The psychosocial impact of prostate cancer screening for BRCA1 and BRCA2 carriers.

OBJECTIVES: To report the long-term outcomes from a longitudinal psychosocial study that forms part of the 'Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted Screening in men at higher genetic risk and controls' (IMPACT) study. The IMPACT study is a multi-national study of targeted prostate cancer (PrCa) screening in individuals with a known germline pathogenic variant (GPV) in either the BReast CAncer gene 1 (BRCA1) or the BReast CAncer gene 2 (BRCA2). SUBJECTS AND METHODS: Participants enrolled in the IMPACT study were invited to complete a psychosocial questionnaire prior to each annual screening visit for a minimum of 5 years. The questionnaire included questions on sociodemographics and the following measures: Hospital Anxiety and Depression Scale, Impact of Event Scale, 36-item Short-Form Health Survey, Memorial Anxiety Scale for PrCa, Cancer Worry Scale, risk perception and knowledge. RESULTS: A total of 760 participants completed questionnaires: 207 participants with GPV in BRCA1, 265 with GPV in BRCA2 and 288 controls (non-carriers from families with a known GPV). We found no evidence of clinically concerning levels of general or cancer-specific distress or poor health-related quality of life in the cohort as a whole. Individuals in the control group had significantly less worry about PrCa compared with the carriers; however, all mean scores were low and within reported general population norms, where available. BRCA2 carriers with previously high prostate-specific antigen (PSA) levels experience a small but significant increase in PrCa anxiety (P = 0.01) and PSA-specific anxiety (P < 0.001). Cancer risk perceptions reflected information provided during genetic counselling and participants had good levels of knowledge, although this declined over time. CONCLUSION: This is the first study to report the longitudinal psychosocial impact of a targeted PrCa screening programme for BRCA1 and BRCA2 carriers. The results reassure that an annual PSA-based screening programme does not have an adverse impact on psychosocial health or health-related quality of life in these higher-risk individuals. These results are important as more PrCa screening is targeted to higher-risk groups.

Donor Ability of Bisphosphinemonoxide Ligands Relevant to Late-Metal Olefin Polymerization Catalysis.

Late-transition-metal catalysts for polymerization of olefins have drawn a significant amount of attention owing to their ability to tolerate and incorporate polar comonomers. However, a systematic way to experimentally quantify the electronic properties of the ligands used in these systems has not been developed. Quantified ligand parameters will allow for the rational design of tailored polymerization catalysts, which would target specific polymer properties. We report a series of platinum complexes bearing bisphosphinemonoxide ligands, which resemble those used in the polymerization catalysts of Nozaki and Chen. Their electronic properties are investigated experimentally, and trends are rationalized by using computed spectral properties. Benchmarking computational data with known experimental parameters further enhances the utility of both methods for determining optimal ligands for catalytic application.

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.

Standardizing variation: Scaling up clinical genomics in Australia.

PURPOSE: Clinical genomics demands close interaction of physicians, laboratory scientists, and genetic professionals. Taking genomics to scale requires an understanding of the underlying processes from the perspective of nongenetic physicians who are new to the field. We identified components of the processes amenable to adaptation when scaling up clinical genomics. METHODS: Semistructured interviews informed by the Theoretical Domains Framework with nongenetic physicians, who were using clinical genomics in practice, were guided by an annotated process map with 7 steps following the patient's journey. Findings from the individual maps were synthesized into an overview process map and a series of individual maps by common location and specialty. Interviews were analyzed using the Theoretical Domains Framework. RESULTS: In total, 16 nongenetic physicians (eg, nephrologists, immunologists) participated, generating 1 overview and 10 individual process maps. Sixteen common steps were identified across clinical specialties and locations, with variations over 9 steps. We report the potential for standardization across these 9 steps. CONCLUSION: When scaling up complex interventions, it is essential to identify steps where variation can be accommodated. With these results we show how process mapping can be used to identify steps where variation is acceptable during scale up to accommodate adaptation to local context, allowing for the inevitable evolution of factors influencing ongoing implementation and sustainability.

