Selective advantage of mutant stem cells in human clonal hematopoiesis is associated with attenuated response to inflammation and aging.

Clonal hematopoiesis (CH) arises when hematopoietic stem cells (HSCs) acquire mutations, most frequently in the DNMT3A and TET2 genes, conferring a competitive advantage through mechanisms that remain unclear. To gain insight into how CH mutations enable gradual clonal expansion, we used single-cell multi-omics with high-fidelity genotyping on human CH bone marrow (BM) samples. Most of the selective advantage of mutant cells occurs within HSCs. DNMT3A- and TET2-mutant clones expand further in early progenitors, while TET2 mutations accelerate myeloid maturation in a dose-dependent manner. Unexpectedly, both mutant and non-mutant HSCs from CH samples are enriched for inflammatory and aging transcriptomic signatures, compared with HSCs from non-CH samples, revealing a non-cell-autonomous effect. However, DNMT3A- and TET2-mutant HSCs have an attenuated inflammatory response relative to wild-type HSCs within the same sample. Our data support a model whereby CH clones are gradually selected because they are resistant to the deleterious impact of inflammation and aging.

Fractionated vs single-dose gemtuzumab ozogamicin with determinants of benefit in older patients with AML: the UK NCRI AML18 trial.

Addition of gemtuzumab ozogamicin (GO) to induction chemotherapy improves outcomes in older patients with acute myeloid leukemia (AML), but it is uncertain whether a fractionated schedule provides additional benefit to a single dose. We randomized 852 older adults (median age, 68-years) with AML/high-risk myelodysplasia to GO on day 1 (GO1) or on days 1 and 4 (GO2) of course 1 induction. The median follow-up period was 50.2 months. Although complete remission (CR) rates after course 1 did not significantly differ between arms (GO2, 63%; GO1, 57%; odds ratio [OR], 0.78; P = .08), there were significantly more patients who achieved CR with a measurable residual disease (MRD)<0.1% (50% vs 41%; OR, 0.72; P = .027). This differential MRD reduction with GO2 varied across molecular subtypes, being greatest for IDH mutations. The 5-year overall survival (OS) was 29% for patients in the GO2 arm and 24% for those in the GO1 arm (hazard ratio [HR], 0.89; P = .14). In a sensitivity analysis excluding patients found to have adverse cytogenetics or TP53 mutations, the 5-year OS was 33% for GO2 and 26% for GO1 (HR, 0.83; P = .045). In total, 228 (27%) patients received an allogeneic transplantation in first remission. Posttransplant OS was superior in the GO2 arm (HR, 0.67; P = .033); furthermore, the survival advantage from GO2 in the sensitivity analysis was lost when data of patients were censored at transplantation. In conclusion, GO2 was associated with a greater reduction in MRD and improved survival in older adults with nonadverse risk genetics. This benefit from GO2 was dependent on allogeneic transplantation to translate the better leukemia clearance into improved survival. This trial was registered at www.isrctn.com as #ISRCTN 31682779.

Co-designing a peer-led model of delivering behavioural activation for people living with depression or low mood in Australian farming communities.

INTRODUCTION: Farmers face a range of factors that negatively influence their mental health and suicide risk, yet have limited access to appropriate support. Behavioural activation (BA) is an evidence-based therapy that can be effectively delivered by nonclinical workers. Working with members of farming communities to deliver BA to their peers has the potential to overcome many well-established barriers to mental health help-seeking and improve outcomes for this at-risk group. OBJECTIVE: This paper describes the findings of a co-design phase informing the development of a peer (farmer)-led approach for delivering BA for farmers living with depression or low mood. DESIGN: This qualitative study used a co-design approach involving members of the target community. Focus groups were transcribed and analysed using Thematic Analysis and the Framework approach. FINDINGS: Ten online focus groups with 22 participants were held over 3 months. Four overarching, interlinked themes were identified: (i) filling the gap in rural mental health support; (ii) alignment with the farming context-tailoring how, where and when we engage about mental health; (iii) the 'messenger' is as important as the message; and (iv) sustainability, governance and support. DISCUSSION: Findings suggest BA could be a contextually appropriate model of support for the farming community-given its practical and solution-focused approach-and could help improve access to support. Having peer workers deliver the intervention was viewed as appropriate. Ensuring governance structures are developed to support peers to deliver the intervention will be essential to facilitate effectiveness, safety and sustainability. CONCLUSION: Insights gained through co-design have been critical to the success of developing this new model of support for members of farming communities experiencing depression or low mood.

