Co-design of a paediatric oncology medicines database (ProCure) to support complex care provision for children with a hard-to-treat cancer.

Objectives: Paediatric oncologists often encounter challenges when seeking compassionate access to off-label therapies for their patients. This study employed implementation science and co-design techniques to develop the ProCure medicines database, with the goal of streamlining the application process and addressing identified barriers in paediatric oncology. Methods: This study utilised an exploratory qualitative research design. Seventeen healthcare providers, including oncologists, nurse consultants, and allied health professionals, participated in semi-structured interviews guided by the Consolidated Framework for Implementation Research (CFIR) and a visual process map aid. Deductive qualitative data analysis, according to the CFIR constructs, identified key barriers and facilitators. Collaborative design sessions engaged multidisciplinary teams to develop the ProCure beta version. Results: Barriers to off-label therapy access included resource-intensive applications, time sensitive decision-making, and complex pharmaceutical information. Facilitators included Drug Access Navigators, Molecular Tumour Boards, and a multi-disciplinary approach. ProCure addressed end-user needs by centralising medicines information. Additional features suggested by healthcare providers included blood-brain-barrier penetrability data and successful application examples. Conclusion: ProCure represents a promising solution to the challenges paediatric oncologists face in accessing off-label therapies. By centralising information, it simplifies the application process, aids decision-making, and promotes a collaborative approach to patient care. The potential of the database to stream and enhance off-label therapy access underscores its relevance in improving paediatric oncology practise. Further research and implementation efforts are warranted to assess ProCure's real-world impact and refine its features based on user feedback.

Exploring Web-Based Information and Resources That Support Adolescents and Young Adults With Cancer to Resume Study and Work: Environmental Scan Study.

BACKGROUND: Adolescents and young adults (AYAs) diagnosed with cancer experience physical, cognitive, and psychosocial effects from cancer treatment that can negatively affect their ability to remain engaged in education or work through cancer treatment and in the long term. Disengagement from education or work can have lasting implications for AYAs' financial independence, psychosocial well-being, and quality of life. Australian AYAs with cancer lack access to adequate specialist support for their education and work needs and report a preference for web-based support that they can access from anywhere, in their own time. However, it remains unclear what web-based resources exist that are tailored to support AYAs with cancer in reaching their educational or work goals. OBJECTIVE: This study aimed to determine what web-based resources exist for Australian AYAs with cancer to (1) support return to education or work and (2) identify the degree to which existing resources are age-specific, cancer-specific, culturally inclusive, and evidence-based; are co-designed with AYAs; use age-appropriate language; and are easy to find. METHODS: We conducted an environmental scan by searching Google with English search terms in August 2022 to identify information resources about employment and education for AYAs ever diagnosed with cancer. Data extraction was conducted in Microsoft Excel, and the following were assessed: understandability and actionability (using the Patient Education and Materials Tool), readability (using the Sydney Health Literacy Laboratory Health Literacy Editor), and whether the resource was easy to locate, evidence-based, co-designed with AYAs, and culturally inclusive of Aboriginal and Torres Strait Islander peoples. The latter was assessed using 7 criteria previously developed by members of the research team. RESULTS: We identified 24 web-based resources, comprising 22 written text resources and 12 video resources. Most resources (21/24, 88%) were published by nongovernmental organizations in Australia, Canada, the United States, and the United Kingdom. A total of 7 resources focused on education, 8 focused on work, and 9 focused on both education and work. The evaluation of resources demonstrated poor understandability and actionability. Resources were rarely evidence-based or co-designed by AYAs, difficult to locate on the internet, and largely not inclusive of Aboriginal and Torres Strait Islander populations. CONCLUSIONS: Although web-based resources for AYAs with cancer are often available through the websites of hospitals or nongovernmental organizations, this environmental scan suggests they would benefit from more evidence-based and actionable resources that are available in multiple formats (eg, text and audio-visual) and tailored to be age-appropriate and culturally inclusive.

Communicating with families of young people with hard-to-treat cancers: Healthcare professionals' perspectives on challenges, skills, and training.