Feasibility of Targeted Next-Generation DNA Sequencing for Expanding Population Newborn Screening.

BACKGROUND: Newborn screening (NBS) is an effective public health intervention that reduces death and disability from treatable genetic diseases, but many conditions are not screened due to a lack of a suitable assay. Whole genome and whole exome sequencing can potentially expand NBS but there remain many technical challenges preventing their use in population NBS. We investigated if targeted gene sequencing (TGS) is a feasible methodology for expanding NBS. METHODS: We constructed a TGS panel of 164 genes which screens for a broad range of inherited conditions. We designed a high-volume, low-turnaround laboratory and bioinformatics workflow that avoids the technical and data interpretation challenges associated with whole genome and whole exome sequencing. A methods-based analytical validation of the assay was completed and test performance in 2552 newborns examined. We calculated annual birth estimates for each condition to assess cost-effectiveness. RESULTS: Assay analytical sensitivity was >99% and specificity was 100%. Of the newborns screened, 1.3% tested positive for a condition. On average, each individual had 225 variants to interpret and 1.8% were variants of uncertain significance (VUS). The turnaround time was 7 to 10 days. Maximum batch size was 1536 samples. CONCLUSIONS: We demonstrate that a TGS assay could be incorporated into an NBS program soon to increase the number of conditions screened. Additionally, we conclude that NBS using TGS may be cost-effective.

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.

The Relationship Between Psychological Distress and Physical Activity Is Non-linear and Differs by Domain: a Cross-Sectional Study.

BACKGROUND: There is increasing evidence for the relationship between physical activity (PA), sedentary behaviour and mental health. Limited data exists on sex-specific associations. We aimed to identify associations between PA dose and domain and television time with psychological distress, including sex-stratified models. METHODS: A total of 22,176 adults from the Melbourne Collaborative Cohort Study follow-up 2 cohort (2003-2007) participated in this cross-sectional study. Occupational, household, transport, leisure PA, hours watching television and psychological distress were assessed. Restricted cubic splines were used to examine the relationships between PA domains, television viewing time and psychological distress. RESULTS: The relationships between PA and psychological distress were non-linear (p < 0.05) and differed by PA domain. There were dose-dependent, inverse associations between distress with transport (B[95% CI] = -0.39[-0.49, -0.30]) and leisure PA (B[95% CI] = -0.35[-0.46, -0.25]). The effect estimates for transport and leisure PA with distress were larger for women. For household domain, a U-shaped curve with an elongated tail was seen. Median PA was associated with lower distress compared with lower quantities (B[95% CI] = -0.12[-0.22, -0.03]); however, this association was not evident with increasing household PA. There were no clear associations between occupational PA and distress. Higher television viewing was associated with higher distress (B[95% CI] = 0.16[0.02, 0.30]). CONCLUSIONS: Increasing PA and reducing television viewing may contribute to reduced psychological distress, particularly in women. Future interventions should incorporate leisure and transport PA and decrease television viewing to assess the impact on mental health.

Using a theory informed approach to design, execute, and evaluate implementation strategies to support offering reproductive genetic carrier screening in Australia.

BACKGROUND: Health care professionals play a central role in offering reproductive genetic carrier screening but face challenges when integrating the offer into practice. The aim of this study was to design, execute, and evaluate theory-informed implementation strategies to support health care professionals in offering carrier screening. METHODS: An exploratory multi-method approach was systematically employed based on the Theoretical Domain Framework (TDF). Implementation strategies were designed by aligning TDF barriers reported by health care professionals involved in a large carrier screening study, to behaviour change techniques combined with study genetic counsellors' experiential knowledge. The strategies were trialled with a subset of health care professionals and evaluated against controls, using findings from questionnaires and interviews with healthcare professionals. The primary outcome measure was the number of couples who initiated enrolment. RESULTS: Health care professionals (n = 151) reported barriers in the TDF Domains of skills, e.g., lack of practice in offering screening, and challenges of environmental context and resources, e.g., lack of time, which informed the design of a skills video and a waiting room poster using the TDF-behaviour change technique linking tool. Following implementation, (Skills video n = 29 vs control n = 31 and Poster n = 46 vs control n = 34) TDF barrier scores decreased across all groups and little change was observed in the primary outcome measure. The skills video, though welcomed by health care professionals, was reportedly too long at seven minutes. The waiting room poster was seen as easily implementable. CONCLUSIONS: As carrier screening moves towards mainstream healthcare, health care professionals report barriers to offering screening. To meet their needs, developing and testing experiential and theory-informed strategies that acknowledge contextual factors are essential.

