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Nawaf J Shatnawi,1 Nabil A Al-Zoubi,1 Lujain A Al-Bakkar,1 Ammar M Abu-Baker,1 Yousef S Khader,2 Mamoon Al-Omari,3 Mowafeq A El-Heis3 1Department of Surgery, Jordan University of Science and Technology, Irbid, Jordan; 2Department of Community Medicine, Public Health and Family Medicine, Jordan University of Science and Technology, Irbid, Jordan; 3Department of Radiology, Jordan University of Science and Technology, Irbid, JordanCorrespondence: Nawaf J Shatnawi, Department of Surgery, Jordan University of Science and Technology, P.O. Box 3030, Irbid, 22110, Jordan, Tel + 962 795576267, Email nshatnawi@yahoo.com Nabil A Al-Zoubi, Department of General Surgery/Vascular Surgery, Jordan University of Science and Technology, P.O. Box 3030, Irbid, 22110, Jordan, Tel + 962 795774637, Email dr_nabeil_z3bi@yahoo.comPurpose: Chronic limb-threatening ischemia in patients with diabetes is associated with a high risk of adverse outcomes. The associated co-morbidities, the heterogeneity of foot presentation and the distribution of atherosclerotic lesions led to the emergence of multiple revascularization strategies and scoring systems to improve management outcomes. This study aimed to introduce a new index, the revascularization index (RI), and to assess its predictive value for the outcomes of primary endovascular intervention in patients with type 2 diabetes presenting with chronic limb-threatening ischemia.Patients and Methods: A retrospective electronic medical records review was conducted for patients with type 2 diabetes presenting with chronic limb-threatening ischemia managed at King Abdullah University Hospital by primary endovascular interventions between January 2014 and August 2019. The RI was analyzed for its predictive value for the treatment outcomes.Results: A total of 187 patients were included in this study, with a major lower limb amputation rate of 19.3%. The performance of the RI was excellent in predicting secondary revascularization (AUC = 0.80, 95% CI: 0.73– 0.86, p-value < 0.001), good to predict major amputation (AUC = 0.76, 95% CI: 0.67– 0.85, p-value = 0.047), and poor in predicting death (AUC = 0.46, 95% CI: 0.40– 0.55, p-value = 0.398). RI of < 1.21 was significantly associated with a higher risk of major lower limb amputation (HR = 5.8, 95% CI: 1.25– 26.97, p-value < 0.025), and RI of < 1.3 was associated with a higher risk for secondary revascularization.Conclusion: The RI can be used to predict major adverse lower limb events (MALE). It might be used as a guide for the extent of endovascular interventions for diabetic chronic limb-threatening ischemia with multi-level outflow atherosclerotic disease.Keywords: chronic limb-threatening ischemia, diabetes mellitus, angioplasty, amputation, revascularization index

Perfluorosulfonic acids (PFSAs) are commonly used as solid polymer electrolyte membranes (PEMs) in electrochemical energy devices, where they are vulnerable to attack by radical species during operation. A popular strategy to combat this problem is to introduce radical scavengers like cerium (Ce) ions that neutralize these species before they attack the PFSA. Such cation doping creates a multi-ion system, in which understanding the mechanisms of cation solvation and transport becomes important for the effective design and utilization of PFSA-cation systems. Ce ions also provide a representative model system for multication-exchanged ionomers in electrochemical systems. In this study, hydration and conductivity measurements, along with X-ray fluorescence and scattering, are employed to elucidate how Ce ion exchange alters PFSA's ionic solvation, as well as nano- and mesoscale morphologies, which ultimately control its ion transport properties. A molecular transport model is used to deconvolute the impact of Ce ions on the local solvation structure of water in the membrane from mesoscale changes of the transport pathways. The combined experimental and theoretical analysis reveals a nonlinear decrease in conductivity driven by cation solvation at the molecular level and morphological changes at longer length scales. Migration-diffusion coupling, its nonlinear dependence on ion exchange and hydration, and its overall implications for ionomer performance are also discussed. These findings have the potential to be translated into other mixed cation-ionomer systems for a wide range of energy and environmental devices.