Steering Straight: Adapting suicide risk safety planning as a prevention-focused self-management resource for the Australian farming community.

OBJECTIVE: This paper draws on the principles of suicide risk safety planning to co-design a farming community resource for preventing and managing risks to mental health. SETTING: This project was undertaken in the Great South Coast Region of Victoria, Australia. PARTICIPANTS: A working group (n = 6-8) from the Victorian farming community contributed to the iterative co-design and co-production of Steering Straight: My plan to keep on track. Twenty-four members of the farming community pilot tested Steering Straight. DESIGN: Co-design to develop, pilot and refine the resource with working group and target farming community. RESULTS: Steering Straight was viewed positively by the farming community as a tool that prompts prioritising well-being; encourages reflection, planning and concrete steps towards taking action; helps set and meet personal goals; is simple and practical; and identifies pathways to support. Most participants (94%) completed Steering Straight on their own, taking approximately 15-30 min to create their personalised plan. Questions most likely to be filled in related to recognising personal signs of deteriorating well-being and listing and planning enjoyable activities. A majority of participants (67%) kept a hard copy of their Steering Straight plan on hand to refer back to, while 78% expressed a preference for a digital version. CONCLUSION: The co-design and co-production process resulted in a tailored prevention-focused resource that was accepted and valued by the farming community.

Utilizing the Delphi method to develop parent and child surveys to understand exposure to farming hazards and attitudes toward farm safety.

Children on farms are at increased risk of injury. In Australia, children under 15 years consistently represent ~15% of all farm-related fatalities. This study aimed to develop parent and child surveys to gain a greater understanding of children's (5-14 years) exposure to occupational risk on farms by exploring their exposure to farm hazards, risk-taking behavior, their use and attitudes toward safety measures, and experience of farm-related injury. As farming communities are heterogeneous, a modified Delphi method was undertaken to ensure input from a diverse group. Seventeen experts participated in a three round process-the first two rounds required rating of proposed survey questions in an online questionnaire and the final round was an online discussion. Consensus was defined as 75% agreement or higher. This process resulted in 155 parent questions and 124 child questions reaching consensus to include. The modified Delphi method developed surveys that provide insight into the behaviors and attitudes of children (individuals) and their parents on farms (family) and will assist in informing how community, organizations and policy frameworks can improve child safety on farms. It will assist in identifying and understanding common farming exposures/behaviors of children and their parents to inform the development of targeted and culturally appropriate injury prevention strategies. As farming groups are heterogeneous, these survey scan be used on varying farming cohorts to identify their unique farming hazards and challenges. Child farm-related injuries are a problem globally and must be addressed; children are dependent on adults and communities to create safe environments for them.

From co-design to co-production: Approaches, enablers, and constraints in developing a public health, capacity-building solution.

INTRODUCTION: Investigating how co-designed knowledge can be translated to co-produce a public health capacity-building solution for difficult-to-engage population groups drawing on the co-production experience of a prevention-focused, capacity-building mental health solution targeting primary producers. DESIGN: A qualitative study undertaken in rural and regional Victoria involving members of the design working group including project team (7px), digital design team (5px), marketing team (3px), and funding partner representatives. The study design involved reflective practice to collect data to identify the phases of co-production and assess the design working group members' experiences. The analysis involved inductive coding using Braun and Clarke's thematic analysis. OBJECTIVE: Identifying major points of divergence and/or convergence; enablers and/or constraints; and ways to better navigate and strengthen the co-production process. FINDING: Given members of the design working group, diverse skills sets divergence was experienced in all co-production phases. Divergence was also experienced between the project team and the funding partner given the uniqueness of working conditions and requirements of workers in the primary production industry. The project team applied an iterative development process to project management; encouraging iterative cycles to create/test/revise among the teams, and with the funding partner, until each was satisfied with the end result (convergence). DISCUSSION & CONCLUSION: When developing a co-created public health prevention campaign it is critical that the project team focuses on relationship building among the members of the design working group and ensures adequate resourcing, development of shared understanding of project goals and target audience, ongoing communication, and a commitment to working iteratively.