OBJECTIVES: Hard-to-treat childhood cancers are those where standard treatment options do not exist and the prognosis is poor. Healthcare professionals (HCPs) are responsible for communicating with families about prognosis and complex experimental treatments. We aimed to identify HCPs' key challenges and skills required when communicating with families about hard-to-treat cancers and their perceptions of communication-related training. METHODS: We interviewed Australian HCPs who had direct responsibilities in managing children/adolescents with hard-to-treat cancer within the past 24 months. Interviews were analyzed using qualitative content analysis. RESULTS: We interviewed 10 oncologists, 7 nurses, and 3 social workers. HCPs identified several challenges for communication with families including: balancing information provision while maintaining realistic hope; managing their own uncertainty; and nurses and social workers being underutilized during conversations with families, despite widespread preferences for multidisciplinary teamwork. HCPs perceived that making themselves available to families, empowering them to ask questions, and repeating information helped to establish and maintain trusting relationships with families. Half the HCPs reported receiving no formal training for communicating prognosis and treatment options with families of children with hard-to-treat cancers. Nurses, social workers, and less experienced oncologists supported the development of communication training resources, more so than more experienced oncologists. SIGNIFICANCE OF RESULTS: Resources are needed which support HCPs to communicate with families of children with hard-to-treat cancers. Such resources may be particularly beneficial for junior oncologists and other HCPs during their training, and they should aim to prepare them for common challenges and foster greater multidisciplinary collaboration.

Professionally led support groups for people living with advanced or metastatic cancer: a systematic scoping review of effectiveness and factors critical to implementation success within real-world healthcare and community settings.

PURPOSE: To examine the effectiveness of professionally led support groups for people with advanced or metastatic cancer, and identify factors critical to implementation success within real-world settings. METHODS: Databases (MEDLINE; PsychINFO; CINAHL) and grey literature were searched for empirical publications and evaluations. Articles were screened for eligibility and data systematically extracted, charted and summarised using a modified scoping review methodology. Implementation factors were mapped using Proctor's implementation framework and the Consolidated Framework for Implementation Research 2.0. RESULTS: A total of 1691 publications were identified; 19 were eligible for inclusion (8 randomised controlled trials, 7 qualitative studies, 2 cohort studies, 2 mixed methods studies). Most (n=18) studies focused on tumour-specific support groups. Evidence supported professionally led support groups in reducing mood disturbances (n=5), distress (i.e. traumatic stress, depression) (n=4) and pain (n=2). Other benefits included social connectedness (n=6), addressing existential distress (n=5), information and knowledge (n=6), empowerment and sense of control (n=2), relationships with families (n=2) and communication with health professionals (n=2). Thirteen studies identified factors predicting successful adoption, implementation or sustainment, including acceptability (n=12; 63%), feasibility (n=6; 32%) and appropriateness (n=1; 5%). Key determinants of successful implementation included group leaders' skills/experience, mode of operation, travelling distance, group composition and membership and resourcing. CONCLUSIONS: Professionally led tumour-specific support groups demonstrate effectiveness in reducing mood disturbances, distress and pain among patients. Successful implementation hinges on factors such as leadership expertise, operational methods and resource allocation. IMPLICATIONS FOR CANCER SURVIVORS: Professionally led support groups may fill an important gap in supportive care for people with advanced or metastatic cancer.

Models of care and the advanced practice nurse role in caring for children and adolescents with a cancer predisposition syndrome: a scoping review protocol.

OBJECTIVE: This scoping review will examine the literature describing models of care, barriers and facilitators of care, and gaps in care delivery for children and adolescents with a cancer predisposition syndrome (CPS). It will also explore how advanced practice nurses contribute to the delivery of care for children and adolescents with a CPS. INTRODUCTION: Cancer remains a leading cause of death in children and adolescents. Pediatric CPS clinics proactively aim for early diagnosis or prevention of cancer in children and adolescents with a CPS. Additionally, the holistic well-being of individuals requires a multidisciplinary team, including advanced practice nurses, to manage their complex health care needs. INCLUSION CRITERIA: This review will consider both published and unpublished literature exploring aspects of models of care and the role of the nurse in pediatric CPS clinics. Literature published in English from 1991 will be considered. METHODS: This scoping review will follow the JBI methodology for scoping reviews. The review will include searches in MEDLINE, Embase, and CINAHL Complete. Gray literature searches will be conducted in OAIster and Social Science Research Network (SSRN), as well as websites of hospitals in the USA and the UK with large pediatric cancer centers. Two reviewers will screen titles, abstracts, and full-text articles. An extraction table will be used to extract relevant data from all included articles and facilitate data analysis. Results will be presented in narrative and tabular format. REVIEW REGISTRATION: Open Science Framework osf.io/axkp7/.

A mainstreaming oncogenomics model: improving the identification of Lynch syndrome.

