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The aim of this article is to explore how the Swedish ideal of ‘progressive fatherhood’ is represented in the context of a photo competition and exhibition organised by the Swedish Embassy in postcolonial Zimbabwe. Drawing on Rose’s (2016) method of visual discourse analysis (VDA), the article examines how Zimbabwean fathers are represented as being progressive through both image and text, and the extent to which these representations could be seen to challenge or ‘mimic’ (Bhabha, 1984) the Swedish ideal of ‘progressive fatherhood’. While some of these representations reproduced certain binaries, they also presented the kind of ambivalent, ‘postfeminist’ relationship with gender equality that has been identified in other contexts. Overall, these representations were found to go beyond colonial mimicry by challenging and extending the Swedish ideal of ‘progressive fatherhood’ beyond the context of the middle-class, nuclear family.

GS, the stimulatory heterotrimeric G protein, is an essential regulator of osteogenesis and bone turnover. To determine if increasing GαS in osteoblasts alters bone responses to hyperparathyroidism, we used a transgenic mouse line overexpressing GαS in osteoblasts (GS-Tg mice). Primary osteoblasts from GS-Tg mice showed increased basal and parathyroid hormone (PTH)-stimulated cAMP and greater responses to PTH than cells from WT mice. Skeletal responses to 2-week continuous PTH administration (cPTH) in female mice resulted in trabecular bone loss in WT mice but 74% and 34% increase in trabecular bone mass in long bones and vertebrae, respectively, in GS-Tg mice. Vertebral biomechanical strength was compromised by cPTH treatment in WT mice but not in GS-Tg. Increased peritrabecular fibrosis was greatly increased by cPTH in Gs-Tg compared to WT mice and corresponded with greater increases in Wnt pathway proteins in trabecular bone. Cortical bone responded negatively to cPTH in WT and Gs-Tg mice with large increases in porosity, decreased cortical thickness and compromised biomechanical properties. These results demonstrate that hyperparathyroidism can increase trabecular bone when GS expression and cAMP stimulation in osteoblasts are increased but this is not the case in cortical bone where increased GS expression exacerbates cortical bone loss.

Advances in mathematical and computational technologies have brought unique and ground-breaking benefits to diverse fields throughout society (engineering, medicine, economics, etc.). Within legal systems, however, the potential applications of data science and innovative mathematical tools have yet to be embraced with the same ambition. The complex decision-making that is needed for reaching just verdicts is often seen as out of reach for such approaches and, in the case of criminal trials, this inhibits exploration into whether machine learning could have a positive impact. Here, through assigning numerical scores to prosecution and defence evidence, and employing an approach based on dimensionality reduction, we showed that evidence strands presented at historical murder trials could be used to train effective machine-learning algorithms (or models). We tested the evidence quantification approach with the trained model and showed that, through machine learning, criminal cases could be clearly classified (probability >99.9%) as belonging to either a guilty or a not-guilty category. The classification was found to be as expected for all test cases. All guilty test cases that were not wrongful convictions were correctly assigned to the guilty category by our model and, crucially, test cases that were wrongful convictions were correctly assigned to the not-guilty category. This work demonstrated the potential for machine learning to benefit criminal trial decision-making, and should motivate further testing and development of the model and datasets for assisting the judicial process.

Background Training is essential before working on a clinical trial, yet there is limited evidence on effective training methods. In low and middle income countries (LMICs), training of research staff was considered the second highest priority in a global health methodological research priority setting exercise. Methods We explored whether an enhanced training package in a neonatal feasibility study in Kenya and India, utilising elements of the train-the-trainer approach, altered clinicians and researchers’ clinical trials knowledge. A lead “trainer” was identified at each site who attended a UK-based introductory course on clinical trials. A two-day in-country training session was conducted at each hospital. Sessions included the study protocol, governance, data collection and ICH-Good Clinical Practice (GCP). To assess effectiveness of the training package, participants completed questionnaires at the start and end of the study period, including demographics, prior research experience, protocol-specific questions, informed consent and ICH-GCP. Results Thirty participants attended in-country training sessions and completed baseline questionnaires. Around three quarters had previously worked on a research study, yet only half had previously received training. Nineteen participants completed questionnaires at the end of the study period. Questionnaire scores were higher at the end of the study period, though not significantly so. Few participants ‘passed’ the informed consent and ICH-Good Clinical Practice (GCP) modules, using the Global Health Network Training Centre pass mark of ≥ 80%. Participants who reported having prior research experience scored higher in questionnaires before the start of the study period. Conclusions An enhanced training package can improve knowledge of research methods and governance though only small improvements in mean scores between questionnaires completed before and at the end of the study period were seen and were not statistically significant. This is the first report evaluating a clinical trial training package in a neonatal trial in LMICs. Due to the Covid-19 pandemic, research activity was paused and there was a significant time lapse between training and start of the study, which likely impacted upon the scores reported here. Given the burden of disease in LMICs, developing high-quality training materials which utilise a variety of approaches and build research capacity, is critical.

The absence of functional dystrophin with mutations of the dystrophin-encoding gene in Duchenne muscular dystrophy (DMD) results in muscle inflammation and degeneration, as well as bone fragility. Long-term glucocorticoid therapy delays the muscular disease progression but suppresses growth hormone secretion, resulting in short stature and further deleterious effects on bone strength. This study evaluated the therapeutic potential of daily growth hormone therapy in growing mdx mice as a model of DMD. Growth hormone treatment on its own or in combination with glucocorticoids significantly improved muscle histology and function and decreased markers of inflammation in mdx mice. Glucocorticoid treatment thinned cortical bone and decreased bone strength and toughness. Despite the minimal effects of growth hormone on bone microarchitecture, it significantly improved biomechanical properties of femurs and vertebrae, even in the presence of glucocorticoid treatment. Together these studies suggest that the use of growth hormone in DMD should be considered for improvements to muscle and bone health. © 2019 American Society for Bone and Mineral Research.

