Barriers and enablers to promoting grandchildren's physical activity and reducing screen time: a qualitative study with Australian grandparents.

BACKGROUND: With an increasing number of grandparents providing care to their grandchildren, calls have been made for these caregivers to be considered important stakeholders in encouraging children's engagement in health-promoting behaviors, such as physical activity. Understanding the perspectives of grandparents who provide care is crucial to informing efforts that aim to increase children's physical activity, yet little is understood about their perceptions of specific barriers and enablers to promoting children's physical activity and reducing screen time. The present study sought to explore these perceptions. METHODS: Semi-structured focus groups and individual interviews were conducted with grandparents who reported providing care to a grandchild aged 3 to 14 years. A total of 20 grandparents were sampled (mean age = 67.8 years). Data were subjected to reflexive thematic analysis. RESULTS: Key reported barriers to physical activity included (i) the effort (physical and logistical) and financial cost associated with organizing physical activities, (ii) grandparents' age and mobility issues (e.g., due to injury or illness), (iii) caring for children of different ages (e.g., older children having different physical activity interests than younger children), and (iv) a local environment that is not conducive to physical activity (e.g., lack of appropriate facilities). Barriers to reducing screen time included (i) parents sending children to care with electronic devices and (ii) children's fear of missing out on social connection that occurs electronically. Strategies and enablers of physical activity included (i) integrating activity into caregiving routines (e.g., walking the dog), (ii) involving grandchildren in decision making (e.g., asking them in which physical activities they wish to engage), (iii) encouraging grandchildren to engage in activity with other children, and (iv) creating a physical and social environment that supports activity (e.g., owning play equipment). A common strategy for reducing screen time was the creation of a home environment that is not conducive to this activity (e.g., removing electronic devices from view). CONCLUSIONS: Findings suggest that grandparents may benefit from resources that assist them to identify activities that are inexpensive and require minimal effort to organize. Activities that account for grandparents' age and health status, as well as any environmental barriers, are likely to be well-received.

Parents on the Concept of Physical Literacy: What Do They Know, What Do They Do, and What Do They Want?

Physical literacy development in early childhood, viewed by many as the foundation for lifelong physical activity engagement, is significantly influenced by parents. Our aim was to explore parents' understanding of physical literacy and gain insight into their perspectives on physical literacy promotion. We recruited 18 parents of children between 5 and 8 years old in Australia. Using semistructured interviews and thematic analysis, we identified several key issues regarding parents' understanding and implementation of physical literacy. Parents expressed interest in improving their implementation of physical literacy practices and had (often unintentionally) provided support for physical literacy subcomponents in the past. However, they described difficulties prioritizing physical literacy above other parental demands and expressed conflicting perceptions regarding where the responsibility should lie for developing their child's physical literacy (e.g., at home or at school). To ensure that the physical literacy "message" reaches parents, we encourage physical literacy promoters to consider the target (e.g., responsibility, priorities, and awareness) of their promotional strategies. Further investigation into the influence of sociocultural and economic factors on parents' understanding and application of physical literacy is warranted.

'It's been a lifelong thing for me': parents' experiences of facilitating a healthy lifestyle for their children with severe obesity.

OBJECTIVE: For parents and guardians, assisting children/adolescents with severe obesity to lose weight is often a key objective but a complex and difficult challenge. Our aim in this study was to explore parents' (and guardians') perspectives on the challenges they have faced in assisting their children/adolescents with severe obesity to lead a healthy lifestyle. METHODS: Thirteen parents/guardians were interviewed from a pool of families who had been referred but did not engage between 2016 and 2018 (N = 103), with the Perth Children's Hospital Healthy Weight Service, a clinical obesity program for children/adolescents (parent age M = 43.2 years, children age M = 10.3 years). Using semi-structured interviews and thematic analysis, we identified 3 broad themes. RESULTS: Parental weight-related factors reflected parents' own lifelong obesity narrative and its effect on their own and their families' ability to live a healthy lifestyle. Perceived inevitability of obesity in their child reflected parents' feelings that the obesity weight status of their children/adolescent was a persistent and overwhelming problem that felt 'out of control'. Lastly, parents reported challenges getting medical help stemming from co-morbid medical diagnosis in their child/adolescent, and difficulties with medical professionals. CONCLUSION: This study demonstrates that parents face challenges in supporting healthy lifestyle for children/adolescents with severe obesity due to parents own internal weight biases and their negative experiences within the healthcare system when seeking help.