A small microwatt fuel cell stack with 8 cells was designed, fabricated, and tested for passive operation with pure H2 and O2 to provide continuous power for multiple decades with uncontrolled fluctuating ambient conditions. The stack was designed to operate with dead ended gas flows with water removal via passive membrane diffusion to notches in the bipolar plates. Two stacks with active areas of 0.2 cm2, one with 200 nm of membrane and the other with 400 urn, were assembled and tested at varying temperatures and current conditions. Temperatures ranged -55 °C to 70 °C, with focus on the lower temperatures. Factors affecting water production and removal included temperature, gas crossover, and membrane thickness. Currents were applied from 16 uA to 10 mA after the cells were stabilized at temperature, followed by a period of drying to observe water transport to the external peripheries of the cell. A two-dimensional multiphysics model was developed to further explore the water management system in varying conditions.

A combined chemical/mechanical accelerated stress test (AST) was developed for proton exchange membrane (PEM) fuel cells based on relative humidity cycling (RHC) between dry and saturated gases at open circuit voltage (OCV). Membrane degradation and failure were investigated using scanning electron microscopy and small- and wide-angle X-ray scattering. Changes to membrane thickness, hydrophilic domain spacing, and crystallinity were observed to be most similar between field-operated cells and OCV RHC ASTs, where local thinning and divot-type defects are the primary failure modes. While RHC in air also reproduces these failure modes, it is not aggressive enough to differentiate between different membrane types in >1,333 hours (55 days) of testing. Conversely, steady-state OCV tests result in significant ionomer morphology changes and global thinning, which do not replicate field degradation and failure modes. It is inferred that during the OCV RHC AST, the decay of the membrane’s mechanical properties is accelerated such that materials can be evaluated in hundreds, instead of thousands, of hours, while replicating the degradation and failure modes of field operation; associated AST protocols are recommended as OCV RHC at 90◦C for 500 hours with wet/dry cycle durations of 30s/45s and 2m/2m for automotive and bus operation, respectively.

Limited information of occupational injury statistics within academic settings exists. Universities and colleges are an important and insightful work environment due to the varied nature of the work performed by employee groups. The objective of this study was to describe occupational injuries for all work groups in a large research intensive university. A retrospective database analysis was conducted on 2029 employee incident reports over a five year period (2000-2004) to determine general and departmental prevalence of injury types, locations, and mechanisms. Demographic analysis revealed an average age of 42 years and 9 years of work experience. Overall, the most frequent injuries were to the hand (40%), were musculoskeletal in nature (42%), and resulted from being 'struck or contacted by' (33%). The greatest number of incidents occurred in food services, followed by physical plant and staff services. Closer examination of incidents reported by food services indicated 53% of injuries occurred to the hand and 72% required first aid. Notable too was that 19% of physical plant injuries occurred to the back, but these reports accounted for 40% of total back injuries and 50% of all lost time claims in the total database. Further epidemiological research in academic institutions is needed to better understand the inherent injury risk in this work sector. [ABSTRACT FROM AUTHOR]

Medical examiners and coroners (ME/Cs) are essential public health partners for terrorism preparedness and response. These medicolegal investigators support both public health and public safety functions and investigate deaths that are sudden, suspicious, violent, unattended, and unexplained. Medicolegal autopsies are essential for making organism-specific diagnoses in deaths caused by biologic terrorism. This report has been created to 1) help public health officials understand the role of ME/Cs in biologic terrorism surveillance and response efforts and 2) provide ME/Cs with the detailed information required to build capacity for biologic terrorism preparedness in a public health context. This report provides background information regarding biologic terrorism, possible biologic agents, and the consequent clinicopathologic diseases, autopsy procedures, and diagnostic tests as well as a description of biosafety risks and standards for autopsy precautions. ME/Cs' vital role in terrorism surveillance requires consistent standards for collecting, analyzing, and disseminating data. Familiarity with the operational, jurisdictional, and evidentiary concerns involving biologic terrorism-related death investigation is critical to both ME/Cs and public health authorities. Managing terrorism-associated fatalities can be expensive and can overwhelm the existing capacity of ME/Cs. This report describes federal resources for funding and reimbursement for ME/C preparedness and response activities and the limited support capacity of the federal Disaster Mortuary Operational Response Team. Standards for communication are critical in responding to any emergency situation. This report, which is a joint collaboration between CDC and the National Association of Medical Examiners (NAME), describes the relationship between ME/Cs and public health departments, emergency management agencies, emergency operations centers, and the Incident Command System. [ABSTRACT FROM AUTHOR]

