Parents as Agents of Change in the Treatment of Childhood Obesity and the Promotion of Children\u27s Health Behaviours

The overarching purpose of this dissertation was to investigate the role of parents as agents of change in the treatment of childhood obesity and the promotion of children’s health behaviours. In order to achieve this purpose, four studies were conducted. The purpose of Study 1 was to explore parents’ perceptions of nutritional literacy, as well as their needs for nutritional literacy information, supports, and resources at familial and community levels. Next, Study 2 described the theoretical components and model used in the development and implementation of a parent-focused childhood overweight and obesity intervention (i.e., C.H.A.M.P. Families). The purpose of Study 3 was to investigate the impact of the C.H.A.M.P. Families program on: (a) children’s standardized body mass index (BMI-z); and (b) parental self-efficacy for promoting children’s health behaviours. Finally, the aim of Study 4 was to explore parents’ perspectives of their experiences in and the influence of C.H.A.M.P. Families, as well as their recommendations related to future paediatric overweight and obesity treatment interventions. The findings presented in Study 1 showed that parents perceived nutritional literacy as having an understanding of nutrition and healthy eating, as well as having the skills to translate such knowledge into practice. All participants agreed that nutritional literacy was important, and the majority believed that it could be improved within their families. With regard to the resources parents identified as needing to enhance nutritional literacy in their families, professional advice, practical skills, kid-friendly recipes, and environmental information were identified. Food regulation, accessible community programming, and school-based policies and curriculum were the needs identified at the community level. In Study 2, the “C.H.A.M.P. Families” intervention was described in detail. This 13-week parent-focused program involved eight group-based (parent-only) educations delivered to parents of children aged 6-14 years with overweight or obesity (i.e., body mass index equal to or greater than the 85th percentile for age and sex). The program also included eight home-based (family) activities and two group-based (family) follow-up support sessions. In addition to a description of the intervention and feasibility analyses, Study 2 detailed the use of the unique theoretical framework that integrated evidence-based group dynamics principles and motivational interviewing techniques within the broader context of Social Cognitive Theory. Several practical examples related to the application of specific theoretical constructs and evidence-based strategies within a parent-focused paediatric obesity interventions were presented. In Study 3, the results demonstrated that the C.H.A.M.P. Families intervention had a small, positive effect on both parental self-efficacy for promoting child health behaviours and child BMI-z, from baseline to post-intervention. However, the results also showed that these improvements were not maintained at the 6-month follow-up. Finally, findings from Study 4 showed that C.H.A.M.P. Families was well-received by parents. Parents highlighted several positive outcomes for children and families and underscored specifically the importance of the group environment, content and materials, and additional program components (e.g., home visits). Many participants also noted important socioenvironmental and personal barriers related to health behaviour changes for themselves and their child(ren), and recommended that future programs emphasize greater child involvement and additional information and strategies

Impact of awareness and concerns of climate change on children\u27s mental health: a scoping review protocol

OBJECTIVE: The purpose of this scoping review is to identify and describe the existing literature on the impact of the overarching awareness and concerns of climate change on children\u27s mental health and well-being. INTRODUCTION: Children are widely acknowledged as being disproportionately at risk to the effects of climate change, yet research overlooks the impact that climate change has on their mental health. Children\u27s overarching awareness of climate change, and its global effects, may influence their mental health and well-being. INCLUSION CRITERIA: This review will include all research that addresses school-aged children\u27s (aged 3-19) mental-health issues stemming from an awareness of climate change. It will not include research that examines direct impacts of climate change on children\u27s mental health, such as trauma from a specific climate-related event. METHODS: Searches will be conducted across eight research databases (Cochrane Database of Systematic Reviews, CINAHL, Embase, GreenFILE, PubMed, PsycINFO, Web of Science, and Scopus) and three unpublished/gray literature databases (ProQuest Dissertations and Theses, GreyLit.org, and OpenGrey). Data will be extracted for author(s), year of publication, country of origin, purpose, population, methodology, concepts of interest, outcomes, and key findings relating to the scoping review objectives. Findings will be presented as a narrative summary

