à 74,6 %) pendant la mise en œuvre active sur le site d'intervention, tandis que le site témoin n'a montré aucune utilisation pendant toute la période d'étude. L'utilisation incrémentielle de HEARSTMAP (chaque pourcentage d'augmentation) a été associée à une réduction de 1,8 minutes (IC à 95 % : 0,8-2,9 de la durée du séjour aux urgences et 0,3 % (IC à 95 % : 0,2-0,5 du taux de visites de retour dans les 30 jours). Cela se traduit par une réduction moyenne ajustée de 85,3 minutes de la durée du séjour aux urgences et de 15,2 % des visites de retour sur 30 jours pour les jeunes ayant des présentations sur la santé mentale. CONCLUSIONS: L'utilisation de HEARTSMAP au SU peut réduire la durée du séjour et des visites de retour pour les visites d'urgence pédiatriques en santé mentale, dans un contexte de ressources fixes.

Comparison of risk engagement and protection survey (REPS) among mothers and fathers of children aged 6-12 years.

BACKGROUND: Parental attitudes regarding child safety and risk engagement play important roles in child injury prevention and health promotion efforts. Few studies have compared mothers' and fathers' attitudes on these topics. This study used the risk engagement and protection survey (REPS) previously validated with fathers to compare with data collected from mothers. METHODS: Multi-group confirmatory factor analysis was used with a sample of 234 mothers and 282 fathers. Eligible parents had a child 6-12 years attending a paediatric hospital for an injury-related or other reason. We tested the factor structure of the survey by examining configural, metric and scalar invariance. Following this, mothers' and fathers' mean scores on the two identified factors of child injury protection and risk engagement were compared. RESULTS: Comparing mothers' and fathers' data showed the two-factor structure of the REPS held for the mothers' data. Comparing mean scores for the two factors suggested that fathers and mothers held equivalent attitudes. For the combined sample, parent injury protection attitude scores were significantly higher for daughters versus sons. In addition, attitude scores were significantly lower for injury protection and higher for risk engagement among parents born in Canada compared with those who were not. CONCLUSIONS: The REPS allows for valid assessment of injury protection and risk engagement factors for fathers and mothers. Mothers conceptualised the two factors as distinct concepts, similar to fathers. The REPS can be used to inform parenting programme development, implementation and evaluation.

Changes in parents' perceived injury risk after a medically-attended injury to their child.

Unintentional injuries are a major cause of hospitalization and death for children worldwide. Since children who sustain a medically-attended injury are at higher risk of recurrence, it is crucial to generate knowledge that informs interventions to prevent re-incidence. This study examines when, in the year following a medically-attended injury, parents perceive the greatest risk of injury recurrence. Since perception of injury risk is associated with parental preventive behavior, this can inform decisions on the timing of parent-targeted interventions to prevent re-injury. Study participants were 186 English-fluent parents of children 0 to 16 years, presenting at the British Columbia Children's Hospital for an unintentional pediatric injury. Parents were excluded if their child had a disability or chronic health condition. Perceived risk of the same and of any injury recurring were elicited from parents, when they sought treatment at the hospital, as well as one, four, and twelve months later. The study ran between February 2011 and December 2013. Mixed-effects models were used to analyze changes in parents' responses. Analysis indicates that perceived risk of the same injury recurring did not change. However, perceived risk of any injury recurring increased from baseline to first follow-up, then decreased during the rest of the year. Overall, perceived risk of any injury was higher for parents whose child had a history of injuries. Visits to the Emergency Department for a pediatric injury may not be optimal timing to deploy injury prevention interventions for parents. Follow-up visits (when parents' perceived risk is highest) may be better.

Concomitant attenuation of HMG-CoA reductase expression potentiates the cancer cell growth-inhibitory effect of statins and expands their efficacy in tumor cells with epithelial characteristics.

HMG-CoA reductase (HMGCR) inhibitors, statins, are potent cholesterol reducing drugs that exhibit anti-tumor effects in vitro and in animal models, including attenuation of metastasis formation, and their use correlates with reduced cancer-specific mortality in retrospective human cohort studies. However, E-cadherin expressing epithelial- and mixed epithelial-mesenchymal cancer cell lines (reflective of primary and outgrowing metastatic tumor cells, respectively) require higher statin concentrations than mesenchymal-like tumor cells (reflective of in-circulation metastatic tumor cells) to achieve the same degree of growth inhibition. Here, we show that attenuation of HMGCR expression in the presence of atorvastatin leads to stronger growth inhibition than dual target blockade of the mevalonate pathway in relatively statin resistant cell lines, mainly through inhibition of protein prenylation pathways. Thus, combined inhibition of the mevalonate pathway's rate-limiting enzyme, HMGCR, can improve atorvastatin's growth inhibitory effect on epithelial- and mixed mesenchymal-epithelial cancer cells, a finding that may have implications for the design of future anti-metastatic cancer therapies.

Go Play Outside! Effects of a risk-reframing tool on mothers' tolerance for, and parenting practices associated with, children's risky play: study protocol for a randomized controlled trial.