We conducted a retrospective analysis of claims data from a large HMO in the southwestern United States to determine whether compliance with the Agency for Health Care Policy and Research (AHCPR) guideline for antidepressant therapy duration varied by antidepressant class, and how compliance correlated with depression-related, non-depression-related, and total health care costs Compliance and treatment costs were evaluated for 12 months following the first antidepressant prescription for all HMO enrollees who were diagnosed with depressive disorde and met inclusion criteria over a 2 1/2 year period (N = 5,627). Patients who were initially prescribed selective serotonin reuptake inhibitors (SSRIs) were more likely to meet AHCPR treatment duration recommendation; (>/= 150 days of therapy) than were patients initially prescribed tricyclic antidepressants (TCAs) or atypical/ heterocyclic antidepressants (p < 0.001). Among patients complian with the AHCPR recommendations, mean total and non-depression-related costs were significantly lower for those prescribed SSRI: than for those prescribed TCAs or atypical/ heterocyclic agents. As compliance improved mean total health care costs remained stable in the SSRI cohort but generally increased in the other two cohorts. [ABSTRACT FROM AUTHOR]

Abstract Background The rise of the internet and related technologies has significant implications for the treatment of complex health problems, including the combination of depression and alcohol/other drug (AOD) misuse. To date, no research exists to test the real world uptake of internet and computer-delivered treatment programs in clinical practice. This study is important, as it is the first to examine the adoption of the SHADE treatment program, a DVD-based psychological treatment for depression and AOD use comorbidity, by clinicians working in a publicly-funded AOD clinical service. The study protocol that follows describes the methodology of this dissemination trial. Methods/design 19 clinicians within an AOD service on the Central Coast of New South Wales, Australia, will be recruited to the trial. Consenting clinicians will participate in a baseline focus group discussion designed to explore their experiences and perceived barriers to adopting innovation in their clinical practice. Computer comfort and openness to innovation will also be assessed. Throughout the trial, current, new and wait-list clients will be referred to the research program via the clinical service, which will involve clients completing a baseline and 15-week follow-up clinical assessment with independent research assistants, comprising a range of mental health and AOD measures. Clinicians will also complete session checklists following each clinical session with a client, outlining the extent to which the SHADE computer program was used. Therapeutic alliance will be measured at intake and discharge from both the clinician and client perspectives. Discussion This study will provide comprehensive data on the factors associated with the adoption of an innovative, computer-delivered evidence-based treatment program, SHADE, by clinicians working in an AOD service. The results will contribute to the development of a model of dissemination of SHADE, which could be applied to a range of technological innovations. Clinical trials registry Australian Clinical Trial Registration Number: ACTRN12611000382976.

Abstract Background A large proportion of people attending residential alcohol and other substance abuse treatment have a co-occurring mental illness. Empirical evidence suggests that it is important to treat both the substance abuse problem and co-occurring mental illness concurrently and in an integrated fashion. However, the majority of residential alcohol and other substance abuse services do not address mental illness in a systematic way. It is likely that computer delivered interventions could improve the ability of substance abuse services to address co-occurring mental illness. This protocol describes a study in which we will assess the effectiveness of adding a computer delivered depression and substance abuse intervention for people who are attending residential alcohol and other substance abuse treatment. Methods/Design Participants will be recruited from residential rehabilitation programs operated by the Australian Salvation Army. All participants who satisfy the diagnostic criteria for an alcohol or other substance dependence disorder will be asked to participate in the study. After completion of a baseline assessment, participants will be randomly assigned to either a computer delivered substance abuse and depression intervention (treatment condition) or to a computer-delivered typing tutorial (active control condition). All participants will continue to complete The Salvation Army residential program, a predominantly 12-step based treatment facility. Randomisation will be stratified by gender (Male, Female), length of time the participant has been in the program at the commencement of the study (4 weeks or less, 4 weeks or more), and use of anti-depressant medication (currently prescribed medication, not prescribed medication). Participants in both conditions will complete computer sessions twice per week, over a five-week period. Research staff blind to treatment allocation will complete the assessments at baseline, and then 3, 6, 9, and 12 months post intervention. Participants will also complete weekly self-report measures during the treatment period. Discussion This study will provide comprehensive data on the effect of introducing a computer delivered, cognitive behavioral therapy based co-morbidity treatment program within a residential substance abuse setting. If shown to be effective, this intervention can be disseminated within other residential substance abuse programs. Trial registration Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12611000618954