Duchenne Muscular Dystrophy (DMD) is a progressive muscle disorder caused by genetic mutations of the dystrophin encoding gene. In the absence of functional dystrophin, DMD patients suffer from muscle inflammation and wasting, as well as compromised bone health with increased risk of fracture. The use of high dose glucocorticoids (GC) as the standard therapy also contributes to bone fragility. This study examined the effects of intermittent, daily administered parathyroid hormone (iPTH), an approved bone anabolic therapy, on growing bone and dystrophic muscle in the presence and absence of prednisone treatment using the Mdx mouse model of DMD. Five-weeks of prednisone treatment in Mdx mice decreased cortical bone thickness and area (p 0.001), with a large increase in endocortical osteoclasts that were significantly improved by PTH treatment (p 0.001). GC-induced decreases in cortical bone toughness and modulus were improved with iPTH therapy (p 0.05). Mdx mice showed significantly less bone mass in trabecular compartments of lumbar vertebrae and iPTH treatment, with or without glucocorticoids, significantly improved structural and material properties of this bone. Prednisone improved grip strength and endurance of treadmill running, which were maintained and further improved, respectively, in co-treated Mdx mice. Altogether, our study demonstrates that iPTH therapy significantly ameliorated GC-induced bone loss and maintained or further enhanced the positive effects of GCs on dystrophic muscle function. These findings give insight into the potential for use of teriparatide to treat growing bone in children with DMD.

Background Waiting lists are an ongoing issue for publicly funded community and hospital-based health services. Parents and caregivers are instrumental supports in the health and well-being of young and school-aged children, yet little is known about the way they can be supported during waiting periods. Given mounting evidence about the value of early intervention in physical and mental health literature, and waits for some public health services extending past 12 months, it is both timely and warranted to explore interim interventions that may be applied in this period. Methods Intervention studies that have applied an educational programme, information, group-based support or individualised therapy to primary caregivers of children (heron referred to as parent-directed interventions), waiting for diagnostic assessment at any inpatient or outpatient health service and aged between 1 and 12 years of age, will be reviewed. These will include intervention studies of any type that have included more than 5 participants or participant groups and where a control or comparison group has been included. Abstract screening, full-text review, data extraction and risk of bias will be conducted by two reviewers. Relevant databases in health and education will be systematically searched using key words and Medical Subject Headings (MeSH) and grey literature will be explored. Databases will include PubMed, Ovid for MEDLINE and PsycINFO, EBSCO for the Cumulative Index of Nursing and Allied Health Literature (CINAHL), and the Education Resources Information Center (ERIC). Covidence© will be used to support abstract and full text screening, which will be completed by two main reviewers. Results will be tabulated, summarised and meta-analysed using a random-effects model, in any instance where concordant outcome measures have been applied. Results will be published and reported in line with PRISMA reporting guidelines. Discussion Given little is known about effective support for families when children are awaiting diagnostic assessment for any medical, developmental or behavioural condition, the authors will synthesise existing evidence about parent-directed interventions in this period. It is hoped that by understanding the existing evidence interventions that are proven to be effective will be adopted and intervention innovation can occur. Systematic review registration PROSPERO 2020 CRD42020159360

BackgroundClinical aggression episodes, that is aggression and externalising behaviours that create risk, in acute care hospitals are increasing. Acute care staff are often not confident or trained in the management of aggression. Various aggression management training formats have been described in practice including face to face training, written learning resources, web- and media-based training resources, and simulation training. The aim of this systematic review is to assess whether simulation-based training is effective in increasing de-escalation knowledge, skills, and behaviour of staff working in the acute care setting.MethodsWe designed and registered a study protocol for a systematic review of studies evaluating simulation-based training for the management of patients with aggression. We will include randomised controlled trials, non-randomised controlled trials, quasi-experimental studies, and observational studies including health care professionals and trainees in acute health care settings. Comprehensive searches will be conducted in the following databases (from January 1980 onwards): PubMed, MEDLINE, PsycINFO, CINAHL, and the Cochrane Library. The reference lists of selected studies, trial registers, and leading journals will also be searched. Two reviewers will independently screen all citations, full-text articles, and abstract data. Potential discrepancies will be resolved through discussion. The primary outcomes will include patient outcomes (e.g. frequency of clinical aggression), quality of care (e.g. frequency of emergency situations, physical/chemical/mechanical restraint), and adverse effects (e.g. patient/family complaints, patient harms, staff harms). Secondary outcomes will include workplace resource use, health care provider-related outcomes, knowledge (de-escalation techniques), performance, attitudes, and satisfaction. The study methodological risk of bias will be appraised using appropriate tools. A narrative synthesis will be performed for included studies. If feasible, we will conduct random-effects meta-analysis of data. Additional analyses will be conducted to explore the potential sources of heterogeneity (e.g. participant characteristics, interventions, and follow-up).DiscussionThis systematic review will identify, evaluate, and integrate the evidence on simulation-based training programmes for acute care health professionals on managing clinical aggression. The results of this study will inform the implementation of effective training strategies. Implications for future research will be discussed.Systematic review registrationPROSPERO registration number CRD42020151002

Background Patients with coronary artery disease have an increased risk for developing vascular cognitive impairment. Endothelial function is often diminished and has been associated with lower cognitive performance in these patients. The link between endothelial function and cognition in coronary artery disease is not fully understood. Angiogenesis may play a role in mediating the association between endothelial function and cognition since angiogenic processes rely heavily on the endothelium. Objective The aim of this study was to determine if markers of angiogenesis mediate the relationship between endothelial function and cognition in coronary artery disease patients. Methods In 50 participants with coronary artery disease, endothelial function was assessed using peripheral arterial tonometry. Vascular endothelial growth factor (pro-angiogenic) and endostatin (anti-angiogenic) were measured in peripheral serum samples. Cognition was assessed using the Montreal Cognitive Assessment. A mediation analysis, using a bias corrected inferential bootstrapping method with 10,000 permutations, was used to determine if vascular endothelial growth factor or endostatin mediated an association between peripheral arterial tonometry measures and cognitive performance on the Montreal Cognitive Assessment. Results Endostatin, but not vascular endothelial growth factor, mediated a relationship between endothelial function and cognitive performance when controlling for total years of education, body mass index, coronary artery bypass graft, stent, diabetes, and diuretic use. This analysis was also significant when delayed recall was substituted for the overall score on the Montreal Cognitive Assessment. Conclusion These results suggest that endostatin mediates an association between endothelial function and cognitive performance in coronary artery disease.