Support needs and experiences of young people living in families with mental illness.

INTRODUCTION: Children and adolescents living in families affected by mental illness are at elevated risk of developing mental health problems. A range of interventions have been designed to help these young people; however, the effectiveness of these programs is, in some cases, mixed. Our aim was to understand in detail the support needs and experiences of a group of Australian children and adolescents living in families with mental illness. METHODS: Our study is a qualitative in nature. In 2020-2021, we interviewed 25 Australian young people (Mage = 13.60, SD = 2.26, 20 females and 5 males) living with family members affected by mental illness to understand their (the young people's) experiences, and to identify the types of support that these young people considered important or effective. We conducted reflexive thematic analyses of interview data, underpinned by interpretivist assumptions. RESULTS: We identified seven themes within two higher-order categories reflecting our aims to understand (1) lived experiences within families affected by mental illness (i.e., increased responsibilities, missing out, and stigmatization), and (2) support experiences, needs, and preferences (i.e., respite, shared experiences with like-minded others, education, and flexibility). CONCLUSIONS: Our findings hold substantial practical value by informing services, interventions, and conversations that better support young people living in families affected by mental illness.

The Right Advice, from the Right Person, in the Right Way: Non-Engaged Consumer Families' Preferences for Lifestyle Intervention Design Relating to Severe Obesity in Childhood.

Family-based lifestyle interventions for children/adolescents with severe levels of obesity are numerous, but evidence indicates programs fail to elicit short- or longer-term weight loss outcomes. Families with lived experience can provide valuable insight as we strive to improve outcomes from programs. Our aim was to explore elements that families desired in a program designed to treat severe levels of obesity in young people. We recruited a cross-sectional sample of 13 families (parents and young people) who had been referred but had not engaged with the state-wide Perth Children's Hospital, Healthy Weight Service (Perth, Australia), between 2016 and 2018. Utilizing semi-structured interviews and reflexive qualitative thematic analysis, we identified two broad themes, (1) bridging the gap between what to do and how to do it, and (2) peers doing it with you. The first theme reflected parents' and young people's feelings that programs ought to teach specialist-designed practical strategies utilizing non-generic information tailored to address the needs of the family, in a collaboratively supportive way, and encourage young people to learn for themselves. The second theme reflected the importance of social connection facilitated by peer support, and intervention programs should be offered in a group format to foster inclusion. Families indicated a willingness to engage in tertiary intervention programs but desired support from specialized health professionals/programs to be tailored to their needs, sensitive to their experiences and challenges and provide useful practical strategies that support the knowledge-to-action process.

Molecular characterization of fast-growing melanomas.

BACKGROUND: The rate of growth of primary melanoma is a robust predictor of aggressiveness, but the mutational profile of fast-growing melanomas (FGMM) and the potential to stratify patients at high risk of death has not been comprehensively studied. OBJECTIVE: To investigate the epidemiologic, clinical, and mutational profile of primary cutaneous melanomas with a thickness ≥ 1 mm, stratified by rate of growth. METHODS: Observational prospective study. Deep-targeted sequencing of 40 melanoma driver genes on formalin fixed, paraffin-embedded primary melanoma samples. Comparison of FGMM (rate of growth > 0.5 mm/month) and nonFGMM (rate of growth ≤ 0.5 mm/month). RESULTS: Two hundred patients were enrolled, among wom 70 had FGMM. The relapse-free survival was lower in the FGMM group (P = .014). FGMM had a higher number of predicted deleterious mutations within the 40 genes than nonFGMM (P = .033). Ulceration (P = .032), thickness (P = .006), lower sun exposure (P = .049), and fibroblast growth factor receptor 2 (FGFR2) mutations (P = .037) were significantly associated with fast growth. LIMITATIONS: Single-center study, cohort size, potential memory bias, number of investigated genes. CONCLUSION: Fast growth is linked to specific tumor biology and environmental factors. Ulceration, thickness, and FGFR2 mutations are associated with fast growth. Screening for FGFR2 mutations might provide an additional tool to better identify FGMM, which are probably good candidates for adjuvant therapies.