Introduction: "Mainstreaming" is a proposed strategy to integrate genomic testing into oncology. The aim of this paper is to develop a mainstreaming oncogenomics model by identifying health system interventions and implementation strategies for mainstreaming Lynch syndrome genomic testing. Methods: A rigorous theoretical approach inclusive of conducting a systematic review and qualitative and quantitative studies was undertaken using the Consolidated Framework for Implementation Research. Theory-informed implementation data were mapped to the Genomic Medicine Integrative Research framework to generate potential strategies. Results: The systematic review identified a lack of theory-guided health system interventions and evaluation for Lynch syndrome and other mainstreaming programs. The qualitative study phase included 22 participants from 12 health organizations. The quantitative Lynch syndrome survey included 198 responses: 26% and 66% from genetic and oncology health professionals, respectively. Studies identified the relative advantage and clinical utility of mainstreaming to improve genetic test access and to streamline care, and adaptation of current processes was recognized for results delivery and follow-up. Barriers identified included funding, infrastructure and resources, and the need for process and role delineation. The interventions to overcome barriers were as follows: embedded mainstream genetic counselors, electronic medical record genetic test ordering, results tracking, and mainstreaming education resources. Implementation evidence was connected through the Genomic Medicine Integrative Research framework resulting in a mainstreaming oncogenomics model. Discussion: The proposed mainstreaming oncogenomics model acts as a complex intervention. It features an adaptable suite of implementation strategies to inform Lynch syndrome and other hereditary cancer service delivery. Implementation and evaluation of the model are required in future research.

In person and virtual process mapping experiences to capture and explore variability in clinical practice: application to genetic referral pathways across seven Australian hospital networks.

Genetic referral for Lynch syndrome (LS) exemplifies complex clinical pathways. Identifying target behaviours (TBs) for change and associated barriers requires structured group consultation activities with busy clinicians - consolidating implementation activities whilst retaining rigour is crucial. This study aimed to: i) use process mapping to gain in-depth understandings of site-specific LS testing and referral practices in Australian hospitals and support identification of TBs for change, ii) explore if barriers to identified TBs could be identified through process mapping focus-group data, and iii) demonstrate pandemic-induced transition from in-person to virtual group interactive process mapping methods. LS clinical stakeholders attended interactive in-person or virtual focus groups to develop site-specific "process maps" visually representing referral pathways. Content analysis of transcriptions informed site-specific process maps, then clinical audit data was compared to highlight TBs for change. TBs were reviewed in follow-up focus groups. Secondary thematic analysis explored barriers to identified TBs, coded against the Theoretical Domains Framework (TDF). The transition from in-person to pandemic-induced virtual group interactive process mapping methods was documented. Process mapping highlighted six key areas of clinical practice variation across sites and site-specific TBs for change were identified. Key barriers to identified TBs emerged, categorised to seven TDF domains. Process mapping revealed variations in clinical practices surrounding LS referral between sites. Incorporating qualitative perspectives enhances process mapping by facilitating identification of TBs for change and barriers, providing a pathway to developing targeted interventions. Virtual process mapping activities produced detailed data and enabled comprehensive map development.

To achieve change in the health system using implementation approaches, time-poor clinicians must engage in information-gathering and idea-generation activities. This research revealed that qualitative process mapping focus groups held both in-person and virtually can be used to streamline these activities, by simultaneously identifying target behaviours for change, and barriers to change, while gaining information about site-specific clinical processes. Hospital process mapping shows that complex clinical processes vary significantly between sites, and that understanding local variation is crucial to developing targeted interventions. This study has informed new approaches to implementation research methods.

Serum testosterone and prostate cancer in men with germline BRCA1/2 pathogenic variants.

