Utrophin levels have recently been shown to be more abundant in slow vs. fast muscles, but the nature of the molecular events underlying this difference remains to be fully elucidated. Here, we determined whether this difference is due to the expression of utrophin A or B, and examined whether transcriptional regulatory mechanisms are also involved. Immunofluorescence experiments revealed that slower fibers contain significantly more utrophin A in extrasynaptic regions as compared with fast fibers. Single-fiber RT-PCR analysis demonstrated that expression of utrophin A transcripts correlates with the oxidative capacity of muscle fibers, with cells expressing myosin heavy chain I and IIa demonstrating the highest levels. Functional muscle overload, which stimulates expression of a slower, more oxidative phenotype, induced a significant increase in utrophin A mRNA levels. Because calcineurin has been implicated in controlling this slower, high oxidative myofiber program, we examined expression of utrophin A transcripts in muscles having altered calcineurin activity. Calcineurin inhibition resulted in an 80% decrease in utrophin A mRNA levels. Conversely, muscles from transgenic mice expressing an active form of calcineurin displayed higher levels of utrophin A transcripts. Electrophoretic mobility shift and supershift assays revealed the presence of a nuclear factor of activated T cells (NFAT) binding site in the utrophin A promoter. Transfection and direct gene transfer studies showed that active forms of calcineurin or nuclear NFATc1 transactivate the utrophin A promoter. Together, these results indicate that expression of utrophin A is related to the oxidative capacity of muscle fibers, and implicate calcineurin and its effector NFAT in this mechanism.

Utrophin has been studied extensively in recent years in an effort to find a cure for Duchenne muscular dystrophy. In this context, we previously showed that mice expressing enhanced muscle calcineurin activity (CnA*) displayed elevated levels of utrophin around their sarcolemma. In the present study, we therefore crossed CnA* mice with mdx mice to determine the suitability of elevating calcineurin activity in preventing the dystrophic pathology. Muscles from mdx/CnA* displayed increased nuclear localization of NFATc1 and a fiber type shift towards a slower phenotype. Measurements of utrophin levels in mdx/CnA* muscles revealed an approximately 2-fold induction in utrophin expression. Consistent with this induction, we also observed that members of the dystrophin-associated protein (DAP) complex were present at the sarcolemma of mdx/CnA* mouse muscle. This restoration of the utrophin-DAP complex was accompanied by significant reductions in the extent of central nucleation and fiber size variability. Importantly, assessment of myofiber sarcolemmal damage, as monitored by the intracellular presence of IgM and albumin as well as by Evans blue uptake in vivo, revealed a net amelioration of membrane integrity. Finally, immunofluorescence experiments using Mac-1 antibodies showed a reduction in the number of infiltrating immune cells in muscles from mdx/CnA* mice. These results show that elevated calcineurin activity attenuates the dystrophic pathology and thus provides an effective target for pharmacological intervention.

RESEARCH pediatric dentistryAims To investigate patterns of referral, disease and treatment for healthy children who had received two or more dental general anaesthetics (DGA) for exodontia. Methods Records from 200 episodes of repeat DGA were studied retrospectively. Results The mean age of patients at first referral was 5y4m, and the mean interval before repeat was 22 months. Self-referrals rose from 14% at DGA1 to 30% at DGA2. New caries at second referral, where all diagnosed disease had been treated at DGA1, accounted for only 15% of the total. Where a specific request was made in the referral, only 8% of letters matched the charting made in hospital. 30% of all specific requests were honoured, but then required treatment for previously diagnosed caries at DGA2. 75% of single-tooth extractions required repeat DGA for caries left at DGA1. Conclusions It may be too optimistic to address only the most grossly diseased teeth when a child requires GA exodontia. A more radical treatment-planning approach, combining primary care, secondary care and public health considerations, may be required to avoid the unnecessary use of DGA.