Abstract Background Mental health inpatients smoke at higher rates than the general population and are disproportionately affected by tobacco dependence. Despite the advent of smoke free policies within mental health hospitals, limited systems are in place to support a cessation attempt post hospitalisation, and international evidence suggests that most smokers return to pre-admission smoking levels following discharge. This protocol describes a randomised controlled trial that will test the feasibility, acceptability and efficacy of linking inpatient smoking care with ongoing community cessation support for smokers with a mental illness. Methods/Design This study will be conducted as a randomised controlled trial. 200 smokers with an acute mental illness will be recruited from a large inpatient mental health facility. Participants will complete a baseline survey and will be randomised to either a multimodal smoking cessation intervention or provided with hospital smoking care only. Randomisation will be stratified by diagnosis (psychotic, non-psychotic). Intervention participants will be provided with a brief motivational interview in the inpatient setting and options of ongoing smoking cessation support post discharge: nicotine replacement therapy (NRT); referral to Quitline; smoking cessation groups; and fortnightly telephone support. Outcome data, including cigarettes smoked per day, quit attempts, and self-reported 7-day point prevalence abstinence (validated by exhaled carbon monoxide), will be collected via blind interview at one week, two months, four months and six months post discharge. Process information will also be collected, including the use of cessation supports and cost of the intervention. Discussion This study will provide comprehensive data on the potential of an integrated, multimodal smoking cessation intervention for persons with an acute mental illness, linking inpatient with community cessation support. Trial Registration Australian and New Zealand Clinical Trials Registry ANZTCN: ACTRN12609000465257

Abstract Background The increasing popularity and use of the internet makes it an attractive option for providing health information and treatment, including alcohol/other drug use. There is limited research examining how people identify and access information about alcohol or other drug (AOD) use online, or how they assess the usefulness of the information presented. This study examined the strategies that individuals used to identify and navigate a range of AOD websites, along with the attitudes concerning presentation and content. Methods Members of the general community in Brisbane and Roma (Queensland, Australia) were invited to participate in a 30-minute search of the internet for sites related to AOD use, followed by a focus group discussion. Fifty one subjects participated in the study across nine focus groups. Results Participants spent a maximum of 6.5 minutes on any one website, and less if the user was under 25 years of age. Time spent was as little as 2 minutes if the website was not the first accessed. Participants recommended that AOD-related websites should have an engaging home or index page, which quickly and accurately portrayed the site's objectives, and provided clear site navigation options. Website content should clearly match the title and description of the site that is used by internet search engines. Participants supported the development of a portal for AOD websites, suggesting that it would greatly facilitate access and navigation. Treatment programs delivered online were initially viewed with caution. This appeared to be due to limited understanding of what constituted online treatment, including its potential efficacy. Conclusions A range of recommendations arise from this study regarding the design and development of websites, particularly those related to AOD use. These include prudent use of text and information on any one webpage, the use of graphics and colours, and clear, uncluttered navigation options. Implications for future website development are discussed.

Abstract Background The largest single cause of death among people with severe mental disorders is cardiovascular disease (CVD). The majority of people with schizophrenia and bipolar disorder smoke and many are also overweight, considerably increasing their risk of CVD. Treatment for smoking and other health risk behaviours is often not prioritized among people with severe mental disorders. This protocol describes a study in which we will assess the effectiveness of a healthy lifestyle intervention on smoking and CVD risk and associated health behaviours among people with severe mental disorders. Methods/Design 250 smokers with a severe mental disorder will be recruited. After completion of a baseline assessment and an initial face-to-face intervention session, participants will be randomly assigned to either a multi-component intervention for smoking cessation and CVD risk reduction or a telephone-based minimal intervention focusing on smoking cessation. Randomisation will be stratified by site (Newcastle, Sydney, Melbourne, Australia), Body Mass Index (BMI) category (normal, overweight, obese) and type of antipsychotic medication (typical, atypical). Participants will receive 8 weekly, 3 fortnightly and 6 monthly sessions delivered face to face (typically 1 hour) or by telephone (typically 10 minutes). Assessments will be conducted by research staff blind to treatment allocation at baseline, 15 weeks, and 12-, 18-, 24-, 30- and 36-months. Discussion This study will provide comprehensive data on the effect of a healthy lifestyle intervention on smoking and CVD risk among people with severe mental disorders. If shown to be effective, this intervention can be disseminated to treating clinicians using the treatment manuals. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR) identifier: ACTRN12609001039279

