ARID1A suppresses R-loop-mediated STING-type I interferon pathway activation of anti-tumor immunity.

Clinical trials have identified ARID1A mutations as enriched among patients who respond favorably to immune checkpoint blockade (ICB) in several solid tumor types independent of microsatellite instability. We show that ARID1A loss in murine models is sufficient to induce anti-tumor immune phenotypes observed in ARID1A mutant human cancers, including increased CD8+ T cell infiltration and cytolytic activity. ARID1A-deficient cancers upregulated an interferon (IFN) gene expression signature, the ARID1A-IFN signature, associated with increased R-loops and cytosolic single-stranded DNA (ssDNA). Overexpression of the R-loop resolving enzyme, RNASEH2B, or cytosolic DNase, TREX1, in ARID1A-deficient cells prevented cytosolic ssDNA accumulation and ARID1A-IFN gene upregulation. Further, the ARID1A-IFN signature and anti-tumor immunity were driven by STING-dependent type I IFN signaling, which was required for improved responsiveness of ARID1A mutant tumors to ICB treatment. These findings define a molecular mechanism underlying anti-tumor immunity in ARID1A mutant cancers.

Collaboration between distinct SWI/SNF chromatin remodeling complexes directs enhancer selection and activation of macrophage inflammatory genes.

Macrophages elicit immune responses to pathogens through induction of inflammatory genes. Here, we examined the role of three variants of the SWI/SNF nucleosome remodeling complex-cBAF, ncBAF, and PBAF-in the macrophage response to bacterial endotoxin (lipid A). All three SWI/SNF variants were prebound in macrophages and retargeted to genomic sites undergoing changes in chromatin accessibility following stimulation. Cooperative binding of all three variants associated with de novo chromatin opening and latent enhancer activation. Isolated binding of ncBAF and PBAF, in contrast, associated with activation and repression of active enhancers, respectively. Chemical and genetic perturbations of variant-specific subunits revealed pathway-specific regulation in the activation of lipid A response genes, corresponding to requirement for cBAF and ncBAF in inflammatory and interferon-stimulated gene (ISG) activation, respectively, consistent with differential engagement of SWI/SNF variants by signal-responsive transcription factors. Thus, functional diversity among SWI/SNF variants enables increased regulatory control of innate immune transcriptional programs, with potential for specific therapeutic targeting.

A Genome-wide CRISPR Screen Reveals a Role for the Non-canonical Nucleosome-Remodeling BAF Complex in Foxp3 Expression and Regulatory T Cell Function.

Regulatory T (Treg) cells play a pivotal role in suppressing auto-reactive T cells and maintaining immune homeostasis. Treg cell development and function are dependent on the transcription factor Foxp3. Here, we performed a genome-wide CRISPR loss-of-function screen to identify Foxp3 regulators in mouse primary Treg cells. Foxp3 regulators were enriched in genes encoding subunits of the SWI/SNF nucleosome-remodeling and SAGA chromatin-modifying complexes. Among the three SWI/SNF-related complexes, the Brd9-containing non-canonical (nc) BAF complex promoted Foxp3 expression, whereas the PBAF complex was repressive. Chemical-induced degradation of Brd9 led to reduced Foxp3 expression and reduced Treg cell function in vitro. Brd9 ablation compromised Treg cell function in inflammatory disease and tumor immunity in vivo. Furthermore, Brd9 promoted Foxp3 binding and expression of a subset of Foxp3 target genes. Our findings provide an unbiased analysis of the genetic networks regulating Foxp3 and reveal ncBAF as a target for therapeutic manipulation of Treg cell function.

Heterozygous Mutations in SMARCA2 Reprogram the Enhancer Landscape by Global Retargeting of SMARCA4.

Mammalian SWI/SNF complexes are multi-subunit chromatin remodeling complexes associated with an ATPase (either SMARCA4 or SMARCA2). Heterozygous mutations in the SMARCA2 ATPase cause Nicolaides-Baraitser syndrome (NCBRS), an intellectual disability syndrome associated with delayed speech onset. We engineered human embryonic stem cells (hESCs) to carry NCBRS-associated heterozygous SMARCA2 K755R or R1159Q mutations. While SMARCA2 mutant hESCs were phenotypically normal, differentiation to neural progenitors cells (NPCs) was severely impaired. We find that SMARCA2 mutations cause enhancer reorganization with loss of SOX3-dependent neural enhancers and prominent emergence of astrocyte-specific de novo enhancers. Changes in chromatin accessibility at enhancers were associated with an increase in SMARCA2 binding and retargeting of SMARCA4. We show that the AP-1 family member FRA2 is aberrantly overexpressed in SMARCA2 mutant NPCs, where it functions as a pioneer factor at de novo enhancers. Together, our results demonstrate that SMARCA2 mutations cause impaired differentiation through enhancer reprogramming via inappropriate targeting of SMARCA4.