Aims In light of the recent safety concerns relating to NSAID use in COVID-19, we sought to evaluate cardiovascular and respiratory complications in patients taking NSAIDs during acute lower respiratory tract infections. Methods We carried out a systematic review and meta-analysis of randomised controlled trials and observational studies. Studies of adult patients with short-term NSAID use during acute lower respiratory tract infections, including bacterial and viral infections, were included. Primary outcome was all-cause mortality. Secondary outcomes were cardiovascular, renal and respiratory complications. Results In total, eight studies including two randomised controlled trials, three retrospective and three prospective observational studies enrolling 44140 patients were included. Five of the studies were in patients with pneumonia, two in patients with Influenza, and one in patients with acute bronchitis. There was uncertainty as to the effects on mortality (RR 0.87 [0.63, 1.18]), but pleuro-pulmonary complications were more common with NSAID use (RR 2.62 [1.96, 3.50]). However, all studies exhibited high risks of bias, primarily due to lack of adjustment for confounding variables. Cardiovascular outcomes were not reported by any of the included studies. Conclusion Short-term NSAID use during acute lower respiratory tract infections was associated with more pleuro-pulmonary complications although this may be due to confounding by indication. There remains significant uncertainty on the effects on mortality. Such results should be interpreted cautiously given the very low quality of evidence. Mechanistic and clinical studies addressing the captioned subject are urgently needed, especially in relation to COVID-19.

Primary hyperparathyroidism (PHPT) is an endocrine disorder characterized by elevated parathyroid hormone (PTH) levels and hypercalcemia caused by the overactive parathyroid glands, resulting in negative impacts on the skeleton including bone loss and increased bone fragility1. PTH binds and activates parathyroid hormone type 1 receptor (PTH1R) which primary couples to Gαs, stimulating the downstream effectors that mediate bone remodeling processes2. PTH1R activity is regulated by arrestins, specially β-arrestin2 (β-arr2), through signal termination and receptor internalization2. Previously, we have seen anabolic effects of hyperparathyroidism (cPTH) on trabecular bone in mice overexpressing Gαs3. We hypothesized that increased Gαs protein levels in osteoblasts outcompete β-arr binding to PTH1R, leading to reduced signal termination and increased bone formation. To test this hypothesis, we are testing if the deletion of β-arr2 will also result in an anabolic response to cPTH in this study. The response of β-arr2 knockout (KO) mice to cPTH have yet to be documented. The hypothesis of this study is that β-arr2 KO mice treated with cPTH will exhibit anabolic effects on the trabecular bone. Nine-week-old wild-type (WT) C57BL/6 and β-arr2 KO mice were treated for 14 days with either rPTH1-34 (80ng/g/day) or saline (PBS) using micro-osmotic pumps to simulate hyperparathyroidism. There are 8 groups (n=10 per group) including both sexes, 2 genotypes (WT and KO), and 2 treatment groups (PTH and PBS). Two 30 mg/kg doses of 0.6% calcein green were administered subcutaneously to mice at 7 and 2 days prior to euthanasia to label bones. Decalcified tibiae were embedded in paraffin for histological analysis. Undecalcified tibiae were embedded in plastic for dynamic histomorphometry. Micro-computed tomography (μCT) was used to access bone microarchitecture of femurs and vertebrae followed by biomechanical testing of bone strength. The μCT data of distal femurs show that cPTH treatment increased bone volume in female KO mice (6.864 ± 2.318 vs 4.690 ± 1.555 %; P= 0.0328; n=9 per group) and maintained bone in male KO mice (13.37 ± 2.860 vs 13.38 ± 3.135; P= 0.9968, n= 10) compared to control. Histological analysis show higher osteoclastic activity in both sexes and genotypes when treated with cPTH, suggesting that the anabolic response may be at the level of osteoblasts and osteocytes. These promising results support our hypothesis that arrestin-mediated PTH receptor downregulation plays an importance role in bone weakness associated with hyperparathyroidism. These studies are important for understanding the clinical phenotype of PHPT patients and suggest that inhibition of β-arr2 in PHPT could be a path for drug therapy. References: (1) Mosekilde L. Clin Endocrinol 2008;69:1-9. (2) Ferrari SL et al., J Biol Chem 1999; 274:29968–29975 (3) Zhang L. PhD thesis University of Toronto, 2018.

Osteoporosis, the most common bone disease in humans, is characterised by decreased bone mass and increased fracture risk1. Osteoporosis development is associated with an imbalance of bone resorption and deposition mediated by all three bone cell types; osteoblasts, osteocytes and osteoclasts2. Current treatments for osteoporosis either prevent further bone resorption (Bisphosphonates and anti-RANKL) or increase bone deposition through anabolism (Teriparatide and Abaloparatide)3. The two anabolic treatments are truncated analogues of endogenous peptides; parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP), respectively. Both are administered intermittently, act on PTH1R receptors on osteoblasts and osteocytes leading to an increase in bone mineral density and bone strength. However, both treatments also have side-effects of hypercalcemia and cortical bone porosity caused by osteoclast stimulation. We therefore compared an array of PTH and PTHrP analogues for potential stimulation of catabolic side effects and desired anabolic effects. Screening assays used are UMR106-01 osteocytic cells that have high levels of PTH1R to measure mRNAs involved in anabolic responses (suppression of WNT inhibitors SOST and Dkk1) and catabolic responses (stimulation of RANKL/OPG, IL6). Peptides were also analysed by real-time cellular impedance assays (xCELLigence) to measure unbiased receptor stimulation. xCELLigence assays showed PTH1-34, PTHrP1-34 and Abaloparatide had the highest potencies (3.7 nM,1.4 nM,1.7nM respectively) while Tyr1PTH1-34 and PTH2-34 had significantly decreased potencies (64nM and 130nM), the β-arrestin biased agonist, D-Trp12Tyr34PTH7–34, had no effect. PTH1-34 potently inhibited SOST (IC50 0.29nM), and catabolic genes (RANK/OPG EC50 0.5nM, IL6 EC50 2.5nM). PTHrP1-34 provided higher potencies for anabolic (inhibited SOST IC50 0.08nM) and catabolic (RANKL/OPG EC50 0.3nM, IL6 EC50 1nM) genes. Altering the first amino acid to Tyrosine; Tyr1PTH1-34 caused potent anabolic responses (SOST IC50 0.97nM) yet showed decreased potency for catabolic responses (RANKL/OPG EC50 20nM, IL6 EC50 > 100nM). Removing the first amino acid of PTH to PTH2-34 drastically decreases the effectiveness of the peptide (OPG, SOST and RANKL IC50 – no effect, IL6 EC50 > 100nM). These results indicate the importance of the N-terminal amino acid for PTH affinity and efficacy and suggest that Tyr1PTH1-34 may offer the best combination of bone stimulation without causing hypercalcemia. References 1 A.Gupta, L. March. (2016) Treating osteoporosis, Aust Prescr 2 Chen X, et al. (2018) Osteoblast–osteoclast interactions. Connect. Tissue Res 3 Tu KN, et al. (2018) Osteoporosis: A review of treatment options. P T