Perceptions of a family-based lifestyle intervention for children with overweight and obesity: a qualitative study on sustainability, self-regulation, and program optimization.

BACKGROUND: Family-based lifestyle interventions (FBLIs) are an important method for treating childhood weight problems. Despite being recognized as an effective intervention method, the optimal structure of these interventions for children's overweight and obesity has yet to be determined. Our aim was to better understand participants' (a) implementation of behaviour strategies and long-term outcomes, (b) perceptions regarding the optimal structure of FBLIs, and (c) insights into psychological concepts that may explain the success of these programs. METHODS: Purposive sampling was used to recruit participants. We conducted focus groups as well as one-to-one interviews with parents (n = 53) and children (n = 50; aged 7-13, M = 9.4 yr, SD = 3.1) three months following their involvement in a 10-week, multi-component, FBLI involving education and activities relating to healthy nutrition, physical activity, and behavior modification. Using an interpretivist approach, a qualitative study design was employed to examine participant experiences. RESULTS: We identified three higher-order categories: (a) participants' program experiences and perceptions (b) lifestyle changes post-program, and (c) recommendations for optimizing family-based programs. Themes identified within these categories included (a) support and structure & content, (b) diet and physical activity, and (c) in-program recommendations and post-program recommendations. CONCLUSIONS: We identified several challenges that can impair lasting behavior change (e.g., physical activity participation) following involvement in a FBLI. On optimizing these programs, participants emphasized fun, interactive content, interpersonal support, appropriate educational content, and behavior change techniques. Concepts rooted in motivational theory could help address calls for greater theoretical and mechanistic insight in FBLIs. Findings may support research advancement and assist health professionals to more consistently realize the potential of these interventions.

MAN v FAT Soccer: Feasibility Study and Preliminary Efficacy of a Sport-Based Weight-Loss Intervention for Overweight and Obese Men in Australia.

MAN v FAT Soccer is a sport-based weight-loss program for overweight and obese men that originated in the United Kingdom (i.e., as MAN v FAT Football) and appears to successfully engage men with weight loss. We sought to explore whether the program would work in an Australian context by (a) establishing a foundation for the implementation of the program on a larger scale and (b) determining how large-scale implementation is most feasible. We conducted a nonrandomized, single intervention group feasibility trial of MAN v FAT Soccer in Australia with 418 male participants with a body mass index greater than 27.50 kg/m2. Results indicate that the program is acceptable, with participants reporting positive perceptions of the various components of the program and a high proportion reporting intentions to recommend the program to others (95.9%). Furthermore, preliminary effectiveness results indicate positive changes in weight (4.6% reduction) and physical activity (88.5% increase) and improvements in psychological outcomes such as depression (17.6% decrease), stress (19.0% decrease), and body appreciation (19.1% increase). Our findings provide general support for the feasibility of MAN v FAT Soccer and the notion that leveraging competition and masculinity may help drive men's health behavior change.

Overweight and obese men's experiences in a sport-based weight loss intervention for men.