Retrospective analysis of factors influencing the implementation of a program to address unprofessional behaviour and improve culture in Australian hospitals.

BACKGROUND: Unprofessional behaviour among hospital staff is common. Such behaviour negatively impacts on staff wellbeing and patient outcomes. Professional accountability programs collect information about unprofessional staff behaviour from colleagues or patients, providing this as informal feedback to raise awareness, promote reflection, and change behaviour. Despite increased adoption, studies have not assessed the implementation of these programs utilising implementation theory. This study aims to (1) identify factors influencing the implementation of a whole-of-hospital professional accountability and culture change program, Ethos, implemented in eight hospitals within a large healthcare provider group, and (2) examine whether expert recommended implementation strategies were intuitively used during implementation, and the degree to which they were operationalised to address identified barriers. METHOD: Data relating to implementation of Ethos from organisational documents, interviews with senior and middle management, and surveys of hospital staff and peer messengers were obtained and coded in NVivo using the Consolidated Framework for Implementation Research (CFIR). Implementation strategies to address identified barriers were generated using Expert Recommendations for Implementing Change (ERIC) strategies and used in a second round of targeted coding, then assessed for degree of alignment to contextual barriers. RESULTS: Four enablers, seven barriers, and three mixed factors were found, including perceived limitations in the confidential nature of the online messaging tool ('Design quality and packaging'), which had downstream challenges for the capacity to provide feedback about utilisation of Ethos ('Goals and Feedback', 'Access to Knowledge and Information'). Fourteen recommended implementation strategies were used, however, only four of these were operationalised to completely address contextual barriers. CONCLUSION: Aspects of the inner setting (e.g., 'Leadership Engagement', 'Tension for Change') had the greatest influence on implementation and should be considered prior to the implementation of future professional accountability programs. Theory can improve understanding of factors affecting implementation, and support strategies to address them.

Structured approaches to implementation of clinical genomics: A scoping review.

PURPOSE: This study aimed to assess the extent to which structured approaches to implementation of clinical genomics, proposed or adapted, are informed by evidence. METHODS: A systematic approach was used to identify peer-reviewed articles and gray literature to report on 4 research questions: 1. What structured approaches have been proposed to support implementation? 2. To what extent are the structured approaches informed by evidence? 3. How have structured approaches been deployed in the genomic setting? 4. What are the intended outcomes of the structured approaches? RESULTS: A total of 30 unique structured approaches to implementation were reported across 23 peer-reviewed publications and 11 gray literature articles. Most approaches were process models, applied in the preadoption implementation phase, focusing on a "service" outcome. Key findings included a lack of implementation science theory informing the development/implementation of newly designed structured approaches in the genomic setting and a lack of measures to assess implementation effectiveness. CONCLUSION: This scoping review identified a significant number of structured approaches developed to inform the implementation of genomic medicine into clinical practice, with limited use of implementation science to support the process. We recommend the use of existing implementation science theory and the expertise of implementation scientists to inform the design of genomic programs being implemented into clinical care.

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.

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.

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.

Would they accept it? An interview study to identify barriers and facilitators to user acceptance of a prescribing advice service.