Abstract Background The introduction of total smoking bans represents an important step in addressing the smoking and physical health of people with mental illness. Despite evidence indicating the importance of staff support in the successful implementation of smoking bans, limited research has examined levels of staff support prior to the implementation of a ban in psychiatric settings, or factors that are associated with such support. This study aimed to examine the views of psychiatric inpatient hospital staff regarding the perceived benefits of and barriers to implementation of a successful total smoking ban in mental health services. Secondly, to examine the level of support among clinical and non-clinical staff for a total smoking ban. Thirdly, to examine the association between the benefits and barriers perceived by clinicians and their support for a total smoking ban in their unit. Methods Cross-sectional survey of both clinical and non-clinical staff in a large inpatient psychiatric hospital immediately prior to the implementation of a total smoking ban. Results Of the 300 staff, 183 (61%) responded. Seventy-three (41%) of total respondents were clinical staff, and 110 (92%) were non-clinical staff. More than two-thirds of staff agreed that a smoking ban would improve their work environment and conditions, help staff to stop smoking and improve patients' physical health. The most prevalent clinician perceived barriers to a successful total smoking ban related to fear of patient aggression (89%) and patient non-compliance (72%). Two thirds (67%) of all staff indicated support for a total smoking ban in mental health facilities generally, and a majority (54%) of clinical staff expressed support for a ban within their unit. Clinical staff who believed a smoking ban would help patients to stop smoking were more likely to support a smoking ban in their unit. Conclusions There is a clear need to more effectively communicate to staff the evidence that consistently applied smoking bans do not increase patient aggression. There is also a need to communicate the benefits of smoking bans in aiding the delivery of smoking cessation care, and the benefits of both smoking bans and such care in aiding patients to stop smoking.

OBJECTIVE: Our aim was to examine perinatal outcomes in women who are infected with human immunodeficiency virus (HIV) and who receive highly active antiretroviral therapy compared with the general population. STUDY DESIGN: In this retrospective cohort study, we compared 151 HIV-positive and 302 HIV-negative women. We defined highly active antiretroviral therapy as concomitant use of at least 3 antiretroviral drugs. We calculated frequencies and odds ratios for adverse pregnancy outcomes. RESULTS: Compared with control subjects, smoking (odds ratio, 4.62; 95% confidence interval [CI], 2.58-8.27), drug abuse (odds ratio, 5.48; 95% CI, 2.21-13.59), and spontaneous preterm birth (adjusted odds ratio, 2.27; 95% CI, 1.22-4.25) were more common among HIV-positive women. HIV-positive women were more likely to deliver a small-for-gestational-age infant, but this was due to higher tobacco and cocaine use. Neonatal outcomes were otherwise similar. CONCLUSION: HIV-positive women are at increased risk for preterm birth and lower birthweight infants; therefore, antenatal surveillance should include fetal growth assessment. Highly active antiretroviral therapy use does not increase maternal complications. [ABSTRACT FROM AUTHOR]