Objectives: To characterize the stated practices of qualified Canadian physicians toward tracheostomy for pediatric prolonged mechanical ventilation and whether subspecialty and comorbid conditions impact attitudes toward tracheostomy. Design: Cross sectional web-based survey. Subjects: Pediatric intensivists, neonatologists, respirologists, and otolaryngology-head and neck surgeons practicing at 16 tertiary academic Canadian pediatric hospitals. Interventions: Respondents answered a survey based on three cases (Case 1: neonate with bronchopulmonary dysplasia; Cases 2 and 3: children 1 and 10 years old with pediatric acute respiratory distress syndrome, respectively) including a series of alterations in relevant clinical variables. Measurements and Main Results: We compared respondents’ likelihood of recommending tracheostomy at 3 weeks of mechanical ventilation and evaluated the effects of various clinical changes on physician willingness to recommend tracheostomy and their impact on preferred timing (≤ 3 wk or > 3 wk of mechanical ventilation). Response rate was 165 of 396 (42%). Of those respondents who indicated they had the expertise, 47 of 121 (38.8%), 23 of 93 (24.7%), and 40 of 87 (46.0%) would recommend tracheostomy at less than or equal to 3 weeks of mechanical ventilation for cases 1, 2, and 3, respectively (p < 0.05 Case 2 vs 3). Upper airway obstruction was associated with increased willingness to recommend earlier tracheostomy. Life-limiting condition, severe neurologic injury, unrepaired congenital heart disease, multiple organ system failure, and noninvasive ventilation were associated with a decreased willingness to recommend tracheostomy. Conclusion: This survey provides insight in to the stated practice patterns of Canadian physicians who care for children requiring prolonged mechanical ventilation. Physicians remain reluctant to recommend tracheostomy for children requiring prolonged mechanical ventilation due to lung disease alone at 3 weeks of mechanical ventilation. Prospective studies characterizing actual physician practice toward tracheostomy for pediatric prolonged mechanical ventilation and evaluating the impact of tracheostomy timing on clinically important outcomes are needed as the next step toward harmonizing care delivery for such patients.

Background: Antimicrobial stewardship interventions to curtail the use of third-generation cephalosporins and antipseudomonal penicillins for the treatment of complicated appendicitis in children are challenging given the tendency to treat complicated disease with broad-spectrum antimicrobials. Reasons for this are unclear, but there is a paucity of contemporary microbiologic data associated with the child presenting with either acute perforated or gangrenous appendicitis. This study aimed to justify the appropriateness of an empiric regimen consisting of ampicillin, tobramycin/gentamicin plus metronidazole and to analyze duration of postoperative therapy. Methods: We conducted a retrospective cohort study from February 1, 2017, to October 31, 2018, in children who underwent appendectomy or interventional radiologic drainage for primary complicated appendicitis. The primary outcome was the proportion of patients who had a pathogen isolated from peritoneal fluid culture that was not susceptible to the recommended empiric therapy. The secondary outcomes were the total duration of antimicrobial therapy and the proportion of patients with a postoperative infectious complication within 30 days after intervention. Results: Of 425 children with primary acute appendicitis, 158 (37%) had complicated appendicitis at presentation. Culture was performed in 53 (40%) of the 133 who underwent a surgical or interventional radiologic intervention. The group with peritoneal cultures was more likely to present with longer symptom duration before admission [3 (interquartile range, 2–5) vs 2 (interquartile range, 1–2) days; P < 0.001] and with purulent peritonitis [47% (25/53) vs 13% (10/80); P < 0.001]. The most common pathogens isolated were anaerobes (81%), Escherichia coli (74%) and Streptococcus anginosus group (62%). Only 4% of isolated bacteria were resistant to empiric therapy. Postoperative infectious complications were documented in 23 (17%) patients and were not associated with the presence of a resistant pathogen or the choice of antimicrobial agents but with more severe disease and higher C-reactive protein values (303 vs 83 mg/L; P=0.03) at presentation. Conclusions: In a cohort of previously healthy children presenting with complicated appendicitis requiring surgical drainage, the most common bacteria from peritoneal cultures continue to be S. anginosus, aminoglycoside-susceptible Gram-negative bacilli and anaerobes. In an attempt to reduce extended-spectrum cephalosporin use, these data were useful in supporting the use of metronidazole with ampicillin and an aminoglycoside, rather than third-generation cephalosporins.

Aim: This study aimed to evaluate the validity, reliability and acceptability of the Implementation Leadership Scale in the Chinese nursing context. Design: This study utilized a cross-sectional design. Methods: This study was conducted in one general tertiary hospital with 234 nurses (85.3% response rate) from 35 clinical units in China. Content validity, structural validity, convergent validity, reliability (internal consistency), agreement indices and acceptability were evaluated. The data collection was from December 1st, 2017 to June 30th, 2018. Results: Confirmatory factor analysis demonstrated a good model fit to the fourfactor implementation leadership model. The psychometric testing also indicated good convergent validity, high internal consistency and acceptable aggregation. Most participants completed the scale in two minutes or less and agreed or strongly agreed that the questions were relevant to implementation leadership, clear and easy to answer.