CRISPR screen in regulatory T cells reveals modulators of Foxp3.

Regulatory T (Treg) cells are required to control immune responses and maintain homeostasis, but are a significant barrier to antitumour immunity1. Conversely, Treg instability, characterized by loss of the master transcription factor Foxp3 and acquisition of proinflammatory properties2, can promote autoimmunity and/or facilitate more effective tumour immunity3,4. A comprehensive understanding of the pathways that regulate Foxp3 could lead to more effective Treg therapies for autoimmune disease and cancer. The availability of new functional genetic tools has enabled the possibility of systematic dissection of the gene regulatory programs that modulate Foxp3 expression. Here we developed a CRISPR-based pooled screening platform for phenotypes in primary mouse Treg cells and applied this technology to perform a targeted loss-of-function screen of around 500 nuclear factors to identify gene regulatory programs that promote or disrupt Foxp3 expression. We identified several modulators of Foxp3 expression, including ubiquitin-specific peptidase 22 (Usp22) and ring finger protein 20 (Rnf20). Usp22, a member of the deubiquitination module of the SAGA chromatin-modifying complex, was revealed to be a positive regulator that stabilized Foxp3 expression; whereas the screen suggested that Rnf20, an E3 ubiquitin ligase, can serve as a negative regulator of Foxp3. Treg-specific ablation of Usp22 in mice reduced Foxp3 protein levels and caused defects in their suppressive function that led to spontaneous autoimmunity but protected against tumour growth in multiple cancer models. Foxp3 destabilization in Usp22-deficient Treg cells could be rescued by ablation of Rnf20, revealing a reciprocal ubiquitin switch in Treg cells. These results reveal previously unknown modulators of Foxp3 and demonstrate a screening method that can be broadly applied to discover new targets for Treg immunotherapies for cancer and autoimmune disease.

BRD9 regulates interferon-stimulated genes during macrophage activation via cooperation with BET protein BRD4.

Macrophages induce a number of inflammatory response genes in response to stimulation with microbial ligands. In response to endotoxin Lipid A, a gene-activation cascade of primary followed by secondary-response genes is induced. Epigenetic state is an important regulator of the kinetics, specificity, and mechanism of gene activation of these two classes. In particular, SWI/SNF chromatin-remodeling complexes are required for the induction of secondary-response genes, but not primary-response genes, which generally exhibit open chromatin. Here, we show that a recently discovered variant of the SWI/SNF complex, the noncanonical BAF complex (ncBAF), regulates secondary-response genes in the interferon (IFN) response pathway. Inhibition of bromodomain-containing protein 9 (BRD9), a subunit of the ncBAF complex, with BRD9 bromodomain inhibitors (BRD9i) or a degrader (dBRD9) led to reduction in a number of interferon-stimulated genes (ISGs) following stimulation with endotoxin lipid A. BRD9-dependent genes overlapped highly with a subset of genes differentially regulated by BET protein inhibition with JQ1 following endotoxin stimulation. We find that the BET protein BRD4 is cobound with BRD9 in unstimulated macrophages and corecruited upon stimulation to ISG promoters along with STAT1, STAT2, and IRF9, components of the ISGF3 complex activated downstream of IFN-alpha receptor stimulation. In the presence of BRD9i or dBRD9, STAT1-, STAT2-, and IRF9-binding is reduced, in some cases with reduced binding of BRD4. These results demonstrate a specific role for BRD9 and the ncBAF complex in ISG activation and identify an activity for BRD9 inhibitors and degraders in dampening endotoxin- and IFN-dependent gene expression.

Glycaemic patterns during breastfeeding with postpartum use of closed-loop insulin delivery in women with type 1 diabetes.