The Julia Creek dunnart, Sminthopsis douglasi , is a small, threatened carnivorous marsupial occurring in scattered populations in the grasslands of central and northwestern Queensland, Australia. The distribution of the species is largely unknown due to sporadic survey efforts and its historically low detection using traditional live trapping methods. There is an urgent need to determine the best methods of detection to optimise survey methodologies and more effectively manage species conservation efforts. In this study, we compared the effectiveness of live (Elliott) traps, baited white flash camera traps and thermal imagery binocular surveying for detecting S. douglasi . We deployed 40 white flash camera traps at two sites in Bladensburg National Park (south of Winton), where the species is known to occur, for three consecutive periods between June and November 2022. Four comparative sessions of live trapping were undertaken between April and August 2022 at the same locations. During the live trapping periods, a total of 12 nights of surveying were conducted with thermal imagery binoculars in a preliminary assessment of the technique. The total live trapping effort was 3600 trap nights (approximately 700 trap nights per site in each trapping event). Live trapping resulted in 12 detections of individual S. douglasi from 19 total captures. The highest trap success on a given trapping session was 1.71%, and overall trap success from both sites across all sessions was 0.53%. In comparison, baited camera traps (deployed facing the ground at 70 cm range) took 1,269,884 images over 5383 trap nights. There were 11 confirmed images of S. douglasi , on three individual occasions, which represented 2.10% of all small mammal captures and just 0.0009% of the total images. Four species of small mammals were detected using camera traps, whereas live trapping detected only two species. No small mammals were detected on any of the 12 thermal binocular surveys. Overall, our study highlights the comparative high utility of traditional live trapping for detecting S. douglasi . This research provides a framework for ongoing monitoring of the Bladensburg National Park population. It will be more broadly beneficial for informing the best detection techniques of S. douglasi in ongoing work investigating the overall distribution of the species. Similar studies assessing multiple detection methods for small terrestrial mammals have shown an advantage of white flash camera traps compared to other traditional detection techniques. Our contrasting results serve as a reminder that the utility of different techniques for detecting small mammals is best assessed on a species-by-species basis., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Ecology and Evolution published by John Wiley & Sons Ltd.)

Background: Few evidence-based resources exist to support generalist occupational therapists address driving in practice. This pilot study aimed to evaluate whether a driving clinical decision pathway can assist generalist occupational therapists to address driving with clients., Methods: Using a before (Timepoint-1) and after (Timepoint-2) design, data were collected at a multi-site outpatient community rehabilitation service. Medical record audits documenting how driving was addressed in practice and descriptive surveys of therapist's perceptions of pathway use were collected at Timepoints 1 and 2. A driving clinical decision pathway was implemented over 6 months. Descriptive statistics and content analysis were used to analyse and compare data over time., Results: Timepoint-1 data from 102 client medical records, and 13 clinician surveys were compared against Timepoint-2 data from 144 records and 8 surveys. Following implementation of the pathway, the number of assessments used by generalist occupational therapists increased three-fold, to inform driving process recommendations which increased two-fold. Clinicians' self-reported knowledge, skills and confidence also increased two-fold., Conclusion: A comprehensive driving clinical decision pathway provided clinicians with increased structure and support to guide practice change and promote role fulfilment in addressing return to driving with adults following a change in health status.

Global biodiversity loss continues unabated, and in Australia, the rate of recent mammal extinctions is among the worst in the world. Meanwhile, the diversity among and within many endemic mammal species remains undescribed. This information is crucial to delineate species boundaries and thus inform decision-making for conservation. Sminthopsis virginiae (the red-cheeked dunnart) is a small, dasyurid marsupial found in four disjunct populations around the northern coast of Australia and New Guinea. There are three currently recognized subspecies, each occupying a distinct geographic location. Sminthopsis v. virginiae occurs in Queensland, S. v. rufigenis is distributed across New Guinea and the Aru Islands, and S. v. nitela has populations in the Top End of the Northern Territory and the Kimberley region of Western Australia. Previous molecular work has suggested the current subspecies definitions are not aligned with DNA sequence data, though the sampling was limited. We undertook a comprehensive genetic and morphological review of S. virginiae to clarify relationships within the species. This included mitochondrial (CR, 12S, and cytb) and nuclear (omega-globin, IRBP, and bfib7) loci, and morphometric analysis of skulls and whole wet-preserved specimens held in museums. Maximum Likelihood and Bayesian phylogenetic analyses resolved samples into two distinct clades, demarcated by the Gulf of Carpentaria in Australia's north. Sminthopsis. v. nitela was consistently separated from S. v. virginiae and S. v. rufigenis , based on the overall body and skull size and craniodental features, while S. v. virginiae and S. v. rufigenis were more difficult to distinguish from each other. Thus, we redescribed S. virginiae , recognizing two species, S. nitela (raised from subspecies) and S. virginiae (now comprising the subspecies S. v. virginiae and S. v. rufigenis ). This study highlights the importance of recognizing cryptic mammal fauna to help address the gap in our knowledge about diagnosing diversity during a time of conservation crisis., Competing Interests: The authors declare no conflict of interest in this manuscript., (© 2024 The Author(s). Ecology and Evolution published by John Wiley & Sons Ltd.)