In Western countries, such as Australia and the UK, a significantly greater proportion of men (relative to women) are overweight and obese, yet relatively few weight loss interventions have been developed that sufficiently target men. This lack of male-focused programming may be in part because 'traditional' weight loss programs are unappealing for what is considered a 'hard-to-reach' population. One program that appears to have such appeal for men is the MAN v FAT Football (MVFF) program, based out of the United Kingdom, which is designed for men with a body mass index of (or greater than) 27.5. MVFF encourages men's participation in a community-based weight loss program that incentivizes weight loss through participation in a football league, and since 2016 MVFF has supported the weight loss efforts of several thousand men. Using MVFF as an exemplar, our aim was to derive insight into how men experience a male-only competitive, sport-based weight loss program. We recruited twenty-seven players (Mage = 41.13, SD = 9.93), and ten coaches (Mage = 31.8, SD = 11.55) from program locations throughout the United Kingdom. Using semi-structured interviews and thematic analysis, we identified several appraisal aspects of the program that players and coaches considered important, including the appeal of sport, competition on a level playing field, being part of a team, camaraderie, accountability, men sharing issues with other men, gender-sensitized environment, likeminded and similar men, and perceptions that traditional weight loss programs are tailored towards women. Player experiences (i.e., competence and enjoyment) and functional supports in the program (e.g., player handbook, weight loss coach) were reported to drive outcomes of effective weight loss and program retention. Interventions aiming to target men may be more successful working with rather than against formulations of identity such as masculinities, and this can be achieved by tailoring program content (e.g., messaging), settings (e.g., among men sharing similar characteristics such as body-type or goals), and mode of delivery (e.g., through organized sports, and leveraging competition to drive healthy behaviours).

Not All Promotion Is Good Promotion: The Pitfalls of Overexaggerated Claims and Controlling Language in Exercise Messaging.

Across 2 studies, the authors explored reactance effects to overexaggerated claims and controlling language in exercise messaging. In Study 1, participants received either a message exaggerating the benefits of an upcoming exercise session or no message. They subsequently undertook a mundane exercise session led by an instructor, which was either need supportive or "realistically controlling." Relative to no-message participants, those who had read the message reported less positive evaluations of the session. These results were observed despite participants in the message condition holding more positive presession expectations, and the effect was apparent even for those who received need-supportive instruction. In Study 2, participants read an advertisement that was written in either autonomy-supportive language or controlling language. Despite reporting comparable expectations, participants who received a controlling-language message reported significantly greater anger and freedom threat-factors commonly linked to contrast effects. These studies highlight the operation of message-driven contrast effects in exercise.

Sequential decitabine and carboplatin treatment increases the DNA repair protein XPC, increases apoptosis and decreases proliferation in melanoma.

BACKGROUND: Melanoma has two key features, an over-representation of UV-induced mutations and resistance to DNA damaging chemotherapy agents. Both of these features may result from dysfunction of the nucleotide excision repair pathway, in particular the DNA damage detection branch, global genome repair (GGR). The key GGR component XPC does not respond to DNA damage in melanoma, the cause of this lack of response has not been investigated. In this study, we investigated the role of methylation in reduced XPC in melanoma. METHODS: To reduce methylation and induce DNA-damage, melanoma cell lines were treated with decitabine and carboplatin, individually and sequentially. Global DNA methylation levels, XPC mRNA and protein expression and methylation of the XPC promoter were examined. Apoptosis, cell proliferation and senescence were also quantified. XPC siRNA was used to determine that the responses seen were reliant on XPC induction. RESULTS: Treatment with high-dose decitabine resulted in global demethylation, including the the shores of the XPC CpG island and significantly increased XPC mRNA expression. Lower, clinically relevant dose of decitabine also resulted in global demethylation including the CpG island shores and induced XPC in 50% of cell lines. Decitabine followed by DNA-damaging carboplatin treatment led to significantly higher XPC expression in 75% of melanoma cell lines tested. Combined sequential treatment also resulted in a greater apoptotic response in 75% of cell lines compared to carboplatin alone, and significantly slowed cell proliferation, with some melanoma cell lines going into senescence. Inhibiting the increased XPC using siRNA had a small but significant negative effect, indicating that XPC plays a partial role in the response to sequential decitabine and carboplatin. CONCLUSIONS: Demethylation using decitabine increased XPC and apoptosis after sequential carboplatin. These results confirm that sequential decitabine and carboplatin requires further investigation as a combination treatment for melanoma.

Does the primary site really matter? Profiling mucinous ovarian cancers of uncertain primary origin (MO-CUP) to personalise treatment and inform the design of clinical trials.