Barriers to recruiting men into chronic disease prevention and management programs in rural areas: Perspectives of program delivery staff

Chronic disease is becoming increasingly prevalent in Canada. Many of these diseases could be prevented by adoption of healthy lifestyle habits including physical activity and healthy eating. Men, especially those in rural areas, are disproportionately affected by chronic disease. However, men are often underrepresented in community-based chronic disease prevention and management (CDPM) programs, including those that focus on physical activity and/or healthy eating. The purpose of this study was to explore the experiences and perceptions of program delivery staff regarding the challenges in recruitment and participation of men in physical activity and healthy eating programs in rural communities, and suggestions for improvement. Semistructured interviews were conducted by telephone with 10 CDPM program delivery staff from rural communities in Southwest Ontario, Canada. Time and travel constraints, relying on spouses, and lack of male program leaders were cited as barriers that contributed to low participation levels by men in CDPM programs. Hiring qualified male instructors and engaging spouses were offered as strategies to increase men’s participation. The results of this study highlight many of the current issues faced by rural health organizations when offering CDPM programming to men. Health care organizations and program delivery staff can use the recommendations in this report to improve male participation levels

Participants’ perceptions of “C.H.A.M.P. families”: A parent-focused intervention targeting paediatric overweight and obesity

Background: Recently, our team implemented a 13-week group-based intervention for parents of children with obesity (“C.H.A.M.P. Families”). The primary objective of this study was to explore, qualitatively, parents’ perspectives of their experiences in and influence of C.H.A.M.P. Families, as well as their recommendations for future paediatric obesity treatment interventions. Methods: Twelve parents (seven mothers, five fathers/step-fathers) representing seven children (four girls, three boys) with obesity participated in one of two focus groups following the intervention. Focus groups were audio recorded and transcribed verbatim and data were analyzed using inductive thematic analysis. Results: Findings showed that parents perceived their participation in C.H.A.M.P. Families to be a positive experience. Participants highlighted several positive health-related outcomes for children, families, and parents. Parents also underscored the importance and positive impact of the group environment, specific educational content, and additional program components such as free child-minding. Recommendations for future interventions were also provided, including greater child involvement and more practical strategies. Finally, parents identified several barriers including socioenvironmental issues, time constraints, and parenting challenges. Conclusions: Researchers developing family-based childhood obesity interventions should consider the balance of parent and child involvement, as well as emphasize group dynamics strategies and positive family communication

The functional and evolutionary impacts of human-specific deletions in conserved elements