As a part of a study of suicide in children aged 17 years and under in three centers-Hennepin County in the United States (US), Auckland in New Zealand (NZ), and South Australia in Australia (AUS) from 2008 to 2017 it was decided to characterize potential risk factors and to determine whether these differed by jurisdiction. Reviewed data included a history of psychiatric illness, symptoms prior to suicide, events preceding suicide, previous suicidal ideation or suicide attempts, and communication of suicidal intent. The most common events preceding suicide were arguments with family/friends and relationship issues; in addition depression with or without expressed suicidal ideation, self-harming behavior, sadness, distress, drug/substance abuse, and anorexia were documented. Suicidal intent was on occasion communicated via technological means. In 79.5% of cases in South Australia decedents had a previously diagnosed psychiatric illness, with 62% in Hennepin County. This compared to a much lower proportion of cases in Auckland (23.8%). Whether this reflects more limited access to psychiatric services or a reluctance to seek support and therapy in Auckland is unclear. It does, however, demonstrate that risk factors for child suicide are not uniform among communities and so extrapolation of data from one area to another may not be appropriate. Disturbingly parents/carers were not aware of the decedent's suicidal intent in 84-87.2% of cases., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Patients with inflammatory bowel disease (IBD) are at increased risk of colorectal cancer (CRC), and this risk increases dramatically in those who develop low-grade dysplasia (LGD). However, there is currently no accurate way to risk-stratify patients with LGD, leading to both over- and under-treatment of cancer risk. Here we show that the burden of somatic copy number alterations (CNAs) within resected LGD lesions strongly predicts future cancer development. We performed a retrospective multi-centre validated case-control study of n=122 patients (40 progressors, 82 non-progressors, 270 LGD regions). Low coverage whole genome sequencing revealed CNA burden was significantly higher in progressors than non-progressors (p=2×10 -6 in discovery cohort) and was a very significant predictor of CRC risk in univariate analysis (odds ratio = 36; p=9×10 -7 ), outperforming existing clinical risk factors such as lesion size, shape and focality. Optimal risk prediction was achieved with a multivariate model combining CNA burden with the known clinical risk factor of incomplete LGD resection. The measurement of CNAs in LGD lesions is a robust, low-cost and rapidly translatable predictor of CRC risk in IBD that can be used to direct management and so prevent CRC in high-risk individuals whilst sparing those at low-risk from unnecessary intervention., Competing Interests: Competing Interests The authors are in discussions about potential commercialisation and clinical translation of the findings described here. Professor Hart has served as consultant, advisory board member or speaker for AbbVie, Arena, Atlantic, Bristol-Myers Squibb, Celgene, Celltrion, Falk, Galapogos, Lilly, Janssen, MSD, Napp Pharmaceuticals, Pfizer, Pharmacosmos, Roche, Shire and Takeda. K Curtius has an investigator-led research grant from Phathom Pharmaceuticals.

Globally, hundreds of mammal species face the threat of extinction in the coming decades, and in many cases, their ecology remains poorly understood. Fundamental ecological knowledge is crucial for effective conservation management of these species, but it is particularly lacking for small, cryptic mammals. The Julia Creek dunnart ( Sminthopsis douglasi ), a threatened, cryptic carnivorous marsupial that occurs in scattered populations in the central west of Queensland, Australia, was once so poorly studied that it was believed extinct. Sporadic research since its rediscovery in the early 1990s has revealed that S. douglasi is distributed across land at risk from many threats. Fundamental knowledge of S. douglasi population density is urgently required to inform conservation management at key sites, yet the species has historically proven hard to detect. Indeed, the status of the largest known population of S. douglasi , in Bladensburg National Park, is unknown. Here, we conducted a population study on S. douglasi at two sites within Bladensburg National Park via live mark-recapture surveys during 2022 and 2023. From likelihood-based spatially explicit capture-recapture (SECR) modelling we provide the first estimates of density and population size for S. douglasi . Live trapping resulted in captures of 49 individual S. douglasi (with 83 captures total, including recaptures). We estimated S. douglasi to occur at a density of 0.38 individuals ha -1 (0.25-0.58) at one site and 0.16 individuals ha -1 (0.09-0.27) at another site, with an estimated mean population size in suitable habitat at Bladensburg National Park of 1211 individuals (776-1646). Our S. douglasi density estimates were similar to that reported for other threatened small mammals in Australia. We also found evidence of extreme S. douglasi population fluctuations over time at Bladensburg National Park, which is of concern for its future conservation. Our study has provided the first estimate of density for S. douglasi , a threatened dasyurid species from the Mitchell Grass Downs of central western Queensland, Australia. Our research provides crucial population data to assist the management of this poorly studied species. We demonstrate a method that can be applied to species with low detection probability to ultimately help address the mammal extinction crisis faced by Australia and the rest of the world., Competing Interests: The authors declare that there are no competing interests., (© 2024 The Author(s). Ecology and Evolution published by John Wiley & Sons Ltd.)