AIMS/HYPOTHESIS: This study aimed to describe the relationship between breastfeeding episodes and maternal glucose levels, and to assess whether this differs with closed-loop vs open-loop (sensor-augmented pump) insulin therapy. METHODS: Infant-feeding diaries were collected at 6 weeks, 12 weeks and 24 weeks postpartum in a trial of postpartum closed-loop use in 18 women with type 1 diabetes. Continuous glucose monitoring (CGM) data were used to identify maternal glucose patterns within the 3 h of breastfeeding episodes. Generalised mixed models adjusted for breastfeeding episodes in the same woman, repeat breastfeeding episodes, carbohydrate intake, infant age at time of feeding and early pregnancy HbA1c. This was a secondary analysis of data collected during a randomised trial (ClinicalTrials.gov registration no. NCT04420728). RESULTS: CGM glucose remained above 3.9 mmol/l in the 3 h post-breastfeeding for 93% (397/427) of breastfeeding episodes. There was an overall decrease in glucose at nighttime within 3 h of breastfeeding (1.1 mmol l-1 h-1 decrease on average; p=0.009). A decrease in nighttime glucose was observed with open-loop therapy (1.2 ± 0.5 mmol/l) but was blunted with closed-loop therapy (0.4 ± 0.3 mmol/l; p<0.01, open-loop vs closed-loop). CONCLUSIONS/INTERPRETATION: There is a small decrease in glucose after nighttime breastfeeding that usually does not result in maternal hypoglycaemia; this appears to be blunted with the use of closed-loop therapy.

Risk factors associated with prevalent vertebral fractures in Duchenne muscular dystrophy.

Patients with Duchenne muscular dystrophy (DMD) have a high fracture burden due to progressive myopathy and steroid-induced osteoporosis. This study in males with DMD showed that markers of systemic glucocorticoid exposure including shorter stature, greater bone age delay, and lower lumbar spine bone mineral density were associated with spine fragility. INTRODUCTION: Fragility  fractures are frequent in DMD. The purpose of this study was to identify clinical factors associated with prevalent vertebral fractures (VF) in boys, teens/young adults with Duchenne muscular dystrophy (DMD). METHODS: This was a cross-sectional study of males aged 4-25 years with DMD. VF were evaluated using the modified Genant semi-quantitative method on T4-L4 lateral spine radiographs. Areal bone mineral density (aBMD) was measured at the lumbar spine (LS) and used to estimate volumetric BMD (vBMD). Clinical factors were analyzed for their association with the Spinal Deformity Index (SDI, the sum of the Genant grades). RESULTS: Sixty participants were enrolled (mean age 11.5 years, range 5.4-19.5). Nineteen participants (32%) had a total of 67 VF; 23/67 VF (34%) were moderate or severe. Participants with VF were shorter (mean height Z-score ± standard deviation: - 3.1 ± 1.4 vs. - 1.8 ± 1.4, p = 0.001), had longer glucocorticoid exposure (mean duration 6.0 ± 3.3 vs. 3.9 ± 3.3 years, p = 0.027), greater bone age (BA) delay (mean BA to chronological age difference - 3.2 ± 3.4 vs. - 1.3 ± 1.2 years, p = 0.035), and lower LSaBMD Z-scores (mean - 3.0 ± 1.0 vs. - 2.2 ± 1.2, p = 0.023). There was no difference in LSvBMD Z-scores. Multivariable Poisson regression showed that every 0.1 mg/kg/day increment in average glucocorticoid daily dose was associated with a 1.4-fold SDI increase (95% confidence interval: 1.1-1.7, p = 0.013). Greater BA delay (p < 0.001), higher weight Z-score (p = 0.004), decreased height Z-score (p = 0.025), and lower LSvBMD Z-score (p = 0.025) were also associated with SDI increase. CONCLUSION: Readily measurable clinical variables were associated with prevalent VF in males with glucocorticoid-treated DMD. These variables may be useful to identify candidates for primary osteoporosis prevention after glucocorticoid initiation.

Efficacy of the Aim2Be Intervention in Changing Lifestyle Behaviors Among Adolescents With Overweight and Obesity: Randomized Controlled Trial.