[INTRODUCTION] Deciphering the molecular and genetic changes that differentiate humans from our closest primate relatives is critical for understanding our origins. Although earlier studies have prioritized how newly gained genetic sequences or variations have contributed to evolutionary innovation, the role of sequence loss has been less appreciated. Alterations in evolutionary conserved regions that are enriched for biological function could be particularly more likely to have phenotypic effects. We thus sought to identify and characterize sequences that have been conserved across evolution, but are then surprisingly lost in all humans. These human-specific deletions in conserved regions (hCONDELs) may play an important role in uniquely human traits.[RATIONALE] Sequencing advancements have identified millions of genetic changes between chimpanzee and human genomes; however, the functional impacts of the ~1 to 5% difference between our species is largely unknown. hCONDELs are one class of these predominantly noncoding sequence changes. Although large hCONDELs (>1 kb) have been previously identified, the vast majority of all hCONDELs (95.7%) are small (<20 base pairs) and have not yet been functionally assessed. We adapted massively parallel reporter assays (MPRAs) to characterize the effects of thousands of these small hCONDELs and uncovered hundreds with functional effects. By understanding the effects of these hCONDELs, we can gain insight into the mechanistic patterns driving evolution in the human genome.[RESULTS] We identified 10,032 hCONDELs by examining conserved regions across diverse vertebrate genomes and overlapping with confidently annotated, human-specific fixed deletions. We found that these hCONDELs are enriched to delete conserved sequences originating from stem amniotes. Overlap with transcriptional, epigenomic, and phenotypic datasets all implicate neuronal and cognitive functional impacts. We characterized these hCONDELs using MPRA in six different human cell types, including induced pluripotent stem cell–derived neural progenitor cells. We found that 800 hCONDELs displayed species-specific regulatory effect effects. Although many hCONDELs perturb transcription factor–binding sites in active enhancers, we estimate that 30% create or improve binding sites, including activators and repressors. Some hCONDELs exhibit molecular functions that affect core neurodevelopmental genes. One hCONDEL removes a single base in an active enhancer in the neurogenesis gene HDAC5, and another deletes six bases in an alternative promoter of PPP2CA, a gene that regulates neuronal signaling. We deeply characterized an hCONDEL in a putative regulatory element of LOXL2, a gene that controls neuronal differentiation. Using genome engineering to reintroduce the conserved chimpanzee sequence into human cells, we confirmed that the human deletion alters transcriptional output of LOXL2. Single-cell RNA sequencing of these cells uncovered a cascade of myelination and synaptic function–related transcriptional changes induced by the hCONDEL.[CONCLUSION] Our identification of hundreds of hCONDELs with functional impacts reveals new molecular changes that may have shaped our unique biological lineage. These hCONDELs display predicted functions in a variety of biological systems but are especially enriched for function in neuronal tissue. Many hCONDELs induced gains of regulatory activity, a surprising discovery given that deletions of conserved bases are commonly thought to abrogate function. Our work provides a paradigm for the characterization of nucleotide changes shaping species-specific biology across humans or other animals.This work was supported by the ENCODE Functional Characterization Center (grant UM1 HG009435 to P.C.S., R.T., and S.K.R.); Broad SPARC (P.C.S.); Howard Hughes Medical Institute (P.C.S.); and the National Institutes of Health (grant R00HG010669 to S.K.R., grants R00HG008179 and R35HG011329 to R.T., grant RF1AG065926 to M.F.G. and K.J.B., grant R01MH125246 to M.F.G. and K.J.B., grant R56MH125237 to M.F.G. and K.J.B., grant 5T32MH014276-45 to M.F.G., and grant R01HG008742 to E.K.); the Liweibo PhD scholarship from the University of Massachusetts Chan Medical School (X.L.); and the Distinguished professor award from the Swedish Medical Research Council (K.L.T.).Peer reviewe

Integrated genomic characterization of oesophageal carcinoma

Oesophageal cancers are prominent worldwide; however, there are few targeted therapies and survival rates for these cancers remain dismal. Here we performed a comprehensive molecular analysis of 164 carcinomas of the oesophagus derived from Western and Eastern populations. Beyond known histopathological and epidemiologic distinctions, molecular features differentiated oesophageal squamous cell carcinomas from oesophageal adenocarcinomas. Oesophageal squamous cell carcinomas resembled squamous carcinomas of other organs more than they did oesophageal adenocarcinomas. Our analyses identified three molecular subclasses of oesophageal squamous cell carcinomas, but none showed evidence for an aetiological role of human papillomavirus. Squamous cell carcinomas showed frequent genomic amplifications of CCND1 and SOX2 and/or TP63, whereas ERBB2, VEGFA and GATA4 and GATA6 were more commonly amplified in adenocarcinomas. Oesophageal adenocarcinomas strongly resembled the chromosomally unstable variant of gastric adenocarcinoma, suggesting that these cancers could be considered a single disease entity. However, some molecular features, including DNA hypermethylation, occurred disproportionally in oesophageal adenocarcinomas. These data provide a framework to facilitate more rational categorization of these tumours and a foundation for new therapies

Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes (, , ) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570