Objectives: The relation of serum androgens and the development of prostate cancer (PCa) is subject of debate. Lower total testosterone (TT) levels have been associated with increased PCa detection and worse pathological features after treatment. However, data from the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) and Prostate Cancer Prevention (PCPT) trial groups indicate no association. The aim of this study is to investigate the association of serum androgen levels and PCa detection in a prospective screening study of men at higher genetic risk of aggressive PCa due to BRCA1/2 pathogenic variants (PVs), the IMPACT study. Methods: Men enrolled in the IMPACT study provided serum samples during regular visits. Hormonal levels were calculated using immunoassays. Free testosterone (FT) was calculated from TT and sex hormone binding globulin (SHBG) using the Sodergard mass equation. Age, body mass index (BMI), prostate-specific antigen (PSA) and hormonal concentrations were compared between genetic cohorts. We also explored associations between age and TT, SHBG, FT and PCa, in the whole subset and stratified by BRCA1/2 PVs status. Results: A total of 777 participants in the IMPACT study had TT and SHBG measurements in serum samples at annual visits, giving 3940 prospective androgen levels, from 266 BRCA1 PVs carriers, 313 BRCA2 PVs carriers and 198 non-carriers. The median number of visits per patient was 5. There was no difference in TT, SHBG and FT between carriers and non-carriers. In a univariate analysis, androgen levels were not associated with PCa. In the analysis stratified by carrier status, no significant association was found between hormonal levels and PCa in non-carriers, BRCA1 or BRCA2 PVs carriers. Conclusions: Male BRCA1/2 PVs carriers have a similar androgen profile to non-carriers. Hormonal levels were not associated with PCa in men with and without BRCA1/2 PVs. Mechanisms related to the particularly aggressive phenotype of PCa in BRCA2 PVs carriers may therefore not be linked with circulating hormonal levels.

Examining the effectiveness and implementation of patient treatment decision-aid tools for men with localised prostate cancer: A systematic review.

OBJECTIVE: Men diagnosed with localised prostate cancer (LPC) often face a difficult process deciding on a treatment choice that suits their personal preferences. This systematic review examines the impact of patient treatment decision-aids (DAs) on decisional outcomes and treatment choice for men diagnosed with LPC. Our secondary aim was to examine how DAs have been implemented into routine clinical practice. METHODS: A systematic search was conducted up to June 2022 using the following databases: Medline, Embase, PsycINFO, CINAHL, Cochrane, Scopus, and Web of Science. Articles were included if they evaluated the effectiveness of treatment DAs for LPC patients on various decisional outcomes and treatment choice. The Mixed-Method Appraisal Tool was used to assess methodological quality and risk of bias. Data on implementation outcomes were also extracted if reported. RESULTS: Twenty-four articles were included for the analysis (seven non-randomised studies, 16 randomised control trials, and one qualitative study). Results showed DAs have the potential to improve patient knowledge but revealed no effects on decisional regret or preparedness in decision-making. Due to the variability in methodology among studies, results varied widely for treatment choice, decision-making involvement, decisional conflict, and treatment decision satisfaction. At least one implementation outcome was reported in 11 of the included studies, with the most commonly assessed outcomes being acceptability and appropriateness. CONCLUSIONS: While DAs appear to improve knowledge, further qualitative evaluations and standardised assessments are needed to better understand men's experiences using DAs and to determine advantages and optimal ways to implement DAs into the treatment decision-making pathway.

Enhanced delivery of antibodies across the blood-brain barrier via TEMs with inherent receptor-mediated phagocytosis.

BACKGROUND: The near impermeability of the blood-brain barrier (BBB) and the unique neuroimmune environment of the CNS prevents the effective use of antibodies in neurological diseases. Delivery of biotherapeutics to the brain can be enabled through receptor-mediated transcytosis via proteins such as the transferrin receptor, although limitations such as the ability to use Fc-mediated effector function to clear pathogenic targets can introduce safety liabilities. Hence, novel delivery approaches with alternative clearance mechanisms are warranted. METHODS: Binders that optimized transport across the BBB, known as transcytosis-enabling modules (TEMs), were identified using a combination of antibody discovery techniques and pharmacokinetic analyses. Functional activity of TEMs were subsequently evaluated by imaging for the ability of myeloid cells to phagocytose target proteins and cells. FINDINGS: We demonstrated significantly enhanced brain exposure of therapeutic antibodies using optimal transferrin receptor or CD98 TEMs. We found that these modules also mediated efficient clearance of tau aggregates and HER2+ tumor cells via a non-classical phagocytosis mechanism through direct engagement of myeloid cells. This mode of clearance potentially avoids the known drawbacks of FcγR-mediated antibody mechanisms in the brain such as the neurotoxic release of proinflammatory cytokines and immune cell exhaustion. CONCLUSIONS: Our study reports a new brain delivery platform that harnesses receptor-mediated transcytosis to maximize brain uptake and uses a non-classical phagocytosis mechanism to efficiently clear pathologic proteins and cells. We believe these findings will transform therapeutic approaches to treat CNS diseases. FUNDING: This research was funded by Janssen, Pharmaceutical Companies of Johnson & Johnson.

The predicted effect and cost-effectiveness of tailoring colonoscopic surveillance according to mismatch repair gene in patients with Lynch syndrome.