BACKGROUND: Aim2Be is a gamified lifestyle app designed to promote lifestyle behavior changes among Canadian adolescents and their families. OBJECTIVE: The primary aim was to test the efficacy of the Aim2Be app with support from a live coach to reduce weight outcomes (BMI Z score [zBMI]) and improve lifestyle behaviors among adolescents with overweight and obesity and their parents versus a waitlist control group over 3 months. The secondary aim was to compare health trajectories among waitlist control participants over 6 months (before and after receiving access to the app), assess whether support from a live coach enhanced intervention impact, and evaluate whether the app use influenced changes among intervention participants. METHODS: A 2-arm parallel randomized controlled trial was conducted from November 2018 to June 2020. Adolescents aged 10 to 17 years with overweight or obesity and their parents were randomized into an intervention group (Aim2Be with a live coach for 6 months) or a waitlist control group (Aim2Be with no live coach; accessed after 3 months). Adolescents' assessments at baseline and at 3 and 6 months included measured height and weight, 24-hour dietary recalls, and daily step counts measured with a Fitbit. Data on self-reported physical activity, screen time, fruit and vegetable intake, and sugary beverage intake of adolescents and parents were also collected. RESULTS: A total of 214 parent-child participants were randomized. In our primary analyses, there were no significant differences in zBMI or any of the health behaviors between the intervention and control groups at 3 months. In our secondary analyses, among waitlist control participants, zBMI (P=.02), discretionary calories (P=.03), and physical activity outside of school (P=.001) declined, whereas daily screen time increased (P<.001) after receiving access to the app compared with before receiving app access. Adolescents randomized to Aim2Be with live coaching reported more time being active outside of school compared with adolescents who used Aim2Be with no coaching over 3 months (P=.001). App use did not modify any changes in outcomes among adolescents in the intervention group. CONCLUSIONS: The Aim2Be intervention did not improve zBMI and lifestyle behaviors in adolescents with overweight and obesity compared with the waitlist control group over 3 months. Future studies should explore the potential mediators of changes in zBMI and lifestyle behaviors as well as predictors of engagement. TRIAL REGISTRATION: ClinicalTrials.gov NCT03651284; https://clinicaltrials.gov/ct2/show/study/NCT03651284. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s13063-020-4080-2.

Severe obesity and global developmental delay in preschool children: Findings from a Canadian Paediatric Surveillance Program study.

Background: The co-presentation of severe obesity (SO) and global developmental delay (GDD) in Canadian preschool children has not been examined. However, SO and GDD may require syndromic diagnoses and unique management considerations. Objectives: To determine (1) minimum incidence; (2) age of onset and risk factors; and (3) health care utilization for co-presenting SO and GDD. Methods: Through the Canadian Paediatric Surveillance Program (CPSP), a monthly form was distributed to participants from February 2018 to January 2020 asking for reports of new cases of SO and GDD among children ≤5 years of age. We performed descriptive statistics for quantitative questions and qualitative content analysis for open-ended questions. Results: Forty-seven cases (64% male; 51% white; mean age: 3.5 ± 1.2 years) were included. Age of first weight concern was 2.5 ± 1.3 years and age of GDD diagnosis was 2.7 ± 1.4 years. Minimum incidence of SO and GDD was 3.3 cases per 100,000 for ≤5 years of age per year. Identified problems included school and/or behavioural problems (n = 17; 36%), snoring (n = 14; 30%), and asthma/recurrent wheeze (n = 10; 21%). Mothers of 32% of cases (n = 15) had obesity and 21% of cases (n = 10) received neonatal intensive care. Microarray was ordered for 57% (n = 27) of children. A variety of clinicians and services were accessed. As reported by CPSP participants, challenges faced by families and health service access were barriers to care. Conclusion: Children with SO and GDD have multiple comorbidities, and require early identification and referral to appropriate services. These cases may also benefit from additional testing to rule out known genetic obesity syndromes.

Individual and family characteristics associated with health indicators at entry into multidisciplinary pediatric weight management: findings from the CANadian Pediatric Weight management Registry (CANPWR).