OBJECTIVE: Advanced stage mucinous ovarian cancers are diagnostically and therapeutically challenging. Histotype specific trials have failed due to low recruitment after excluding non-ovarian primaries. Mucinous ovarian cancers are commonly metastatic from other sites however lack definitive diagnostic markers. We suggest a classification of mucinous ovarian cancers of uncertain primary origin 'MO-CUPs' in clinical trials. This study aims to identify drug targets to guide treatment and future trials. METHODS: We analyzed a large de-identified, multi-platform tumor profiling dataset of MO-CUPs enriched for advanced stage and recurrent cases submitted to Caris Life Sciences. Available data included a 45-gene next-generation sequencing (NGS) panel, gene amplification of HER2 and cMET and 18 immunohistochemical (IHC) markers of drug sensitivity/resistance. RESULTS: Mucinous tumors from 333 patients were analyzed, including 38 borderline tumors and 295 invasive cancers. The most common mutations in a subset (n = 128) of invasive cancers were KRAS (60%), TP53 (38%), PIK3CA (13%) and PTEN (9%). Borderline tumors had higher rates of BRAF mutations, and PGP and TOP2A overexpression than invasive cases. KRAS mutant invasive cancers had lower expression of thymidylate synthase (p = 0.01) and higher expression of TUBB3 (p = 0.01) than KRAS wildtype tumors. CONCLUSIONS: To our knowledge, this is the largest series profiling mucinous ovarian cancers and almost certainly includes cases of ovarian and non-ovarian origin. Given the difficulty recruiting patients to histotype-specific trials in rare subsets of ovarian cancer, it may be more important to focus on identifying potential treatment targets and to personalise treatment and design clinical trials in MO-CUPS agnostic of primary site to overcome these issues.

Australian children's physical activity and screen time while in grandparental care.

OBJECTIVE: The objective of this study was to explore Australian children's engagement in physical activity and screen time while being cared for by their grandparents. METHOD: Grandparents (N = 1,190) providing ≥3 hours of weekly care to a grandchild aged 3-14 years completed an online survey assessing their grandchildren's movement behaviours while in their care. Descriptive statistics were computed for frequency of engagement in unstructured and structured physical activities, minutes spent playing outdoors, and minutes spent engaged in screen time. Regression analyses were conducted to assess socio-demographic predictors of movement behaviours. RESULTS: Playing in the yard was the most common form of physical activity in which grandchildren reportedly participated (77% 'usually' or 'always'), followed by playing with toys/equipment (62%). Few (14-36%) frequently engaged in active transport. Children spent an average of 181 minutes per week engaged in screen-based activities. CONCLUSIONS: There is an opportunity to improve children's movement behaviours while in grandparental care. Communicating to grandparents their importance in supporting an active lifestyle is warranted. IMPLICATIONS FOR PUBLIC HEALTH: Findings highlight the importance of creating environments that facilitate play-based, outdoor activities. Ensuring children have access to play equipment while in the care of grandparents and improving access to and quality of neighbourhood parks may assist with activity promotion.

Concurrent RB1 Loss and BRCA-Deficiency Predicts Enhanced Immunological Response and Long-Term Survival in Tubo-Ovarian High-Grade Serous Carcinoma.

PURPOSE: To evaluate RB1 expression and survival across ovarian carcinoma histotypes, and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC). EXPERIMENTAL DESIGN: RB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 primary HGSC to characterize tumors with concurrent BRCA-deficiency and RB1 loss. RESULTS: RB1 loss was associated with longer OS in HGSC, but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared to patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA-deficiency correlated with transcriptional markers of enhanced interferon response, cell-cycle deregulation, and reduced epithelial-mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1. CONCLUSIONS: Co-occurrence of RB1 loss and BRCA-deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.

The role of altered nucleotide excision repair and UVB-induced DNA damage in melanomagenesis.