Objectives To describe variations in the monitoring, treatment, and discharge of children hospitalized with bronchiolitis among physicians across Canadian paediatric teaching hospitals. Methods We conducted an electronic survey of paediatricians with experience in the management of inpatient bronchiolitis at 20 Canadian paediatric teaching hospitals. Only physicians who worked a minimum of 6 weeks on their hospital inpatient unit in the 2015 calendar year were eligible to participate in the study. The questionnaire explored the monitoring, treatment, and discharge of children with bronchiolitis. Central tendency (mean) and dispersion (SD) statistics were produced for continuous variables and frequency distributions for categorical variables. Results A total of 142 respondents were included in the analysis. 45.1% reported the routine use of continuous oxygen saturation monitoring. 27.5% used a higher cut-off for oxygen supplementation of 92% and 12.7% use a lower cut-off of 88%. 29.6% routinely used deep nasal suctioning. Seventy-three per cent reported using nebulized therapies. 55.6% reported having preprinted order sheets or guidelines for management of inpatient bronchiolitis at their institutions and 28.2% reported having specific discharge criteria. The length of time required to be off oxygen prior to discharge varied (31% at 12 hours, 27.5% at 24 hours, and 24.6% after the last sleep period without oxygen). Conclusion There is significant practice variation in the monitoring, treatment, and discharge of children hospitalized with bronchiolitis within and between Canadian paediatric teaching hospitals. Future research is needed to establish best practices, effective knowledge translation, and implementation strategies to standardize care and decrease length of stay.

Hypospadias is a common anomaly among males 1 with several variations, each with a slightly different surgical approach toward correction of the defects in the urethral fold and ventral foreskin. 1 Previous studies have demonstrated that duration of surgery and type of hypospadias repair impact surgical results. Additional complicating factors were the specific surgical technique, patient age, penile engorgement, postoperative inflammatory response, and tissue edema. [1][2][3][4][5][6][7][8] Recent publications from centers in the United States, India, and Korea report that children undergoing hypospadias repair with caudal regional anesthesia/analgesia could have increased postoperative surgical complications. [2][3][4][5] This was unexpected to many of us, AbstractBackground: Recent publications from the United States, India, and Korea report that children undergoing hypospadias repair with caudal regional anesthesia/analgesia could have increased postoperative surgical complications. Aims:The purpose of this retrospective cohort study was to assess the impact between caudal regional anesthesia, other regional anesthesia, and no regional anesthesia on complications after hypospadias repair at a tertiary care children's hospital in Ottawa, Canada, with an expectation to changing practices if a link was found. Method:We reviewed the health records of 827 children with hypospadias undergoing penile surgery from January 1991-June 2017. The final sample size for the analysis consisted of 764 patients and 825 procedures. Results:The overall complications were almost identical when considering anesthesia effects, and this similarity persisted when we assessed specifically for only surgical complications. We had 716, 94, and 15 subjects who had a caudal block, penile block, and general anesthesia only, respectively, and their complication rates were 28, 31, and 27%, respectively, and their fistula formation rates were 10, 6, and 0%, respectively, and their stricture formation rates were 8, 7, and 20%,, respectively.Hypospadias type and surgical repair technique were marked predictors of complications in the postoperative period.Conclusion: Anesthesia technique appears to have minor impact on complications after hypospadias repair, while surgical technique and type of hypospadias impact complications after hypospadias surgery in children. Based upon these results, we will not change our current practice of using a variety of regional anesthesia techniques for children undergoing hypospadias repair. K E Y W O R D Sanesthesia, caudal, complications, hypospadias repair, regional anesthesia | 761as a caudal has been routine practice of pediatric anesthesiologists for 40+ years and is strongly supported by most surgical colleagues and families.We wanted to review our results and determine if the issues and concerns noted in other centers were also occurring at Children's Hospital of Eastern Ontario, Ottawa, Canada. If so, we would need to change our routine practice to an improved, evidence-based medicine practice, ie, stop ...