OBJECTIVES: (1) To explore individual and family characteristics related to anthropometric and cardiometabolic health indicators and (2) examine whether characteristics that correlate with cardiometabolic health indicators differ across severity of obesity at time of entry to Canadian pediatric weight management clinics. METHODS: We conducted a cross-sectional analysis of 2-17 year olds with overweight or obesity who registered in the CANadian Pediatric Weight Management Registry (CANPWR) between May 2013 and October 2017 prior to their first clinic visit. Individual modifiable health behaviors included dietary intake, physical activity, screen time, and sleep. Family characteristics included parental BMI, family medical history, socioeconomic status and family structure. Linear mixed effects stepwise regression analysis was performed to determine which characteristics were related to each health indicator: BMI z-score; waist circumference; waist to height ratio; blood pressure; glycemia; HDL cholesterol; non-HDL cholesterol; triglycerides. RESULTS: This study included 1296 children (mean age ± standard deviation: 12.1 ± 3.5 years; BMI z-score: 3.55 ± 1.29; 95.3% with obesity). Hours spent sleeping (estimated ß = -0.10; 95% CI [-0.15, -0.05], p = 0.0001), hours per week of organized physical activity (estimated ß = -0.32; 95% CI [-0.53, -0.11], p = 0.0026), daily sugared drink intake (estimated ß = 0.06; 95% CI [0.01, 0.10], p = 0.0136) and maternal BMI (estimated ß = 0.03; 95% CI [0.02, 0.04], p < 0.0001) were associated with BMI z-score (adj. R2 = 0.2084), independent of other individual and family characteristics. Physical activity, total sugared drink intake and sleep duration were associated with glycemia and non-HDL cholesterol, independent of child BMI z-score. However, irrespective of obesity severity, little of the variance (0.86-11.1%) in cardiometabolic health indicators was explained by individual modifiable health behaviors. CONCLUSIONS: Physical activity, total sugared drink intake and hours spent sleeping were related to anthropometric and some cardiometabolic health indicators in children entering pediatric weight management programs. This highlights the importance of these modifiable health behaviors on multiple health indicators in children with obesity.

Re-referring Children for Multidisciplinary Obesity Management.

OBJECTIVES: To examine characteristics of children referred for obesity management based on referral frequency, child- and referrer-related variables associated with re-referral, and determine whether re-referral increased treatment initiation. STUDY DESIGN: This population-level, retrospective analysis included all 2- to 17-year-olds referred for obesity management to 1 of 3 multidisciplinary clinics in Alberta, Canada between April 2013 and December 2017. Children were dichotomized based on referral frequency, specifically once only or more than once (re-referred). Data were retrieved from standardized referral forms and patient registries. Analyses included logistic regression and generalized estimating equations models. RESULT: We analyzed data from 2745 children (47.2% female; mean age: 11.4 years; mean body mass index z score: 3.03) and 2705 physicians (60.2% female; 65.6% pediatricians). Overall, 300 (10.2%) children were re-referred with most (n = 276; 92.0%) being referred twice. Children were less likely to be re-referred if they were referred by a family physician (vs pediatrician) (aOR 0.62; 95% CI 0.46-0.84; P = .0018) or scheduled a clinic appointment following their index referral (aOR: 0.29; 95% CI 0.21-0.4; P < .001). Treatment initiation was higher in children who were referred once only (42.1%) vs their re-referred peers (18.0%; P < .0001); however, for children who were re-referred, they were more likely to initiate treatment following their second referral (aOR 2.3; 95% CI 1.22-4.31; P = .01). This improvement was not sustained on subsequent referrals (aOR 0.44; 95% CI 0.17-1.12; P = .08). CONCLUSIONS: Few children were re-referred for pediatric obesity management; however, for those children who were re-referred, being re-referred once only increased the likelihood of treatment initiation.

The Aim2Be mHealth Intervention for Children With Overweight or Obesity and Their Parents: Person-Centered Analyses to Uncover Digital Phenotypes.