The skeleton has been characterized as an endocrine organ, demonstrating a capacity to modulate cognition, mood and energy homeostasis (1,2). These endocrine actions of the skeleton have been attributed to the osteoblast-derived peptide osteocalcin. In mice, uncarboxylated osteocalcin (ucOCN) decreased the acquisition of type 2 diabetes mellitus (T2DM) and ameliorated depressive- and anxiety-like behaviours (1,2). Clinically, T2DM patients present with reduced serum osteocalcin levels and approximately 1 in 4 also suffer from co-morbid depression (3,4). The cognitive and metabolic benefits of ucOCN are similar to the beneficial effects of exercise that is recommended in treatment of both depression and T2DM. Here we compared the effects of ucOCN or exercise in female C57-BL/6J mice under two different metabolic conditions. Mice were fed either a high-fat diet (60% calories from fat) to induce T2DM or a control diet (10% calories from fat). Groups of mice were either sedentary or exercised daily by 30 min treadmill running for two months, with or without daily administration of ucOCN (30 ng/g/day). Mice with T2DM displayed depressive behaviours marked by a higher immobile time in tail suspension tests compared to control mice (97±25 n=11 vs 207±9.0 s n=12; t21=4.21, P=0.0004). Exercise and osteocalcin both improved depressive behaviour (137±8 n=12; t22=5.85, P References: (1) Ferron et al., Bone. 2012 Feb;50(2):568–575. (2) Oury et al., Cell. 2013 Sep 26:155(1):228–241. (3) Liu et al., Horm Metab Res. 2015 Oct;47(11):813–9. (4) Khaledi et al., Acta Diabetol. 2019 June;56(6):631–650.

Osteocalcin is a protein produced in the osteoblasts of bone and found both in the bone matrix and in circulation1. Mouse studies have demonstrated that osteocalcin administration improves type II diabetes through increased insulin release and sensitivity2. Further, osteocalcin can cross the blood-brain barrier and has been shown to restore memory and cognition in mice3. To date, experiments testing the effects of osteocalcin in mice have almost exclusively been conducted in only one sex and could not account for sex as a biological variable. We hypothesized that osteocalcin and exercise would improve behavioral outcomes and aimed to record any difference in response between sexes. In this study, we compare the effects of daily osteocalcin treatment, with or without daily treadmill exercise, in male and female mice (C57BL/6) on a high-fat diet induced model of type II diabetes. Mice were fed high-fat diet for eight weeks, followed by eight weeks of daily osteocalcin injections and/or treadmill exercise. During the final two weeks of treatment behavioural testing for depressive-like behaviour, anxiety-like behaviour, problem-solving, and memory was completed, and the results obtained in male and female mice were compared. The high-fat diet increased depressive-like behaviour and impaired problem solving in both sexes. Significant interactions between sex and exercise and sex and diet were observed. High-fat diet increased anxiety-like behaviour in females, but not males, while exercise increased anxiety-like behaviour in males. Both treatments improved behavioural outcomes, though no difference could be attributed to the combination of treatments. Exercise and osteocalcin decreased depressive-like behaviour in both sexes. Osteocalcin improved problem solving in both sexes, but exercise only improved problem solving in females. The effects of osteocalcin were similar in both male and female mice, however exercise improved problem-solving only in female mice. This suggests that both sexes benefit from osteocalcin treatment and exercise may be more beneficial in females. The results indicate that osteocalcin and exercise have similar but not identical effects on behaviour that may be reflected in overlapping mechanisms of action. References: (1) Lee et al., Cell. 2007; 130(3): 456-469. (2) Ferron et al., Bone. 2012; 50(2): 568–575. (3) Khrimian et al., J Exp Med. 2017; 214(10): 2859-2873.

Serum osteocalcin is emerging as a potential marker of glucose homeostasis and risk of type 2 diabetes mellitus (T2DM). In mice, osteocalcin knockouts exhibit depressive-like behaviours but knockouts of a putative osteocalcin receptor, GPR158, are resistant to chronic unpredictable mild stress. Recently, osteocalcin release from bone has been suggested to mediate some aspects of the acute stress response. Here, we assess relationships between serum osteocalcin, depression and perceived stress in people with T2DM. Participants with T2DM were assessed for whether they met the DSM-5 criteria for Major Depressive Disorder using the research version of the Structured Clinical Interview for DSM-5 depression criteria (SCID-5RV). Subjective stress was assessed using the Perceived Stress Scale (PSS) with higher scores indicating greater subjective stress. Serum carboxylated (cOCN) and uncarboxylated (unOCN) osteocalcin were assayed from fasting morning blood by commercial ELISA. Among 87 participants (mean age 62.9±9.5, 52% women), 18 (26%) were experiencing a depressive episode (7 men, 11 women). Both serum unOCN and cOCN were associated with higher PSS scores in participants with depression (unOCN, r=0.566, p=0.014; cOCN, r=0.564, p=0.015) but not in those without depression (unOCN, r=0.002, p=0.985; cOCN, r=0.090, p=0.463). A significant interaction was found between depression and PSS scores predicting serum unOCN in a linear model adjusted for age, sex, body mass index, antidepressant use and HbA1c (F=6.225, p=0.015). The results are consistent with reports that osteocalcin release from bone may be a mediator of stress perception; however, among people with T2DM, this relationship was observed only among those currently experiencing a depressive episode.