UVB radiation is the most mutagenic component of the UV spectrum that reaches the earth's surface and causes the development of DNA damage in the form of cyclobutane pyrimidine dimers and 6-4 photoproducts. UV radiation usually results in cellular death, but if left unchecked, it can affect DNA integrity, cell and tissue homeostasis and cause mutations in oncogenes and tumour-suppressor genes. These mutations, if unrepaired, can lead to abnormal cell growth, increasing the risk of cancer development. Epidemiological data strongly associates UV exposure as a major factor in melanoma development, but the exact biological mechanisms involved in this process are yet to be fully elucidated. The nucleotide excision repair (NER) pathway is responsible for the repair of UV-induced lesions. Patients with the genetic disorder Xeroderma Pigmentosum have a mutation in one of eight NER genes associated with the XP complementation groups XP-A to XP-G and XP variant (XP-V). XP is characterized by diminished repair capacity, as well as a 1000-fold increase in the incidence of skin cancers, including melanoma. This has suggested a significant role for NER in melanoma development as a result of UVB exposure. This review discusses the current research surrounding UVB radiation and NER capacity and how further investigation of NER could elucidate the role of NER in avoiding UV-induced cellular death resulting in melanomagenesis.

The Influence of Grandparents on Children's Dietary Health: A Narrative Review.

PURPOSE OF REVIEW: To examine and synthesise recent evidence on the role of grandparents in shaping children's dietary health. RECENT FINDINGS: The influence of grandparents on children's dietary health was evident across studies. Grandparents frequently provide their grandchildren with meals and snacks, and engage in many of the same feeding practices used by parents. Although grandparents report providing their grandchildren with healthy foods, the provision of treat foods high in sugar or fat was a common finding. This provision led to family conflict, with the indulgent behaviours of grandparents seen by parents as a barrier to healthy eating. Grandparents are exerting significant influence on child dietary health. Efforts are needed to ensure these care providers are considered key stakeholders in the promotion of healthy eating and are targeted in policies and programs addressing children's diets. Research that determines how to best support grandparents to foster healthy behaviours in children is critical.

The Stride program: Feasibility and pre-to-post program change of an exercise service for university students experiencing mental distress.

Rates of mental illness are disproportionately high for young adult and higher education (e.g., university student) populations. As such, universities and tertiary institutions often devote significant efforts to services and programs that support and treat mental illness and/or mental distress. However, within that portfolio of treatment approaches, structured exercise has been relatively underutilised and greater research attention is needed to develop this evidence base. The Stride program is a structured 12-week exercise service for students experiencing mental distress. We aimed to explore the feasibility of the program and assess pre- and post-program change, through assessments of student health, lifestyle, and wellbeing outcomes. Drawing from feasibility and effectiveness-implementation hybrid design literatures, we conducted a non-randomised feasibility trial of the Stride program. Participants were recruited from the Stride program (N = 114, Mage = 24.21 years). Feasibility results indicated the program was perceived as acceptable and that participants reported positive perceptions of program components, personnel, and sessions. Participants' pre-to-post program change in depressive symptomatology, physical activity levels, mental health-related quality of life, and various behavioural outcomes were found to be desirable. Our results provide support for the feasibility of the Stride program, and more broadly for the delivery and potential effectiveness of structured exercise programs to support university students experiencing mental distress.

Structured exercise programs for higher education students experiencing mental health challenges: background, significance, and implementation.

The incidence of mental illness is greatest among young adults, and those enrolled in higher education may be particularly vulnerable compared to the general young adult population. Many higher education institutions employ student support staff tasked with implementing strategies to improve student wellbeing and mental illness. However, these strategies tend to be focused on clinical therapies and pharmacological interventions with limited lifestyle approaches. Exercise is an effective method for addressing mental illness and promoting wellbeing, yet widespread provision of structured exercise services to support treatment options for students with mental health challenges has not been fully realized. In an effort to guide exercise strategies for student mental health, we synthesize considerations for developing and delivering exercise programs in higher education settings. We draw directly from the evidence base on existing exercise programs in higher education; and the broader behavior change, exercise adherence, health psychology, implementation science, and exercise prescription literatures. Our broad considerations cover issues regarding program engagement and behavior change, exercise 'dose' and prescription, integration with other on-campus services, and robust research and evaluation. These considerations may provide impetus for widespread program development and implementation, as well as informing research focused on protecting and improving student mental health.