BACKGROUND: Despite the growing number of mobile health (mHealth) interventions targeting childhood obesity, few studies have characterized user typologies derived from individuals' patterns of interactions with specific app features (digital phenotypes). OBJECTIVE: This study aims to identify digital phenotypes among 214 parent-child dyads who used the Aim2Be mHealth app as part of a randomized controlled trial conducted between 2019 and 2020, and explores whether participants' characteristics and health outcomes differed across phenotypes. METHODS: Latent class analysis was used to identify distinct parent and child phenotypes based on their use of the app's behavioral, gamified, and social features over 3 months. Multinomial logistic regression models were used to assess whether the phenotypes differed by demographic characteristics. Covariate-adjusted mixed-effect models evaluated changes in BMI z scores (zBMI), diet, physical activity, and screen time across phenotypes. RESULTS: Among parents, 5 digital phenotypes were identified: socially engaged (35/214, 16.3%), independently engaged (18/214, 8.4%) (socially and independently engaged parents are those who used mainly the social or the behavioral features of the app, respectively), fully engaged (26/214, 12.1%), partially engaged (32/214, 15%), and unengaged (103/214, 48.1%) users. Married parents were more likely to be fullyengaged than independently engaged (P=.02) or unengaged (P=.01) users. Socially engaged parents were older than fullyengaged (P=.02) and unengaged (P=.01) parents. The latent class analysis revealed 4 phenotypes among children: fully engaged (32/214, 15%), partially engaged (61/214, 28.5%), dabblers (42/214, 19.6%), and unengaged (79/214, 36.9%) users. Fully engaged children were younger than dabblers (P=.04) and unengaged (P=.003) children. Dabblers lived in higher-income households than fully and partiallyengaged children (P=.03 and P=.047, respectively). Fully engaged children were more likely to have fully engaged (P<.001) and partiallyengaged (P<.001) parents than unengaged children. Compared with unengaged children, fully and partiallyengaged children had decreased total sugar (P=.006 and P=.004, respectively) and energy intake (P=.03 and P=.04, respectively) after 3 months of app use. Partially engaged children also had decreased sugary beverage intake compared with unengaged children (P=.03). Similarly, children with fully engaged parents had decreased zBMI, whereas children with unengaged parents had increased zBMI over time (P=.005). Finally, children with independently engaged parents had decreased caloric intake, whereas children with unengaged parents had increased caloric intake over time (P=.02). CONCLUSIONS: Full parent-child engagement is critical for the success of mHealth interventions. Further research is needed to understand program design elements that can affect participants' engagement in supporting behavior change. TRIAL REGISTRATION: ClinicalTrials.gov NCT03651284; https://clinicaltrials.gov/ct2/show/NCT03651284. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s13063-020-4080-2.

Diabetic ketoacidosis at type 1 diabetes diagnosis in children during the COVID-19 pandemic.

OBJECTIVE: The COVID-19 pandemic has led to significant public health measures that have resulted in decreased acute pediatric care utilization. We evaluated whether the rate of severe presentations of new onset type 1 diabetes (DM1), such as, diabetic ketoacidosis (DKA) has changed since the COVID-19 public health measures were enacted. RESEARCH DESIGN AND METHODS: A retrospective chart review of children less than 18 years of age presenting with new onset DM1 during the pandemic period of March 17, 2020 to August 31, 2020 was conducted at two tertiary care pediatric hospitals in Alberta, Canada. Rates of DKA and severe DKA were compared to the same time period in the year 2019 (pre-pandemic control). RESULTS: The number of children presenting with newly diagnosed DM1 was similar during the pandemic year of 2020 compared with 2019 (107 children in 2020 vs. 114 in 2019). The frequency of DKA at DM1 onset was significantly higher in the pandemic period (68.2% vs 45.6%; p < 0.001) and incidence of severe DKA was also higher (27.1% in 2020 vs 13.2% in 2019; p = 0.01). CONCLUSIONS: There was a significant increase in DKA and severe DKA in children presenting with new onset DM1 during the COVID-19 pandemic period. This emphasizes the need for educating health care professionals and families to be aware of the symptoms of hyperglycemia and the importance of early diagnosis and treatment even during public health measures for COVID-19.

Physician-related predictors of referral for multidisciplinary paediatric obesity management: a population-based study.

BACKGROUND: It is recommended that primary care-based physicians refer children with overweight and obesity to multidisciplinary paediatric obesity management, which can help to improve weight and health. OBJECTIVE: To determine predictors of referral to multidisciplinary paediatric obesity management. METHODS: This retrospective, population-level study included physicians who could refer 2-17 years old with a body mass index ≥85th percentile to one of three multidisciplinary paediatric obesity management clinics in Alberta, Canada. Physician demographic and procedural data were obtained from Practitioner Claims and Provider Registry maintained by Alberta Health from January 2014 to December 2017. Physician characteristics were compared based on whether they did or did not refer children for obesity management. Univariable and multivariable logistic regression models analysed associations between physician characteristics and referral making. RESULTS: Of the 3863 physicians (3468 family physicians, 395 paediatricians; 56% male; 49.3 ± 12.2 years old; 22.3 ± 12.6 years since graduation) practicing during the study period, 1358 (35.2%) referred at least one child for multidisciplinary paediatric obesity management. Multivariable regression revealed that female physicians (versus males) [odds ratio (OR): 1.68, 95% confidence interval (CI): 1.46-1.93; P < 0.0001], paediatricians (versus family physicians) (OR: 4.89, 95% CI: 3.85-6.21; P < 0.0001) and urban-based physicians (versus non-urban-based physicians) (OR: 2.17, 95% CI: 1.79-2.65; P < 0.0001) were more likely to refer children for multidisciplinary paediatric obesity management. CONCLUSIONS: Approximately one-third of family physicians and paediatricians referred children for multidisciplinary paediatric obesity management. Strategies are needed to improve referral practices for managing paediatric obesity, especially among male physicians, family physicians and non-urban-based physicians as they were less likely to refer children.