PURPOSE: Lynch syndrome-related colorectal cancer (CRC) risk substantially varies by mismatch repair (MMR) gene. We evaluated the health impact and cost-effectiveness of MMR gene-tailored colonoscopic surveillance. METHODS: We first estimated sex- and MMR gene-specific cumulative lifetime risk of first CRC without colonoscopic surveillance using an optimization algorithm. Next, we harnessed these risk estimates in a microsimulation model, "Policy1-Lynch," and compared 126 colonoscopic surveillance strategies against no surveillance. RESULTS: The most cost-effective strategy was 3-yearly surveillance from age 25 to 70 years (pathogenic variants [path_] in MLH1 [path_MLH1], path_MSH2) with delayed surveillance for path_MSH6 (age 30-70 years) and path_PMS2 (age 35-70 years) heterozygotes (incremental cost-effectiveness ratio = Australian dollars (A) $8,833/life-year saved). This strategy averted 60 CRC deaths (153 colonoscopies per death averted) over the lifetime of 1000 confirmed patients with Lynch syndrome (vs no surveillance). This also reduced colonoscopies by 5% without substantial change in health outcomes (vs nontailored 3-yearly surveillance from 25-70 years). Generally, starting surveillance at age 25 (vs 20) years was more cost-effective with minimal effect on life-years saved and starting 5 to 10 years later for path_MSH6 and path_PMS2 heterozygotes (vs path_MLH1 and path_MSH2) further improved cost-effectiveness. Surveillance end age (70/75/80 years) had a minor effect. Three-yearly surveillance strategies were more cost-effective (vs 1 or 2-yearly) but prevented 3 fewer CRC deaths. CONCLUSION: MMR gene-specific colonoscopic surveillance would be effective and cost-effective.

One week of overeating upregulates angiogenic and lipolytic gene expression in human subcutaneous adipose tissue from exercise trained and untrained adults.

Effective storage of excess energy in abdominal subcutaneous adipose tissue during periods of overeating may help attenuate weight-gain-related insulin resistance. The objective of this study was to assess changes in the expression of factors regulating abdominal subcutaneous adipose tissue storage capacity in response to a brief exposure to overeating in nonobese adults. Because exercise can alter the expression of genes involved in regulating adipose tissue storage capacity, we compared the responses to overeating in regular exercisers (EX, n = 11) and nonexercisers (nonEX, n = 11). Abdominal subcutaneous adipose tissue samples and oral glucose tolerance tests were performed before and after participants ate 30% above their estimated daily energy requirements for 1 week. Both EX and nonEX gained ∼1 kg (P < 0.01), and Matsuda insulin sensitivity index was reduced ∼15% (P = 0.04) in both groups. Gene expression of factors involved in lipid metabolism (HSL, ATGL, DGAT, and PPARγ) and angiogenesis (HIF1α and KDR) were increased (P < 0.05), with no differences observed between EX and nonEX. In contrast, protein abundance of these factors did not change. The modest overeating stimulus did not increase markers of inflammation in the systemic circulation or adipose tissue. Overall, our findings indicate that a brief and modest overeating stimulus can impair insulin sensitivity and upregulate genes involved in abdominal adipose tissue storage capacity similarly in exercisers and nonexercisers. ClinicalTrials.gov ID#: NCT02701738.

Comparing cancer genetic counselling using telegenetics with in-person and telephone appointments: Results of a partially randomised patient-preference pilot study.

INTRODUCTION: Direct-to-patient telegenetics, which uses video conferencing to connect health professionals directly to patients' devices, has been widely adopted during the pandemic. However, limited evidence currently supports its use in cancer genetic counselling. METHODS: Before the pandemic, we conducted a two-arm partially randomised patient-preference pilot trial to evaluate direct-to-patient telegenetics for patients and genetic counsellors. Patients were randomised to a standard care (telephone/in-person) or direct-to-patient telegenetics appointment. Patients completed questionnaires before, during and after appointments measuring: psychological distress, perceived genetic counsellor empathy, telegenetics satisfaction and technical challenges. Genetic counsellor-reported outcomes -measured using purpose-designed questionnaires- included telegenetics satisfaction, therapeutic alliance and time for assessment. Open-ended patient and genetic counsellor questionnaire responses were synthesised using content analysis. RESULTS: Fifty-six patients and seven genetic counsellors participated. Thirteen patients switched appointment type. No significant differences in distress (P = 0.84) were identified between direct-to-patient telegenetics and standard care. Perceived genetic counsellor empathy was high for all appointment types. There was no evidence of differences in reported maximum empathy scores between direct-to-patient telegenetics and standard care [telephone (P = 0.57); in-person (P = 0.44)]. Patients reported high direct-to-patient telegenetics satisfaction despite technical challenges in most appointments (65%). Genetic counsellors were satisfied with direct-to-patient telegenetics and perceived high therapeutic alliance irrespective of appointment type. No significant differences in genetic counsellor time were identified between direct-to-patient telegenetics and standard care [telephone (P > 0.90); in-person (P = 0.35)]. DISCUSSION: Our results suggest that direct-to-patient telegenetics is a satisfactory service delivery model that does not appear to compromise patient-genetic counsellor relationships or increase patient distress. These findings support direct-to-patient telegenetics use in cancer genetic counselling, although larger trials are needed.