Participant perspectives of an online co-design process to develop a prevention-focused mental health and well-being platform for primary producers.

OBJECTIVE: To explore participant experiences of an online co-design process to develop a web-based preventative mental health and well-being intervention targeting primary producers in rural Australia. SETTING: Rural Victoria, Australia. PARTICIPANTS: Participants from a primary producer background, including horticulture, fisheries, animal cultivation and farm consultancy, were eligible for the study if they had participated in both the co-design and beta testing processes for a primary producer platform. DESIGN: A qualitative study using semi-structured phone-based interviews was undertaken. A reflexive inductive approach to data analysis was employed to develop themes. RESULTS: Eleven participants were interviewed, with an average age of 51 years, of which 7 were female. Five main themes were developed. These included: (1) participant diversity, (2) impact of online delivery on co-design participation, (3) experiences of the co-design process, (4) maintaining a shared vision and goals and (5) acting on the co-design recommendations. Use of online methods was a clear enabler to engage participants who were geographically dispersed and offers an alternative to more conventional approaches to co-design using face-to-face methods. Some aspects of participant engagement may need a greater focus when conducted online compared with face-to-face. CONCLUSIONS: Using an online co-design method to develop a preventative mental health and well-being web-based platform for primary producers was novel. Findings address a gap in the literature around the experience of participants engaging in a co-design process and identify opportunities to improve participant engagement and experience with the online format.

Rural suicide risk and physical ill health: A qualitative study of the Victorian Suicide Register, 2009-2015.

OBJECTIVE: To gain new insight into contextual factors shaping how physical ill health acts as a stressor in rural suicides-informing the development of appropriate targeted interventions. DESIGN: Retrospective cohort study. SETTING: Non-metropolitan Victoria, Australia. SAMPLE: 802 rural (non-metropolitan) suicide deaths between the years 2009 and 2015. MAIN OUTCOME MEASURE: Qualitative data from the Victorian Suicide Register relating to physical ill health of suicide decedents. RESULTS: Thematic analysis identified 4 themes: (a) 'living with physical ill health in a rural area' highlights both practical and cultural challenges associated with managing physical ill health within the context of life in a rural setting; (b) 'causes and experience of chronic pain' highlights rural risk factors for chronic pain, how pain was experienced and treatment managed; (c) 'when living an independent, contributing life is no longer possible' describes the debilitating physical and mental outcomes of chronic ill health and pain; and (d) 'the cumulative impact of physical ill health and other factors on suicide risk' highlights the complexity of risk factors-in combination with (or as a result of) physical ill health-that contribute to a suicide death. CONCLUSION: Identified themes suggest pathways to improve understanding and support for those experiencing physical ill health and associated suicide risk. These supports include contextually and culturally appropriate rural services to provide effective and necessary treatment, pain relief and mental health support; acknowledgement and response to a culture of alcohol misuse as an (ultimately ineffective) coping strategy; proactive psychosocial support mechanisms; and alternative approaches to support including consideration of innovative peer support models.

Child Farm-Related Injury in Australia: A Review of the Literature.

Children on farms have been identified as a population vulnerable to injury. This review seeks to identify child farm-related injury rates in Australia and to determine the key hazards and contributing risk factors. This critical review utilised the PRISMA guidelines for database searching. Research from the year 2000 onward was included as well as earlier seminal texts. Reference lists were searched, and the relevant research material was explored. Our primary focus was on Australian peer-reviewed literature with international and grey literature examples included. Evidence suggests that there is limited Australian research focusing on child farm-related injuries. Child representation in farm-related injuries in Australia has remained consistent over time, and the key hazards causing these injuries have remained the same for over 20 years. The factors contributing to child rates of farm injury described in the literature include child development and exposure to dangerous environments, the risk-taking culture, multi-generational farming families, lack of supervision, child labour and lack of regulation, limited targeted farm safety programs, underuse of safe play areas, financial priorities and poor understanding and operationalisation of the hierarchy of control. It is well known that children experience injury on farms, and the key hazards that cause this have been clearly identified. However, the level of exposure to hazards and the typical attitudes, behaviours and actions of children and their parents around the farm that contribute to chid injury remain unexplored.