Paediatric overweight and obesity impact one-third of children in Canada and the USA. It is recommended that physicians refer children with overweight and obesity to paediatric obesity management, which can help to improve their weight and health. While referral practices of US physicians have been well characterized, Canadian evidence remains limited. To address this gap, we examined predictors of referral making for paediatric obesity management. Our study included physicians (family physicians and paediatricians) who could refer 2­17 years old with overweight and obesity to three paediatric weight management clinics in Alberta, Canada between January 2014 and December 2017. Descriptive analyses and regression models were performed. Of the 3863 physicians practicing during the study period, 1358 (35.2%) referred at least one child for paediatric obesity management. Referring physicians were more likely to be female, paediatricians and practicing in urban-based clinics. Additional research is needed to explore physicians' decisions to refer children for obesity management, which can inform interventions to enhance referral, and ultimately, improve the health and well-being of children with obesity.

Phage therapy for severe bacterial infections: a narrative review.

Bacteriophage (phage) therapy is re-emerging a century after it began. Activity against antibiotic-resistant pathogens and a lack of serious side effects make phage therapy an attractive treatment option in refractory bacterial infections. Phages are highly specific for their bacterial targets, but the relationship between in vitro activity and in vivo efficacy remains to be rigorously evaluated. Pharmacokinetic and pharmacodynamic principles of phage therapy are generally based on the classic predator-prey relationship, but numerous other factors contribute to phage clearance and optimal dosing strategies remain unclear. Combinations of fully characterised, exclusively lytic phages prepared under good manufacturing practice are limited in their availability. Safety has been demonstrated but randomised controlled trials are needed to evaluate efficacy.

Pathways to eating in children and adolescents with obesity.

BACKGROUND: Paediatric obesity management remains generalised to dietary and exercise modifications with an underappreciation for the contributions of eating behaviours and appetitive traits in the development of obesity. OBJECTIVES: To determine whether treatment-seeking children and adolescents with obesity cluster into phenotypes based on known eating behaviours and appetitive traits ("eating correlates") and how socio-demographic and clinical characteristics associate with different phenotypes. METHODS: A cross-sectional, multi-centre questionnaire was administered between November 2015 and March 2017 examining correlates of eating in children and adolescents attending weight-management programmes in Canada. Latent profile analysis was used to cluster participants based on seven eating correlate scores obtained from questionnaires. Analysis of variance (ANOVA) was used to determine phenotype differences on socio-demographic and clinical characteristics. Multinomial logistic regression models assessed relative risk of specific characteristics associating with a disordered eating phenotype. RESULTS: Participants were 247 children and adolescents (45.3% male, mean BMI z-score = 3.4 ± 1.0 kg/m2) from six paediatric weight management centres in Canada. Seven eating correlates clustered into three distinct phenotypes: (1) loss of control eating, emotional eating, external eating, hyperphagia, impulsivity ("Mixed-Severe"; n = 42, 17%), (2) loss of control eating, emotional eating, external eating, hyperphagia ("Mixed-Moderate"; n = 138, 55.9%), and (3) impulsivity ("Impulsive"; n = 67; 27.1%). Social functioning scores and body esteem were significantly different across groups, with the Mixed-Severe participants having the poorest social functioning and lowest body esteem. Low body esteem indicated a greater risk of being in a multi-correlate group compared to the Impulsive group, while poor social function had a greater risk of clustering in the Mixed-Severe than Impulsive phenotype. CONCLUSIONS: Distinct eating phenotypes were found in treatment-seeking children and adolescents with obesity. Empirical evidence is needed, but these data suggest that tailored treatment approaches could be informed by these classifications to improve weight-management outcomes.

Knowledge and practice of harm-reduction behaviours for alcohol and other illicit substance use in adolescents with type 1 diabetes.