Lynch syndrome testing of colorectal cancer patients in a high-income country with universal healthcare: a retrospective study of current practice and gaps in seven australian hospitals.

BACKGROUND: To inform effective genomic medicine strategies, it is important to examine current approaches and gaps in well-established applications. Lynch syndrome (LS) causes 3-5% of colorectal cancers (CRCs). While guidelines commonly recommend LS tumour testing of all CRC patients, implementation in health systems is known to be highly variable. To provide insights on the heterogeneity in practice and current bottlenecks in a high-income country with universal healthcare, we characterise the approaches and gaps in LS testing and referral in seven Australian hospitals across three states. METHODS: We obtained surgery, pathology, and genetics services data for 1,624 patients who underwent CRC resections from 01/01/2017 to 31/12/2018 in the included hospitals. RESULTS: Tumour testing approaches differed between hospitals, with 0-19% of patients missing mismatch repair deficiency test results (total 211/1,624 patients). Tumour tests to exclude somatic MLH1 loss were incomplete at five hospitals (42/187 patients). Of 74 patients with tumour tests completed appropriately and indicating high risk of LS, 36 (49%) were missing a record of referral to genetics services for diagnostic testing, with higher missingness for older patients (0% of patients aged ≤ 40 years, 76% of patients aged > 70 years). Of 38 patients with high-risk tumour test results and genetics services referral, diagnostic testing was carried out for 25 (89%) and identified a LS pathogenic/likely pathogenic variant for 11 patients (44% of 25; 0.7% of 1,624 patients). CONCLUSIONS: Given the LS testing and referral gaps, further work is needed to identify strategies for successful integration of LS testing into clinical care, and provide a model for hereditary cancers and broader genomic medicine. Standardised reporting may help clinicians interpret tumour test results and initiate further actions.

Relative changes in brain and kidney biomarkers with Exertional Heat Illness during a cool weather marathon.

BACKGROUND: Medical personnel may find it challenging to distinguish severe Exertional Heat Illness (EHI), with attendant risks of organ-injury and longer-term sequalae, from lesser forms of incapacity associated with strenuous physical exertion. Early evidence for injury at point-of-incapacity could aid the development and application of targeted interventions to improve outcomes. We aimed to investigate whether biomarker surrogates for end-organ damage sampled at point-of-care (POC) could discriminate EHI versus successful marathon performance. METHODS: Eight runners diagnosed as EHI cases upon reception to medical treatment facilities and 30 successful finishers of the same cool weather marathon (ambient temperature 8 rising to 12 ºC) were recruited. Emerging clinical markers associated with injury affecting the brain (neuron specific enolase, NSE; S100 calcium-binding protein B, S100ß) and renal system (cystatin C, cysC; kidney-injury molecule-1, KIM-1; neutrophil gelatinase-associated lipocalin, NGAL), plus copeptin as a surrogate for fluid-regulatory stress, were sampled in blood upon marathon collapse/completion, as well as beforehand at rest (successful finishers only). RESULTS: Versus successful finishers, EHI showed significantly higher NSE (10.33 [6.37, 20.00] vs. 3.17 [2.71, 3.92] ug.L-1, P<0.0001), cysC (1.48 [1.10, 1.67] vs. 1.10 [0.95, 1.21] mg.L-1, P = 0.0092) and copeptin (339.4 [77.0, 943] vs. 18.7 [7.1, 67.9] pmol.L-1, P = 0.0050). Discrimination of EHI by ROC (Area-Under-the-Curve) showed performance that was outstanding for NSE (0.97, P<0.0001) and excellent for copeptin (AUC = 0.83, P = 0.0066). CONCLUSIONS: As novel biomarker candidates for EHI outcomes in cool-weather endurance exercise, early elevations in NSE and copeptin provided sufficient discrimination to suggest utility at point-of-incapacity. Further investigation is warranted in patients exposed to greater thermal insult, followed up over a more extended period.