OBJECTIVES: Few studies have explored the factors influencing user uptake of interventions designed to enhance therapeutic drug monitoring (TDM). This study aimed to identify barriers and facilitators to acceptance of a pilot intervention, the TDM Advisory Service (the Service), that provided prescribing advice for the antibiotic, vancomycin at an Australian public hospital. METHODS: A sample of prescribers and pharmacists who had interacted with the Service (n = 10), and a sample who had not (n = 13), participated in semi-structured interviews. Interviews were transcribed verbatim and analysed independently by two researchers for emerging themes. The Theoretical Domains Framework (TDF) was used to synthesise barriers and facilitators to Service acceptance. RESULTS: Key barriers reported by participants who had interacted with the Service aligned with two TDF domains: 'Social Influences' (prescribing hierarchy) and 'Environmental Context and Resources' (accessibility of dose advice). For participants who had not interacted with the Service, key barriers aligned with two TDF domains: 'Knowledge' (uncertainty of Service processes) and 'Environmental Context and Resources' (accessibility of dose advice). Key facilitators for both participant groups aligned with 'Beliefs about Consequences' (improved prescribing and patient outcomes) and 'Environmental Context and Resources' (accessibility of dose advice). A novel domain, 'Trust', was identified. CONCLUSIONS: Independent of participant interaction with the Service, knowledge of Service processes, perceived beneficial outcomes, improved accessibility, and trust in Service capabilities were key determinants of acceptance. This evidence can be used to inform the adoption of strategies to adapt and enhance integration of the Service into clinical workflow.

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.

Barriers and enablers to nurses' use of harm prevention strategies for older patients in hospital: A cross-sectional survey.

BACKGROUND: Preventable harms during hospitalization pose a major challenge for health systems globally. Nurse-led strategies provide comprehensive harm prevention to keep the most vulnerable patients safe in hospital, but gaps in care are common. Nursing roles and activities to prevent harm to patients during acute hospitalization are poorly understood. AIM: The aim of this study was to identify nurses' perceived enablers and barriers to the implementation of comprehensive harm prevention for older people admitted to an acute hospital setting. DESIGN: Anonymous, online, cross-sectional survey. METHODS: The adapted Influences on Patient Safety Behaviours Questionnaire (IPSBQ) was used to collect data from nurses working on five general medicine wards across three hospitals of a single tertiary health service in Australia in 2019. Participants also rated their perceptions of overall quality of care, missed care and awareness of strategies for an eight-factor framework for comprehensive harm prevention. The STROBE reporting checklist was used. RESULTS: Ward response rates between 35% and 58% resulted in 132 complete questionnaires for analyses. High mean scores for behavioural regulation (3.28), beliefs about capabilities (2.96) and environmental context and resources (2.73) indicated these domains were perceived by nurses as enablers. Low mean scores for the domains of intentions (1.65), beliefs about consequences (1.69), optimism (1.72) and professional role and identity (1.85) indicated these were barriers to comprehensive harm prevention by nurses. High perceived quality of care (scored 9-10/10) (p = .024), and awareness of strategies for the eight-factor framework (p = .019) were significant enablers of comprehensive harm prevention. CONCLUSION: Targeted evidence-based strategies that include education, persuasion, incentivization, coercion and modelling would be most useful for promoting comprehensive harm prevention by nurses. However, to be most effective the harm prevention strategy may need to be tailored for each ward.

A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study.

BACKGROUND: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. METHODS: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual. FINDINGS: Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1-2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3-7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0-2·6), MSH6 carriers was 3·0% (four of 135; 0·8-7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0-68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3-46·0). INTERPRETATION: After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings. FUNDING: Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer.

The design, implementation, and effectiveness of intervention strategies aimed at improving genetic referral practices: a systematic review of the literature.