OBJECTIVE: To survey adolescents with type 1 diabetes mellitus (T1DM) about their knowledge and application of harm-reduction recommendations when they engage in alcohol and other illicit substance use. METHODS: Cross-sectional survey and chart review of adolescents with T1DM aged 13 to 18 years. RESULTS: One hundred and ninety patients were approached and 164 were included in the analysis. Mean age was 15.6 years (standard deviation [SD]=1.5). Fifty-one per cent were male. Of those who reported consuming alcohol, 95% knew that they should have a friend or parent check their blood glucose in the middle of the night after drinking but only 62% reported actually doing this in practice. Similarly, 98% reported knowing that they should wear a medic alert identification but only 79% reported actually doing this. Of those who reported consuming cannabis, 14% reported forgetting to check blood glucose and 14% reported forgetting insulin when using cannabis. From the chart review, a significantly lower proportion of adolescents reported substance use during their clinic visits (alcohol 26%, tobacco 19%, illicit substance 25%) compared to the self report in the survey (alcohol 55%, tobacco 30%, illicit substance 32%). CONCLUSIONS: Adolescents' knowledge of harm-reduction practices for the use of alcohol and other illicit substances is not always put to practice. Motivating adolescents to use their knowledge in practice is an important area to improve in diabetes self-management. Those who reported engaging in substance use in the survey had not always reported use during interactions with health care providers. This emphasizes the need for unbiased, universal education of all adolescents in the clinic.

Predicting Enrollment in Multidisciplinary Clinical Care for Pediatric Weight Management.

OBJECTIVES: To characterize the children who were referred, determine the proportion of referred children who enrolled, and examine factors associated with enrollment in multidisciplinary clinical care for pediatric weight management. STUDY DESIGN: This cross-sectional study included the population of children (2-17 years of age; body mass index of ≥85th percentile) referred to 1 of 3 hospital-based multidisciplinary weight management clinics in Alberta, Canada, from April 2013 to April 2016. Referral and enrollment data were obtained from Alberta Health Services databases. Bivariate and multivariable logistic regression models were used to determine the independent and combined effects of predictors of enrollment. RESULTS: Of the 2014 children (51.8% male; mean body mass index z-score: 3.42 ± 0.03) referred to multidisciplinary clinical care, 757 (37.6%) enrolled in care. Most referred children had severe obesity and were referred by physicians. Several factors independently predicted enrollment; however, in our most parsimonious multivariable model, only the time gap (OR, 0.94; 95% CI, 0.88-0.99; P = .03) between the attendance date of the orientation session and the booking date of initial appointment predicted enrollment for all children. Body mass index z-score (OR, 0.81; 95% CI, 0.67-0.98; P = .03) and time gap (OR, 0.92; 95% CI, 0.85-0.99; P = .02) predicted enrollment in children with severe obesity exclusively. CONCLUSIONS: Fewer than 40% of referred children enrolled in multidisciplinary clinical care. Reducing the duration of enrollment and providing additional support for treatment initiation to children with severe obesity may enhance treatment uptake for pediatric weight management.

The CANadian Pediatric Weight management Registry (CANPWR): lessons learned from developing and initiating a national, multi-centre study embedded in pediatric clinical practice.

BACKGROUND: There is increasing recognition of the value of "real-world evidence" in evaluating health care services. Registry-based, observational studies conducted in clinical settings represent a relevant model to achieve this directive. Starting in 2010, we undertook a longitudinal, observational study (the CANadian Pediatric Weight management Registry [CANPWR]), which is embedded in 10 multidisciplinary, pediatric weight management clinics across Canada. The objective of this paper was to share the lessons our team learned from this multi-centre project. METHODS: Data sources included a retrospective review of minutes from 120 teleconferences with research staff and investigators, notes taken during clinical site visits made by project leaders, information from quality control processes to ensure data accuracy and completeness, and a study-specific survey that was sent to all sites to solicit feedback from research team members (n = 9). Through an iterative process, the writing group identified key themes that surfaced during review of these information sources and final lessons learned were developed. RESULTS: Several key lessons emerged from our research, including the (1) value of pilot studies and central research coordination, (2) need for effective and regular communication, (3) importance of consensus on determining outcome measures, (4) challenge of embedding research within clinical practice, and (5) difficulty in recruiting and retaining participants. The sites were, in spite of these challenges, enthusiastic about the benefits of participating in multi-centre collaborative studies. CONCLUSION: Despite some challenges, multi-centre observational studies embedded in pediatric weight management clinics are feasible and can contribute important, practical insights into the effectiveness of health services for managing pediatric obesity in real-world settings.