Concurrent RB1 loss and BRCA-deficiency predicts enhanced immunological response and long-term survival in tubo-ovarian high-grade serous carcinoma.

Background: Somatic loss of the tumour suppressor RB1 is a common event in tubo-ovarian high-grade serous carcinoma (HGSC), which frequently co-occurs with alterations in homologous recombination DNA repair genes including BRCA1 and BRCA2 (BRCA). We examined whether tumour expression of RB1 was associated with survival across ovarian cancer histotypes (HGSC, endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous carcinoma (LGSC)), and how co-occurrence of germline BRCA pathogenic variants and RB1 loss influences long-term survival in a large series of HGSC. Patients and methods: RB1 protein expression patterns were classified by immunohistochemistry in epithelial ovarian carcinomas of 7436 patients from 20 studies participating in the Ovarian Tumor Tissue Analysis consortium and assessed for associations with overall survival (OS), accounting for patient age at diagnosis and FIGO stage. We examined RB1 expression and germline BRCA status in a subset of 1134 HGSC, and related genotype to survival, tumour infiltrating CD8+ lymphocyte counts and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cell lines with and without BRCA1 mutations to model co-loss with treatment response. We also performed genomic analyses on 126 primary HGSC to explore the molecular characteristics of concurrent homologous recombination deficiency and RB1 loss. Results: RB1 protein loss was most frequent in HGSC (16.4%) and was highly correlated with RB1 mRNA expression. RB1 loss was associated with longer OS in HGSC (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.66-0.83, P = 6.8 ×10-7), but with poorer prognosis in ENOC (HR 2.17, 95% CI 1.17-4.03, P = 0.0140). Germline BRCA mutations and RB1 loss co-occurred in HGSC (P < 0.0001). Patients with both RB1 loss and germline BRCA mutations had a superior OS (HR 0.38, 95% CI 0.25-0.58, P = 5.2 ×10-6) compared to patients with either alteration alone, and their median OS was three times longer than non-carriers whose tumours retained RB1 expression (9.3 years vs. 3.1 years). Enhanced sensitivity to cisplatin (P < 0.01) and paclitaxel (P < 0.05) was seen in BRCA1 mutated cell lines with RB1 knockout. Among 126 patients with whole-genome and transcriptome sequence data, combined RB1 loss and genomic evidence of homologous recombination deficiency was correlated with transcriptional markers of enhanced interferon response, cell cycle deregulation, and reduced epithelial-mesenchymal transition in primary HGSC. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1. Conclusions: Co-occurrence of RB1 loss and BRCA mutation was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.

Understanding parent perspectives on engagement with online youth-focused mental health programs.

OBJECTIVE: Online youth-focused health programs often include parent modules-that equip parents with skills to assist their child in improving their health-alongside youth-specific content. BRAVE Self-Help, an evidence-based program designed for children and teenagers with early signs of anxiety, is a popular Australian program that includes six parent modules. Despite its popularity and proven efficacy, BRAVE Self-Help shares the same challenge as many online self-help programs-that of low participant engagement. Using parents registered in BRAVE Self-Help as 'information rich' participants, we explored (a) factors that influenced parent engagement in online health programs, and (b) their recommendations for enhancing parent engagement. DESIGN AND OUTCOME MEASURE: We conducted semi-structured interviews with 14 parents registered in BRAVE Self-Help. Data were analysed through reflexive thematic analysis. RESULTS: Social-, family- and program-related factors drove parents' program engagement and recommendations. Social sub-themes related to the benefits of professional and community support in promoting more engagement. Family sub-themes included difficulties with program engagement due to competing priorities, perceptions that condition severity influenced engagement, and feelings that previously-acquired health knowledge reduced motivation to engage. Program sub-themes included perceived usefulness and ease-of-use. CONCLUSION: Program designers could target support systems, include flexible delivery options, and use iterative design processes to enhance parent engagement.