BACKGROUND Children with autism spectrum disorder (ASD) frequently demonstrate aggression and externalizing behaviors in the acute care hospital environment. Pediatric acute care nursing staff are often not trained in managing aggression and, in particular, lack confidence in preventing and managing externalizing behaviors in children with ASD. High-fidelity simulation exercises will be used in this study to provide deliberate practice for acute care pediatric nursing staff in the management of aggressive and externalizing behaviors. OBJECTIVE The purpose of this study is to conduct a pilot and feasibility cluster randomized controlled trial (RCT) to evaluate the effectiveness of simulation-based education for staff in managing aggression and externalizing behaviors of children with ASD in the hospital setting. METHODS This study has a mixed design, with between-group and within-participant comparisons to explore the acceptability and feasibility of delivering a large-scale cluster RCT. The trial process, including recruitment, completion rates, contamination, and completion of outcome measures, will be assessed and reported as percentages. This study will assess the acceptability of the simulation-based training format for two scenarios involving an adolescent with autism, with or without intellectual disability, who displays aggressive and externalizing behaviors and the resulting change in confidence in managing clinical aggression. Two pediatric wards of similar size and patient complexity will be selected to participate in the study; they will be randomized to receive either simulation-based education plus web-based educational materials or the web-based educational materials only. Change in confidence will be assessed using pre- and posttraining surveys for bedside nursing staff exposed to the training and the control group who will receive the web-based training materials. Knowledge retention 3 months posttraining, as well as continued confidence and exposure to clinical aggression, will be assessed via surveys. Changes in confidence and competence will be compared statistically with the chi-square test using before-and-after data to compare the proportion of those who have high confidence between the two arms at baseline and at follow-up. The simulation-based education will be recorded with trained assessors reviewing participants’ abilities to de-escalate aggressive behaviors using a validated tool. This data will be analyzed using mean values and SDs to understand the variation in performance of individuals who undertake the training. Data from each participating ward will be collected during each shift for the duration of the study to assess the number of aggressive incidents and successful de-escalation for patients with ASD. Total change in Code Grey activations will also be assessed, with both datasets analyzed using descriptive statistics. RESULTS This study gained ethical approval from The Royal Children's Hospital Melbourne Human Research Ethics Committee (HREC) on November 1, 2019 (HREC reference number: 56684). Data collection was completed in February 2020. Data analysis is due to commence with results anticipated by August 2020. CONCLUSIONS We hypothesize that this study is feasible to be conducted as a cluster RCT and that simulation-based training will be acceptable for acute care pediatric nurses. We anticipate that the intervention ward will have increased confidence in managing clinical aggression in children with ASD immediately and up to 3 months posttraining. CLINICALTRIAL Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12620000139976; http://www.ANZCTR.org.au/ACTRN12620000139976.aspx INTERNATIONAL REGISTERED REPORT DERR1-10.2196/18105

Background Children with autism spectrum disorder (ASD) frequently demonstrate aggression and externalizing behaviors in the acute care hospital environment. Pediatric acute care nursing staff are often not trained in managing aggression and, in particular, lack confidence in preventing and managing externalizing behaviors in children with ASD. High-fidelity simulation exercises will be used in this study to provide deliberate practice for acute care pediatric nursing staff in the management of aggressive and externalizing behaviors. Objective The purpose of this study is to conduct a pilot and feasibility cluster randomized controlled trial (RCT) to evaluate the effectiveness of simulation-based education for staff in managing aggression and externalizing behaviors of children with ASD in the hospital setting. Methods This study has a mixed design, with between-group and within-participant comparisons to explore the acceptability and feasibility of delivering a large-scale cluster RCT. The trial process, including recruitment, completion rates, contamination, and completion of outcome measures, will be assessed and reported as percentages. This study will assess the acceptability of the simulation-based training format for two scenarios involving an adolescent with autism, with or without intellectual disability, who displays aggressive and externalizing behaviors and the resulting change in confidence in managing clinical aggression. Two pediatric wards of similar size and patient complexity will be selected to participate in the study; they will be randomized to receive either simulation-based education plus web-based educational materials or the web-based educational materials only. Change in confidence will be assessed using pre- and posttraining surveys for bedside nursing staff exposed to the training and the control group who will receive the web-based training materials. Knowledge retention 3 months posttraining, as well as continued confidence and exposure to clinical aggression, will be assessed via surveys. Changes in confidence and competence will be compared statistically with the chi-square test using before-and-after data to compare the proportion of those who have high confidence between the two arms at baseline and at follow-up. The simulation-based education will be recorded with trained assessors reviewing participants’ abilities to de-escalate aggressive behaviors using a validated tool. This data will be analyzed using mean values and SDs to understand the variation in performance of individuals who undertake the training. Data from each participating ward will be collected during each shift for the duration of the study to assess the number of aggressive incidents and successful de-escalation for patients with ASD. Total change in Code Grey activations will also be assessed, with both datasets analyzed using descriptive statistics. Results This study gained ethical approval from The Royal Children's Hospital Melbourne Human Research Ethics Committee (HREC) on November 1, 2019 (HREC reference number: 56684). Data collection was completed in February 2020. Data analysis is due to commence with results anticipated by August 2020. Conclusions We hypothesize that this study is feasible to be conducted as a cluster RCT and that simulation-based training will be acceptable for acute care pediatric nurses. We anticipate that the intervention ward will have increased confidence in managing clinical aggression in children with ASD immediately and up to 3 months posttraining. Trial Registration Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12620000139976; http://www.ANZCTR.org.au/ACTRN12620000139976.aspx International Registered Report Identifier (IRRID) DERR1-10.2196/18105

Duchenne muscular dystrophy (DMD) results from genetic mutations of the gene encoding dystrophin, leading to muscle inflammation and degeneration that is typically treated with glucocorticoids. DMD and its treatment with glucocorticoids result in poor bone health and high risk of fractures. Insufficient levels of 25-hydroxyvitamin D (25-hydroxy D) that may contribute to weakened bone are routinely found in DMD patients. To determine the effect of 25-hydroxy D deficiency, this study examined the effects of low vitamin D dietary intake with and without glucocorticoids on the musculoskeletal system of the Mdx mouse model of DMD. At 10 weeks of age, Mdx mice on control diet had low trabecular bone mineral density of distal femurs and lumbar vertebrae with increased osteoclast numbers compared to wild-type mice. Low vitamin D intake resulted in 25-hydroxy D deficiency but had no effect on trabecular or cortical bone. Cortical bone loss and bone weakness were induced by glucocorticoids while they improved muscle grip strength in Mdx mice. 25-hydroxy D deficiency did not result in any significant effects on growing bone or muscle in the Mdx mice. In combination with glucocorticoid treatment, low 25-hydroxy D resulted in no change in cortical bone mineral density but bone ductility was significantly increased suggesting lower bone mineralization.