Building capacity from within: qualitative evaluation of a training program aimed at upskilling healthcare workers in delivering an evidence-based implementation approach.

Translating evidence into complex health systems is an ongoing challenge. Building the capacity of healthcare workers in behavioral and implementation science methods may facilitate the use of evidence-based implementation approaches, leading to sustainable and effective translation. The aim was to describe the development, contents and evaluation of a training workshop aimed at upskilling hospital-embedded staff to deliver an evidence-based implementation approach. The Hide and Seek Project (HaSP) is a cluster randomized controlled trial testing two implementation approaches for improving hereditary cancer referral at eight Australian hospitals. Healthcare workers were recruited as "Implementation Leads" and trained via a one-day workshop-TRAining in evideNce-baSed ImpLementATion for hEalth (TRANSLATE). The purpose of TRANSLATE was to upskill Implementation Leads in the delivery of HaSP, as well as implementation science methods more broadly. Implementation Leads participated in semi-structured evaluation interviews, which were analyzed using inductive thematic analysis. Nine Implementation Leads from various professional backgrounds completed the training. Four key themes were identified: (i) training day reactions, (ii) learning, (iii) implementation barriers and facilitators, and (iv) building health system capacity for implementation. Participants reported high levels of satisfaction, and anticipated that the knowledge and skills may be useful in the future. We describe a novel training program focused on the delivery of evidence-based implementation within health systems. Guided by insights from this study, methods to deliver the training on a larger scale and across different contexts are being explored. The prolonged impact of TRANSLATE will be further evaluated at trial completion. Trial registration: ANZCTR, ACTRN12618001072202. Registered on June 27, 2018.

Stakeholder attitudes towards establishing a national genomics registry of inherited cancer predisposition: a qualitative study.

This study aimed to describe the acceptability and perceived barriers and enablers to establish a national registry targeting carriers of pathogenic variants in cancer susceptibility genes from stakeholders' perspectives. Such a registry may effectively target carriers to translate existing research findings into optimised clinical care and provide a population-level resource for further clinical research and new gene and therapy discovery. In-depth interviews were conducted with individuals from four stakeholder groups: carriers of pathogenic variants, healthcare professionals, data custodians from the field of familial cancer, and heads of molecular pathology laboratories. Interview data were subjected to a qualitative analysis guided by a thematic analysis framework using NVivo software. A total of 28 individuals were interviewed: 11 carriers, 8 healthcare professionals, 5 laboratory heads, and 4 data custodians. All carriers and healthcare professionals were enthusiastic about the potential research applications of the registry. Carriers described that altruistic motivations provided the foundation of their support of the planned registry. Some carriers felt comfortable with a broad consent (consenting once, prospectively), while others preferred a narrow consent approach (consenting each time data is accessed). Some carriers and data custodians and registry developers also expressed a reluctance to link family member data without appropriate consent. Participants' enthusiasm and support for a national registry herald a productive and responsive research partnership once the registry has been established. Participants' views can be used to inform the approaches to be taken to develop and manage such a registry as an implicit codesign approach.

What would I do? Perspectives on the factors underlying Lynch syndrome genetic testing and results sharing decisions for high-risk colorectal cancer patients.

OBJECTIVE: Universal tumour testing for Lynch syndrome (LS) in all incident colorectal cancers (CRCs) and sequential diagnostic genetic testing is cost-effective in Australia. Because of this, our study aimed to understand factors underlying possible decisions faced by tumour test-positive CRC patients and their at-risk relatives throughout the LS diagnosis pathway. METHODS: Semi-structured telephone interviews were conducted with 23 participants, using four hypothetical scenarios. Vignette-guided closed- and open-ended questions asked about LS genetic testing uptake, discussing diagnosis with at-risk relatives, and risk-reducing interventions. Personal perspectives on genetic testing were collected pre-post vignette discussion. Inductive thematic analysis was performed on open-ended questions. Decisional pathway diagrams were developed to convey factors influencing complex decision-making processes. RESULTS: Participant responses incorporated unfolding scenario information, resulting in three decision themes: (1) wanting to know one's LS status; (2) informing family about LS; (3) navigating risk-reducing interventions. Across all themes, 'knowledge' emerged as a facilitator, and 'negative emotional experience' as a barrier. Personal supportive views toward genetic testing increased post-interview. CONCLUSIONS: When communicating with tumour test-positive CRC patients or their relatives about LS genetic testing, providing guidance/resources to inform decisions around risk-reducing interventions and informing family members is critical. Scenario-driven interviews provide insight into what individuals might do when facing complex healthcare decisions and could aid informed decision-making. This approach may be applicable in other conditions, particularly with mainstreaming being increasingly introduced into the genetic context.