Translating Co-Design from Face-to-Face to Online: An Australian Primary Producer Project Conducted during COVID-19.

Primary producers face considerable risks for poor mental health. While this population can be difficult to engage in programs to prevent poor mental health, approaches tailored to reflect the context of primary producers' life and work have been successful. This paper reports on the co-design phase of a project designed to prevent poor mental health for primary producers-specifically, the advantages, challenges and considerations of translating face-to-face co-design methods to an online environment in response to COVID-19 restrictions. The co-design phase drew upon the existing seven-step co-design framework developed by Trischler and colleagues. Online methods were adopted for all steps of the process. This paper models how this co-design approach can work in an online, primary producer context and details key considerations for future initiatives of this type. The development of online co-design methods is an important additional research method for use not only during a pandemic but also when operating with limited resources or geographic constraints. Results demonstrate the following: (i) co-designing online is possible given adequate preparation, training and resource allocation; (ii) "hard to reach" populations can be engaged using online methods providing there is adequate early-stage relationship building; (iii) co-design quality need not be compromised and may be improved when translating to online; and (iv) saved costs and resources associated with online methods can be realigned towards intervention/service creation, promotion and user engagement. Suggestions for extending Trischler and colleagues' model are incorporated.

A comparison of farming- and non-farming-related suicides from the United States' National Violent Deaths Reporting System, 2003-2016.

Farmers are at higher risk of suicide than other occupations and the general population. The complex suicide risk factors have not been examined in a large, population-wide study across a significant time period. This observational study draws on existing data from the United States' National Violent Death Reporting System (NVDRS), including 140,523 farming- or non-farming-related suicide decedents between 2003 and 2016 from across 40 states. "Farming-related" decedents included 2,801 suicides. Farmers had higher odds of being male, older, less well-educated, and American Indian/Alaska Native. Farmers had higher odds of using firearms and-when farmers used a gun-higher odds of using a long-arm weapon. Farmers had lower odds of having a known mental health condition or job problem, and lower odds of having made a previous suicide attempt or leaving a suicide note. Findings highlight the complexity of suicide risk within the context of farming in the United States and reinforce the need for tailored prevention efforts; employing means restriction of firearms; and emphasizing that traditional risk factors may not be as common in the farming population.

Electrochemotherapy and basal cell carcinomas: First-time appraisal of the efficacy of electrochemotherapy on survivorship using FACE-Q.

INTRODUCTION: The establishment and success of new treatments are significantly influenced by patient satisfaction. Post-operative scarring is an important outcome for patients, and subsequently influences overall satisfaction with treatment. The objective was to measure post-treatment scarring satisfaction using a novel scale, the FACE-Q Skin Cancer Module, to compare electrochemotherapy (ECT) to traditional surgical excision (SE) to demonstrate equivalence of ECT and SE regarding outcome and survivorship. METHODS AND MATERIALS: This was a multicentre first-time appraisal study of the efficacy of ECT. All patients with facial BCCs treated with either ECT or SE were deemed eligible and subsequently recruited from either a previous clinical trial or outpatient clinics, respectively. Of the 40 participants invited, 25 responses were received. Patient information recorded included age, gender, location and size of BCCs, and time since treatment. Patient outcomes were measured using the FACE-Q Skin Cancer Module. RESULTS: The ECT and SE groups consisted of 14 and 11 patients, respectively. Mean age was 68 years (M:F = 16:9), while mean time since treatment was 4.98 years (range 0.3-9.58 years). Appraisal of scars was significantly higher in the ECT cohort versus SE (p = 0.034). Cancer worry was equivalent across both cohorts (p = 0.804). According to treatment type, no correlation was detected between time since treatment and both appraisal of scars (ECT p = 0.466 and SE p = 0.214) and adverse effects (ECT p = 0.924 and SE p = 0.139). CONCLUSION: Based on this study, ECT has superior scar outcomes and overall equivalence to SE. This demonstrates high patient satisfaction for those treated with ECT without any additional cancer worry.