PURPOSE: Despite rapid advancements in genetics and genomics, referral practices remain suboptimal. This systematic review assesses the extent to which approaches from implementation science have been applied to address suboptimal genetic referral practices. METHODS: A search of MEDLINE, EMBASE, and PsycINFO generated 7,794 articles, of which 28 were included. Lay barriers were mapped to the Theoretical Domains Framework (TDF) and interventions mapped to behavior change techniques. Use of implementation and behavior change frameworks was assessed, and the Theory and Techniques Tool used to determine theoretical alignment. RESULTS: Knowledge was the most frequent retrospectively TDF-coded barrier, followed by environmental context and resources, and skills. Significant referral improvements occurred in 56% of studies. Among these, the most frequent interventions were clinical data review systems, family history collection and referral tools, and embedding genetics staff into nongenetic specialties. Few studies used implementation frameworks or reported implementation outcomes, though some deployed intuitive strategies that aligned with theory. CONCLUSION: Genetic referral interventions are rarely informed by implementation and/or behavior change theories, limiting opportunities for learning across contexts. Retrospective coding has provided a suite of theoretically linked strategies, which may be useful for informing future efforts. Incorporating these strategies into clinical guidelines may facilitate operationalization within the system.

Would they trust it? An exploration of psychosocial and environmental factors affecting prescriber acceptance of computerised dose-recommendation software.

AIMS: Dose-prediction software can optimise vancomycin therapy, improving therapeutic drug monitoring processes and reducing drug toxicity. Success of software in hospitals may be dependent on prescriber uptake of software recommendations. This study aimed to identify the perceived psychosocial and environmental barriers and facilitators to prescriber acceptance of dose-prediction software. METHODS: Semi-structured interviews, incorporating prescribing scenarios, were undertaken with 17 prescribers. Participants were asked to prescribe the next maintenance dose of vancomycin for a scenario(s) and then asked if they would accept a recommendation provided by a dose-prediction software. Interviews further explored opinions of dose-prediction software. Interview transcripts were analysed using an inductive approach to identify themes and the Theoretical Domains Framework was used to synthesise barriers and facilitators to software acceptance. RESULTS: When presented with software recommendations, half of the participants were comfortable with accepting the recommendation. Key barriers to acceptance of software recommendations aligned with 2 Theoretical Domains Framework domains: Knowledge (uncertainty of software capability) and Beliefs about Consequences (perceived impact of software on clinical outcomes and workload). Key facilitators aligned with 2 domains: Beliefs about Consequences (improved efficiency) and Social Influences (influence of peers). A novel domain, Trust, was identified as influential. CONCLUSION: Prescribers reported barriers to acceptance of dose-prediction software aligned with limited understanding of, and scepticism about, software capabilities, as well as concerns about clinical outcomes. Identification of key barriers and facilitators to acceptance provides essential information to design of implementation strategies to support the introduction of this intervention into the workplace.

Psychosocial impact of COVID-19 on cancer patients, survivors, and carers in Australia: a real-time assessment of cancer support services.

PURPOSE: This study aimed to explore the psychosocial impacts of the coronavirus disease (COVID-19) pandemic on cancer patients, survivors, and carers in Australia. METHODS: Using real-time insights from two Cancer Council NSW services-131120 Information and Support Line and Online Community (CCOC) forums-we assessed service demand trends, distress levels (using the distress thermometer), and content from 131120 calls and online posts between 01 December 2019 and 31 May 2020. Emergent themes were identified through an inductive conventional content analysis with 131120 call notes, followed by a deductive directed content analysis on CCOC posts. RESULTS: In total, 688 COVID-19-related 131120 calls (n = 496) and online posts (n = 192) were analysed. Service demand peaked in March 2020 and self-reported distress peaked in May 2020 at an average of 8/10 [Mean = 7.5; SD = 0.9]. Five themes emerged from the qualitative analysis: psychological distress and fear of virus susceptibility, practical issues, cancer service disruptions, information needs, and carer Issues. CONCLUSIONS: The psychosocial impacts of COVID-19 on people affected by cancer are multifaceted and likely to have long-lasting consequences. Our findings drove the development of six recommendations across three domains of support, information, and access. Cancer patients, survivors, and carers already face stressful challenges dealing with a cancer diagnosis or survivorship. The added complexity of restrictions and uncertainty associated with the pandemic may compound this. It is important that healthcare providers are equipped to provide patient-centred care during and after this crisis. Our recommendations provide points of consideration to ensure care is tailored and patient oriented.