BACKGROUND: Children's risky play is associated with a variety of positive developmental, physical and mental health outcomes, including greater physical activity, self-confidence and risk-management skills. Children's opportunities for risky play have eroded over time, limited by parents' fears and beliefs about risk, particularly among mothers. We developed a digital tool and in-person Risk-reframing (RR) workshop to reframe parents' perceptions of risk and change parenting behaviours. The purpose of this paper is to describe our RR intervention, rationale and protocol for a randomised controlled trial to examine whether it leads to increases in mothers' tolerance of risk in play and goal attainment relating to promoting their child's opportunities for risky play. METHODS: We use a randomised controlled trial design and will recruit a total of 501 mothers of children aged 6-12 years. The RR digital tool is designed for a one-time visit and includes three chapters of self-reflection and experiential learning tasks. The RR in-person tool is a 2-h facilitated workshop in which participants are guided through discussion of the same tasks contained within the digital tool. The control condition consists of reading the Position Statement on Active Outdoor Play. Primary outcome is increased tolerance of risk in play, as measured by the Tolerance of Risk in Play Scale. Secondary outcome is self-reported attainment of a behaviour-change goal that participants set for themselves. We will test the hypothesis that there will be differences between the experimental and control conditions with respect to tolerance of risk in play using mixed-effects models. We will test the hypothesis that there will be differences between the experimental and control conditions with respect to goal attainment using logistic regression. DISCUSSION: The results of this trial will have important implications for facilitating the widespread change in parents' risk perception that is necessary for promoting broad societal understanding of the importance of children's risky play. In addition, the findings may provide relevant information for the design of behaviour-change tools to increase parental tolerance of risk. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03374683 . Retrospectively registered on 15 December 2017.

Risk Engagement and Protection Survey (REPS): developing and validating a survey tool on fathers' attitudes towards child injury protection and risk engagement.

INTRODUCTION: Fathers play a unique role in keeping children safe from injury yet understanding of their views and attitudes towards protecting children from injury and allowing them to engage in risks is limited. The purpose of this study was to develop and validate an instrument to measure fathers' attitudes towards these two constructs. METHODS AND FINDINGS: An instrument was developed that used prior qualitative research to inform item generation. The questions were assessed for content validity with experts, then pilot-tested with fathers. The survey was completed by 302 fathers attending hospital with their child for an injury or non-injury reason. Results of confirmatory factor analysis identified eight items relating to the protection from injury factor and six items relating to the risk engagement factor. Correlation between the two factors was low, suggesting these are two independent constructs. CONCLUSIONS: The Risk Engagement and Protection Survey offers a tool for measuring attitudes and assisting with intervention strategy development in ways that reflect fathers' views and promotes a balanced view of children's needs for safety with their needs for engaging in active, healthy risk-taking.

A longitudinal study on quality of life after injury in children.

BACKGROUND: In high income countries, injuries account for 40 % of all child deaths, representing the leading cause of child mortality and a major source of morbidity. The need for studies across age groups, and use of health related quality of life measures that assess functional limitations in multiple health domains, with sampling at specific post-injury time points has been identified. The objective of this study was to describe the impact of childhood injury and recovery on health related quality of life (HRQoL) for the 12 months after injury. METHODS: In this prospective cohort study parents of children 0-16 years old attending British Columbia Children's Hospital for an injury were surveyed over 12 months post-injury. Surveys assessed HRQoL at four points: baseline (pre-injury), one month, four to six months and 12 months post injury. Generalized estimating equation models identified factors associated with changes in HRQoL over time. RESULTS: A total of 256 baseline surveys were completed. Response rates for follow-ups at one, four and twelve months were 74 % (186), 67 % (169) and 64 % (161), respectively. The mean age of participants was 7.9 years and 30 % were admitted to the hospital. At baseline, a retrospective measure of pre-injury health, the mean HRQoL score was 90.7. Mean HRQoL ratings at one, four and 12 months post injury were 77.8, 90.3 and 91.3, respectively. Both being older and being hospitalized were associated with a steeper slope to recovery. CONCLUSIONS: Although injuries are prevalent, the long term impacts of most childhood injuries are limited. Regardless of injury severity, most injured children recuperated quickly, and had regained total baseline status by four month post-injury. However, although hospitalization did not appear to impact long term psychosocial recovery, at four and 12 months post injury a greater proportion of hospitalized children continued to have depressed physical HRQoL scores. Both older and hospitalized children reported greater impact to HRQoL at one month post injury, and both had a steeper slope to recovery and were on par with their peers by four month.

Pediatric Canadian Triage and Acuity Scale (PaedsCTAS) as a Measure of Injury Severity.

This research explored whether the pediatric version of the Canadian Triage Acuity Scale (PaedsCTAS) represented a valid alternative indicator for surveillance of injury severity. Every patient presenting in a Canadian emergency department is assigned a CTAS or PaedsCTAS score in order to prioritize access to care and to predict the nature and scope of care that is likely to be required. The five-level PaedsCTAS score ranges from I (resuscitation) to V (non-urgent). A total of 256 children, 0 to 17-years-old, who attended a pediatric hospital for an injury were followed longitudinally. Of these children, 32.4% (n = 83) were hospitalized and 67.6% (n = 173) were treated in the emergency department and released. They completed the PedsQL(TM), a validated measure of health related quality of life, at baseline (pre-injury status), one-month, four- to six-months, and 12-months post-injury. In this secondary data analysis, PaedsCTAS was found to be significantly associated with hospitalization and length of stay, sensitive to the differences between PaedsCTAS II and III, and related to physical but not psychosocial HRQoL. The findings suggest that PaedsCTAS may be a useful proxy measure of injury severity to supplement or replace hospitalization status and/or length of stay, currently proxy measures.