Suicide and Accidental Death for Australia's Farming Families: How Context Influences Individual Response.

This article presents qualitative data to explore the experience of farming family members faced with accidental or suicide death and understand how this is experienced within the farming context. Individual semistructured interviews were conducted with 25 members of Australian farming families bereaved by suicide or accidental death. Qualitative data was thematically analyzed. Three interconnected themes were identified: acceptance of risk, normalization of death, pragmatic behavior patterns and connection to place. Bereavement and reconstruction of meaning following suicide or accidental death for farming families is influenced by the cultural, social, geographical, and psychological contexts of farming families. This article challenges traditional conceptions of suicide and accidental death as necessarily experienced as "violent" or "traumatic," bereavement as experienced similarly across western cultures, and the reaction to suicide or accidental death as one that challenges people's understanding of their world and leaves them struggling to find a reason why the death occurred.

The ripple effect: a digital intervention to reduce suicide stigma among farming men.

BACKGROUND: Compared with the general population, Australian farmers-particularly men-have been identified as at greater risk of suicide. A complex range of factors are thought to contribute to this risk, including the experience of Stigma. stigma also impacts those who have attempted suicide, their carers, and those bereaved by suicide-manifesting as shame, guilt, social isolation, concealment of death, reduced help seeking and ongoing risk of suicide. This paper evaluates the effectiveness of an intervention, tailored for the farming context, designed to reduce stigma among farming men with a lived experience of suicide. METHODS: The digital intervention used an adult learning model providing opportunity to share insights, reflect, learn and apply new knowledge among people with shared farming interests, suicide experience and cultural context. A range of content-tailored to the gender, farming type and suicide experience of participants-included video stories, postcard messages, education and personal goal setting. Pre- and post- assessment of suicide stigma and literacy was complemented by qualitative data collection during the intervention and participant feedback surveys. RESULTS: The intervention was successful in reaching members of the target group from across Australia's rural communities-with diverse geographic locations and farming industries represented. One hundred and sixty-nine participants from the target group (farming males aged 30-64 years) were recruited. While the Stigma of Suicide Scale failed to identify a reduction in self- or perceived-stigma, qualitative data and participant feedback identified behavioural indicators of stigma reduction. Four subthemes-'growth', 'new realisations', 'hope' and 'encouragement'-highlighted attitudinal and behaviour change indicative of reduced stigma associated with mental health and suicide. Participants' baseline suicide literacy (Literacy of Suicide Scale) was high when compared with previous community samples and total literacy scores did not demonstrate significant improvement over time, although literacy about the link between suicide and alcoholism did significantly improve. CONCLUSIONS: These results highlight opportunities in groups with high suicide literacy for targeted stigma reduction and suicide prevention efforts for both the target group and other populations within Australia and internationally. Results also highlight the need to reassess how stigma change is understood and evaluated across a wider range of population groups. TRIAL REGISTRATION: This research project was registered with the Australian New Zealand Clinical Trials Registry (ANZCTR) (ACTRN12616000289415) on 7th March, 2016.

Does 20-min rounding reduce falls in an aged-care setting? A pilot intervention study.

BACKGROUND: This study investigated if implementation of a 20-min rounding intervention can reduce falls in aged care settings. METHODS: Participants (aged 66-99 years) from five aged care facilities were randomly allocated to intervention (n = 20) or control groups (n = 21). The intervention consisted of 20-min rounding observations over a six month period. The number of falls for all residents of each aged care facility was also collected. RESULTS: For participants of the intervention study, there were no differences for number of falls in the intervention compared to the control group (mean(95%CI) control:2.3(0.8-3.7), intervention:4.0(2.5-5.5), p = 0.108). There was a trend for a decreased average number of falls across all aged care sites (mean±SD, 60.4 ± 35.7 falls occurred prior vs. 53.4 ± 37.4 during the intervention, p = 0.056). There were no fall related fractures in the intervention group during the study. CONCLUSIONS: This study suggests that 20-min rounding may decrease falls for all residents of aged care sites.