The BARCODE1 Pilot: a feasibility study of using germline single nucleotide polymorphisms to target prostate cancer screening.

OBJECTIVES: To assess the feasibility and uptake of a community-based prostate cancer (PCa) screening programme selecting men according to their genetic risk of PCa. To assess the uptake of PCa screening investigations by men invited for screening. The uptake of the pilot study would guide the opening of the larger BARCODE1 study recruiting 5000 men. SUBJECTS AND METHODS: Healthy males aged 55-69 years were invited to participate via their general practitioners (GPs). Saliva samples were collected via mailed collection kits. After DNA extraction, genotyping was conducted using a study specific assay. Genetic risk was based on genotyping 130 germline PCa risk single nucleotide polymorphisms (SNPs). A polygenic risk score (PRS) was calculated for each participant using the sum of weighted alleles for 130 SNPs. Study participants with a PRS lying above the 90th centile value were invited for PCa screening by prostate magnetic resonance imaging (MRI) and biopsy. RESULTS: Invitation letters were sent to 1434 men. The overall study uptake was 26% (375/1436) and 87% of responders were eligible for study entry. DNA genotyping data were available for 297 men and 25 were invited for screening. After exclusions due to medical comorbidity/invitations declined, 18 of 25 men (72%) underwent MRI and biopsy of the prostate. There were seven diagnoses of PCa (38.9%). All cancers were low-risk and were managed with active surveillance. CONCLUSION: The BARCODE1 Pilot has shown this community study in the UK to be feasible, with an overall uptake of 26%. The main BARCODE1 study is now open and will recruit 5000 men. The results of BARCODE1 will be important in defining the role of genetic profiling in targeted PCa population screening. Patient Summary What is the paper about? Very few prostate cancer screening programmes currently exist anywhere in the world. Our pilot study investigated if men in the UK would find it acceptable to have a genetic test based on a saliva sample to examine their risk of prostate cancer development. This test would guide whether men are offered prostate cancer screening tests. What does it mean for patients? We found that the study design was acceptable: 26% of men invited to take part agreed to have the test. The majority of men who were found to have an increased genetic risk of prostate cancer underwent further tests offered (prostate MRI scan and biopsy). We have now expanded the study to enrol 5000 men. The BARCODE1 study will be important in examining whether this approach could be used for large-scale population prostate cancer screening.

Pilot study of an online training program to increase genetic literacy and communication skills in oncology healthcare professionals discussing BRCA1/2 genetic testing with breast and ovarian cancer patients.

The increasing use of genetic testing for BRCA1/2 and other pathogenic variants in the management of women with breast and ovarian cancer necessitates increased genetic literacy in oncology healthcare professionals. This pilot study aimed to evaluate an online training program to increase genetic literacy and communication skills in Australian oncology healthcare professionals tasked with discussing and coordinating mainstream genetic testing with breast and ovarian cancer patients. A training website with embedded videos was developed. This study assesses the website's acceptability and user-friendliness; suggestions for improvement were also elicited. Oncology healthcare professionals were recruited through relevant professional organisations, invited to the study by email, asked to work through the website and then complete an online questionnaire. Thirty-two oncology healthcare professionals completed the questionnaire after viewing the website. Nearly all participants were satisfied with the information contained in the program (very satisfied: n = 14/32, 44%, satisfied: n = 17/32, 53%, neither satisfied nor dissatisfied: n = 1/32, 3%) and reported that they had gained new skills (n = 29/32, 91%) and had increased confidence (n = 29/31, 94%) in communicating with breast and ovarian cancer patients about genetic testing. More than 93% (28/30) of participants endorsed the online program as clearly presented, informative, relevant and useful. This pilot study demonstrated high feasibility and acceptability of the training program to increase genetic literacy and communication skills in oncology healthcare professionals discussing genetic testing with breast and ovarian cancer patients. Further evidence from a randomised trial is needed to evaluate effects on changing clinical practice, improving patient outcomes, and cost-effectiveness.