Background and objective: Aggression and high-risk behaviors, which can result in behavioral emergencies, are common in children with autism and can be magnified in the hospital environment. Children with autism, with or without intellectual disability, have complex communication needs which require a sophisticated level of knowledge, understanding and skill from health care professionals. Pediatric acute care nursing staff are often not trained and lack confidence in managing children with autism. The purpose of this study was to conduct a pilot and feasibility cluster randomized controlled trial (RCT) of simulation-based education for staff in managing behavioral emergencies with autism spectrum disorder (ASD) in the hospital setting.Methods: This study used a mixed method, to explore the acceptability and feasibility of delivering a large-scale cluster RCT and assess trial processes including recruitment, completion rates, contamination, and outcome measures. The simulation-based training format comprised two scenarios involving an adolescent with autism, intellectual disability and aggressive behaviors. Two pediatric wards of similar size and patient complexity were selected to participate in the study and randomized to receive either simulation-based education plus web-based education materials or web-based education materials only. Results: The RCT design is feasible with recruitment, acceptability and completion rates reaching target. Self-perceived baseline levels of confidence in managing aggression in children were mid-range and lower for children with autism and intellectual disability. Forty to fifty percent of intervention participants rated the training highly in terms of developing skills and knowledge respectively. The mean group score for observer ratings of de-escalation across four simulations was 20 out of a possible 35. Data for ward aggression were not collected.Conclusions: Simulation-based education is an acceptable training format for acute care pediatric nurses. This study is feasible to conduct as a cluster RCT with some modifications to this protocol including assessment of baseline differences in confidence. Observer ratings of de-escalation skills indicated that more than one episode of training may be required for acute care pediatric staff to successfully de-escalate aggressive incidents. As such, we will use repeated simulation scenario exercises for each intervention group in the next trial.

Background Lateral flow device (LFD) viral antigen immunoassays have been developed around the world as diagnostic tests for SARS-CoV-2 infection. They have been proposed to deliver an infrastructure-light, cost-economical solution giving results within half an hour. Methods LFDs were initially reviewed by a Department of Health and Social Care team, part of the UK government, from which 64 were selected for further evaluation from 1st August to 15th December 2020. Standardised laboratory evaluations, and for those that met the published criteria, field testing in the Falcon-C19 research study and UK pilots were performed (UK COVID-19 testing centres, hospital, schools, armed forces). Findings 4/64 LFDs so far have desirable performance characteristics (orient Gene, Deepblue, Abbott and Innova SARS-CoV-2 Antigen Rapid Qualitative Test). All these LFDs have a viral antigen detection of >90% at 100,000 RNA copies/ml. 8951 Innova LFD tests were performed with a kit failure rate of 5.6% (502/8951, 95% CI: 5.1–6.1), false positive rate of 0.32% (22/6954, 95% CI: 0.20–0.48). Viral antigen detection/sensitivity across the sampling cohort when performed by laboratory scientists was 78.8% (156/198, 95% CI 72.4–84.3). Interpretation Our results suggest LFDs have promising performance characteristics for mass population testing and can be used to identify infectious positive individuals. The Innova LFD shows good viral antigen detection/sensitivity with excellent specificity, although kit failure rates and the impact of training are potential issues. These results support the expanded evaluation of LFDs, and assessment of greater access to testing on COVID-19 transmission. Funding Department of Health and Social Care. University of Oxford. Public Health England Porton Down, Manchester University NHS Foundation Trust, National Institute of Health Research.

GαS is a heterotrimeric G protein that transduces signals from activated G protein-coupled receptors on the cell surface to stimulate adenylyl cyclase/cyclic adenosine monophosphate (AMP) signaling. GαS plays a central role in mediating numerous growth and maintenance processes including osteogenesis and bone turnover. Decreased GαS expression or activating mutations in GαS both affect bone, suggesting that modulating GαS protein levels may be important for bone health and development. To examine the effects of increased osteoblastic GαS expression on bone development in vivo, we generated transgenic mice with GαS overexpression in osteoblasts (HOM-Gs mice) driven by the 3.6-kilobase (kb) Col1A1 promoter. Both male and female HOM-Gs mice exhibit increased bone turnover with overactive osteoblasts and osteoclasts, resulting in a high bone mass phenotype with significantly reduced bone quality. At 9 weeks of age, HOM-Gs mice have increased trabecular number, volumetric BMD (vBMD), and bone volume; however, the bone was woven and disorganized. There was also increased cortical bone volume despite an overall reduction in size in HOM-Gs mice along with increased cortical porosity and brittleness. The skeletal phenotype of HOM-Gs mice progressed into maturity at 26 weeks of age with further accrual of trabecular bone, whereas WT mice lost trabecular bone at this age. Although cortical bone volume and geometry were similar between mature HOM-Gs and WT mice, increased porosity persisted and the bone was weaker. At the cellular level, these alterations were mediated by an increase in bone resorption by osteoclasts and an overwhelmingly higher increase in bone formation by osteoblasts. In summary, our findings demonstrate that high osteoblastic GαS expression results in aberrant skeletal development in which bone production is favored at the cost of bone quality. © 2017 American Society for Bone and Mineral Research.