Dissecting the early steps of MLL induced leukaemogenic transformation using a mouse model of AML.

Leukaemogenic mutations commonly disrupt cellular differentiation and/or enhance proliferation, thus perturbing the regulatory programs that control self-renewal and differentiation of stem and progenitor cells. Translocations involving the Mll1 (Kmt2a) gene generate powerful oncogenic fusion proteins, predominantly affecting infant and paediatric AML and ALL patients. The early stages of leukaemogenic transformation are typically inaccessible from human patients and conventional mouse models. Here, we take advantage of cells conditionally blocked at the multipotent haematopoietic progenitor stage to develop a MLL-r model capturing early cellular and molecular consequences of MLL-ENL expression based on a clear clonal relationship between parental and leukaemic cells. Through a combination of scRNA-seq, ATAC-seq and genome-scale CRISPR-Cas9 screening, we identify pathways and genes likely to drive the early phases of leukaemogenesis. Finally, we demonstrate the broad utility of using matched parental and transformed cells for small molecule inhibitor studies by validating both previously known and other potential therapeutic targets.

Suicide in Rural Australia: Are Farming-Related Suicides Different?

Rural Australians experience a range of health inequities-including higher rates of suicide-when compared to the general population. This retrospective cohort study compares demographic characteristics and suicide death circumstances of farming- and non-farming-related suicides in rural Victoria with the aim of: (a) exploring the contributing factors to farming-related suicide in Australia's largest agricultural producing state; and (b) examining whether farming-related suicides differ from suicide in rural communities. Farming-related suicide deaths were more likely to: (a) be employed at the time of death (52.6% vs. 37.7%, OR = 1.84, 95% CIs 1.28-2.64); and, (b) have died through use of a firearm (30.1% vs. 8.7%, OR = 4.51, 95% CIs 2.97-6.92). However, farming-related suicides were less likely to (a) have a diagnosed mental illness (36.1% vs. 46.1%, OR=0.66, 95% CIs 0.46-0.96) and, (b) have received mental health support more than six weeks prior to death (39.8% vs. 50.0%, OR = 0.66, 95% CIs 0.46-0.95). A range of suicide prevention strategies need adopting across all segments of the rural population irrespective of farming status. However, data from farming-related suicides highlight the need for targeted firearm-related suicide prevention measures and appropriate, tailored and accessible support services to support health, well-being and safety for members of farming communities.

Vitrimerization: Converting Thermoset Polymers into Vitrimers.

Thermoset polymers with permanently cross-linked networks have outstanding mechanical properties and solvent resistance, but they cannot be reprocessed or recycled. On the other hand, vitrimers with covalent adaptable networks can be recycled. Here we provide a simple and practical method coined as "vitrimerization" to convert the permanent cross-linked thermosets into vitrimer polymers without depolymerization. The vitrimerized thermosets exhibit comparable mechanical properties and solvent resistance with the original ones. This method allows recycling and reusing the unrecyclable thermoset polymers with minimum loss in mechanical properties and enables closed-loop recycling of thermosets with the least environmental impact.

Mechanisms of Progression of Myeloid Preleukemia to Transformed Myeloid Leukemia in Children with Down Syndrome.

Myeloid leukemia in Down syndrome (ML-DS) clonally evolves from transient abnormal myelopoiesis (TAM), a preleukemic condition in DS newborns. To define mechanisms of leukemic transformation, we combined exome and targeted resequencing of 111 TAM and 141 ML-DS samples with functional analyses. TAM requires trisomy 21 and truncating mutations in GATA1; additional TAM variants are usually not pathogenic. By contrast, in ML-DS, clonal and subclonal variants are functionally required. We identified a recurrent and oncogenic hotspot gain-of-function mutation in myeloid cytokine receptor CSF2RB. By a multiplex CRISPR/Cas9 screen in an in vivo murine TAM model, we tested loss-of-function of 22 recurrently mutated ML-DS genes. Loss of 18 different genes produced leukemias that phenotypically, genetically, and transcriptionally mirrored ML-DS.