Glucocorticoids (GCs) have unparalleled anti-inflammatory and immunosuppressive properties, which accounts for their widespread prescription and use. Unfortunately, a limitation to GC therapy is a wide range of negative side effects including Cushing's syndrome, a disease characterized by metabolic abnormalities including muscle wasting and osteoporosis. GC-induced osteoporosis occurs in 30% to 50% of patients on GC therapy and thus, represents an important area of study. Herein, we characterize the molecular and physiologic effects of GC-induced osteoporosis using the Cushing's mouse model, the corticotropin releasing hormone (CRH) transgenic mouse (CRH-Tg). The humeri, femurs, and tibias from wild-type (WT) and CRH-Tg male mice, aged 13 to 14 weeks old were subjected to multiple bone tests including, micro-computed tomography (μCT), static and dynamic histomorphometry, strength testing, and gene expression analyses. The CRH-Tg mice had a 38% decrease in cortical bone area, a 35% decrease in cortical thickness, a 16% decrease in trabecular thickness, a sixfold increase in bone adiposity, a 27% reduction in osteoid width, a 75% increase in bone-resorbing osteoclast number/bone surface, a 34% decrease in bone formation rate, and a 40% decrease in bone strength compared to WT mice. At the gene expression level, CRH-Tg bone showed significantly increased osteoclast markers and decreased osteoblast markers, whereas CRH-Tg muscle had increased muscle atrophy gene markers compared to WT mice. Overall, the CRH-Tg mouse model aged to 14 weeks recapitulated many features of osteoporosis in Cushing's syndrome and thus, represents a useful model to study GC-induced osteoporosis and interventions that target the effects of GCs on the skeleton. © 2017 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

Vitamin D supplementation is important for many chronic pediatric conditions to help maintain bone health; however, there is little evidence about how disease-related factors affect vitamin D status. The objective was to compare 25-hydroxyvitamin D (25(OH)D) concentrations in 3 pediatric cohorts (Duchenne muscular dystrophy [DMD], systemic lupus erythematosus [SLE], and osteogenesis imperfecta [OI]). In a retrospective study of 367 subjects, children with DMD had increased prevalence of vitamin D insufficiency (25% vs 14% [SLE] and 10% [OI], P = .002), despite higher vitamin D3 supplementation doses. Boys with DMD also had higher weight, fat mass, and lower lean mass percentage Z scores. DMD was associated with having higher rates of vitamin D insufficiency than other comparable pediatric chronic disease cohorts, the effect of which may be modulated by clinical factors such as increased adiposity. While corroboration of these results is needed given baseline differences between the patient groups, greater vitamin D supplementation doses may be required to achieve optimal serum 25(OH)D concentrations in boys with DMD.

Background Lower serum concentrations of the osteoblast-derived protein, osteocalcin, have been associated with poorer glycemic control, insulin resistance and atherosclerosis, and with the development of type 2 diabetes (T2DM). Methods This study compares concentrations of two physiological forms of osteocalcin, carboxylated (cOCN) and uncarboxylated (unOCN), between participants with T2DM (n = 20) and age-, gender- and body mass index (BMI)-matched participants without T2DM (n = 40) among patients with coronary artery disease (CAD), and it explores relationships between osteocalcin concentrations and cardiovascular risk factors. Results Concentrations of unOCN (2.71 ± 1.86 vs. 4.70 ± 2.03 ng/mL; t = −3.635, p = 0.001) and cOCN (8.70 ± 2.27 vs. 10.77 ± 3.69 ng/mL; t = −2.30, p = 0.025) were lower in participants with T2DM. In participants without T2DM, concentrations of cOCN were associated with fitness (VO2Peak rho = 0.317, p = 0.047) and lower body fat (rho = −0.324, p = 0.041). In participants with T2DM, lower unOCN was associated with HbA1c (rho = −0.516, p = 0.020). Higher body mass was associated with higher unOCN (rho = 0.423, p = 0.009) in participants without T2DM, but with lower concentrations of both unOCN (rho = −0.590, p = 0.006) and cOCN (rho = −0.632, p = 0.003) in participants with T2DM. Conclusion In patients with CAD, lower osteocalcin concentrations were related to type 2 diabetes, and to adverse fitness, metabolic and obesity profiles.

Glucocorticoids are extensively used to treat patients with Duchenne muscular dystrophy because of their ability to delay muscle damage, prolong ambulation and extend life. However, use of glucocorticoids significantly increases bone loss, fragility and fractures. To determine if antiresorptive bisphosphonates could prevent the effects of glucocorticoids on bone quality, we used dystrophic mdx mice treated with the glucocorticoid prednisone during 8weeks of rapid bone growth from 5 to 13weeks of age and treated some mice with the bisphosphonate pamidronate during the first two weeks of prednisone administration. Prednisone reduced long bone growth, decreased cortical bone thickness and area and decreased the strength of the femurs. Pamidronate treatment protected mice from cortical bone loss but did not increase bone strength. The combination of prednisone and pamidronate inhibited remodeling of metaphyseal trabecular bone with large numbers of trabeculae containing remnants of calcified cartilage. Prednisone improved muscle strength in the mdx mice and decreased serum creatine kinase with evidence of improved muscle histology and these effects were maintained in mice treated with pamidronate.

Intermittent parathyroid hormone (iPTH) treatment and mechanical loading are osteoanabolic stimuli that are partially mediated through actions on G protein-coupled receptors (GPCRs). GPCR signaling can be altered by heterotrimeric G protein Gα subunits levels, which can therefore lead to altered responses to such stimuli. Previous studies have suggested that enhanced signaling through the Gαq/11 pathway inhibits the osteoanabolic actions of PTH. The influence of Gαq/11 signaling on mechanotransduction, however, has not been reported in vivo. Using transgenic mice that specifically overexpress Gα11 in osteoblast lineage cells (G11-Tg mice), we investigated the skeletal effects of elevated Gα11 levels on iPTH and mechanical loading by treadmill exercise. Both regimens increased trabecular and cortical bone in Wild-Type (WT) mice as a result of increased bone formation. In G11-Tg mice, there was no change in trabecular or cortical bone and no increase in bone formation in response to iPTH or exercise. While exercise reduced osteoclast parameters in WT mice, these changes were diminished in G11-Tg mice as expression of M-csf and Trap remained increased. Collectively, our results suggest that osteoblastic upregulation of Gα11 is inhibitory to osteoanabolic actions of both PTH and exercise, and that its suppression may be a promising target for treating bone loss.

Osteoblastic cells indirectly induce osteoclastogenesis in the bone microenvironment by expressing paracrine factors such as RANKL and M-CSF, leading to increased bone resorption. These cytokines can be regulated by a variety of intracellular pathways, which include G protein-coupled receptor signaling. To explore how enhanced signaling of the Gαq/11 pathway in osteoblast lineage cells may mediate osteoclast formation, we cocultured wild-type (WT) preosteoclasts with BMSCs derived from either WT or transgenic mice with osteoblast-specific overexpression of Gα11 (G11-Tg). G11-Tg cocultures had elevated osteoclast numbers with greater resorptive capacity and increased expression of Rankl, Rankl:Opg (osteoprotegerin), and M-csf compared with cocultures with WT BMSCs. As well, cocultures with G11-Tg BMSCs required a higher concentration of OPG to inhibit osteoclast formation and less angiotensin II to increase osteoclast size. These indicate that G11-Tg osteoblasts drive the increased osteoclast formation and osteopenia seen in G11-Tg mice. Pamidronate treatment of G11-Tg mice restored the trabecular bone loss phenotype, as bone mineral density, bone volume, trabecular number, separation, and expressions of osteoblastic and osteoclastic genes were comparable with WT parameters. These changes were characterized by enhanced accumulation of calcified cartilage in trabecular bone, demonstrating that resorption of the cartilaginous intermediate by osteoclasts is more affected by bisphosphonate treatment in G11-Tg mice. In conclusion, overexpression of Gα11 in osteoblastic cells promotes osteoclastogenesis by upregulation of Rankl and M-csf and bone loss by increased osteoclast resorption of the trabecular bone and cartilaginous matrix.

In this paper, we explore the notion of school improvement through the lens of praxis as it relates to equity, inclusion, and transformation, with a particular focus on inquiry-based school and teacher development. We argue that authentic improvement is a consequence of praxis, and highlight, through examples, key ways that authentic school improvement might be achieved through inquiry within a praxis framework. While many recent policy initiatives related to school education in Australia, and internationally, place emphasis on competitive and performance-based mechanisms to drive improvement, the argument in this paper runs counter to these emphases, not in its recognition of the need for school improvement but in its understanding of how that improvement can be defined, developed, and documented. The examples presented illustrate ways in which inquiry-based approaches to teacher professional learning, and teaching practices in classrooms, provide tools for framing authentic school improvement.

Patients with Duchenne muscular dystrophy are at increased risk of decreased bone mineral density and bone fracture as a result of inactivity. To determine if antiresorptive bisphosphonates could improve bone quality and their effects on muscle we studied the Mdx mouse, treated with pamidronate during peak bone growth at 5 and 6 weeks of age, and examined the outcome at 13 weeks of age. Pamidronate increased cortical bone architecture and strength in femurs with increased resistance to fracture. While overall long bone growth was not affected by pamidronate, there was significant inhibition of remodeling in metaphyseal trabecular bone with evidence of residual calcified cartilage. Pamidronate treatment had positive effects on skeletal muscle in the Mdx mice with decreased serum and muscle creatine kinase and evidence of improved muscle histology and grip strength.

Invertebrate visual opsins are G protein-coupled receptors coupled to retinoid chromophores that isomerize reversibly between inactive rhodopsin and active metarhodopsin upon absorption of photons of light. The squid visual system has an arrestin protein that binds to metarhodopsin to block signaling to Gq and activation of phospholipase C. Squid rhodopsin kinase (SQRK) can phosphorylate both metarhodopsin and arrestin, a dual role that is unique among the G protein-coupled receptor kinases. The sites and role of arrestin phosphorylation by SQRK were investigated here using recombinant proteins. Arrestin was phosphorylated on serine 392 and serine 397 in the C-terminus. Unphosphorylated arrestin bound to metarhodopsin and phosphorylated metarhodopsin with similar high affinities (Kd 33 and 21 nM respectively), while phosphorylation of arrestin reduced the affinity 3- to 5-fold (Kd 104 nM). Phosphorylation of metarhodopsin slightly increased the dissociation of arrestin observed during a 1 hour incubation. Together these studies suggest a unique role for SQRK in phosphorylating both receptor and arrestin and inhibiting the binding of these two proteins in the squid visual system. Invertebrate visual systems are inactivated by arrestin binding to metarhodopsin that does not require receptor phosphorylation. Here we show that squid rhodopsin kinase phosphorylates arrestin on two serines (S392,S397) in the C-terminus and phosphorylation decreases the affinity of arrestin for squid metarhodopsin. Metarhodopsin phosphorylation has very little effect on arrestin binding but does increase arrestin dissociation.

Photoreceptors of the squid Loligo pealei contain a G-protein-coupled receptor (GPCR) signaling system that activates phospholipase C in response to light. Analogous to the mammalian visual system, signaling of the photoactivated GPCR rhodopsin is terminated by binding of squid arrestin (sArr). sArr forms a light-dependent, high-affinity complex with squid rhodopsin, which does not require prior receptor phosphorylation for interaction. This is at odds with classical mammalian GPCR desensitization where an agonist-bound phosphorylated receptor is needed to break stabilizing constraints within arrestins, the so-called “three-element interaction” and “polar core” network, before a stable receptor–arrestin complex can be established. Biophysical and mass spectrometric analysis of the squid rhodopsin–arrestin complex indicates that in contrast to mammalian arrestins, the sArr C-tail is not involved in a stable three-element interaction. We determined the crystal structure of C-terminally truncated sArr that adopts a basal conformation common to arrestins and is stabilized by a series of weak but novel polar core interactions. Unlike mammalian arrestin-1, deletion of the sArr C-tail does not influence kinetic properties of complex formation of sArr with the receptor. Hydrogen–deuterium exchange studies revealed the footprint of the light-activated rhodopsin on sArr. Furthermore, double electron–electron resonance spectroscopy experiments provide evidence that receptor-bound sArr adopts a conformation different from the one known for arrestin-1 and molecular dynamics simulations reveal the residues that account for the weak three-element interaction. Insights gleaned from studying this system add to our general understanding of GPCR–arrestin interaction.