Mismatch repair (MMR)-deficient cancer evolves through the stepwise erosion of coding homopolymers in target genes. Curiously, the MMR genes MutS homolog 6 (MSH6) and MutS homolog 3 (MSH3) also contain coding homopolymers, and these are frequent mutational targets in MMR-deficient cancers. The impact of incremental MMR mutations on MMR-deficient cancer evolution is unknown. Here we show that microsatellite instability modulates DNA repair by toggling hypermutable mononucleotide homopolymer runs in MSH6 and MSH3 through stochastic frameshift switching. Spontaneous mutation and reversion modulate subclonal mutation rate, mutation bias and HLA and neoantigen diversity. Patient-derived organoids corroborate these observations and show that MMR homopolymer sequences drift back into reading frame in the absence of immune selection, suggesting a fitness cost of elevated mutation rates. Combined experimental and simulation studies demonstrate that subclonal immune selection favors incremental MMR mutations. Overall, our data demonstrate that MMR-deficient colorectal cancers fuel intratumor heterogeneity by adapting subclonal mutation rate and diversity to immune selection., (© 2024. The Author(s).)

Non-genetic alterations can produce changes in a cell's phenotype. In cancer, these phenomena can influence a cell's fitness by conferring access to heritable, beneficial phenotypes. Herein, we argue that current discussions of 'phenotypic plasticity' in cancer evolution ignore a salient feature of the original definition: namely, that it occurs in response to an environmental change. We suggest 'phenotypic noise' be used to distinguish non-genetic changes in phenotype that occur independently from the environment. We discuss the conceptual and methodological techniques used to identify these phenomena during cancer evolution. We propose that the distinction will guide efforts to define mechanisms of phenotype change, accelerate translational work to manipulate phenotypes through treatment, and, ultimately, improve patient outcomes., Competing Interests: Declaration of interests No interests are declared., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Genomic analysis of the T-cell receptor (TCR) reveals the strength, breadth, and clonal dynamics of the adaptive immune response to pathogens or cancer. The diversity of the TCR repertoire, however, means that sequencing is technically challenging, particularly for samples with low-quality, degraded nucleic acids. Here, we developed and validated FUME-TCRseq, a robust and sensitive RNA-based TCR sequencing methodology that is suitable for formalin-fixed paraffin-embedded samples and low amounts of input material. FUME-TCRseq incorporates unique molecular identifiers into each molecule of cDNA, allowing correction for sequencing errors and PCR bias. Using RNA extracted from colorectal and head and neck cancers to benchmark the accuracy and sensitivity of FUME-TCRseq against existing methods demonstrated excellent concordance between the datasets. Furthermore, FUME-TCRseq detected more clonotypes than a commercial RNA-based alternative, with shorter library preparation time and significantly lower cost. The high sensitivity and the ability to sequence RNA of poor quality and limited amount enabled quantitative analysis of small numbers of cells from archival tissue sections, which is not possible with other methods. Spatially resolved FUME-TCRseq analysis of colorectal cancers using macrodissected archival samples revealed the shifting T-cell landscapes at the transition to an invasive phenotype and between tumor subclones containing distinct driver alterations. In summary, FUME-TCRseq represents an accurate, sensitive, and low-cost tool for the characterization of T-cell repertoires, particularly in samples with low-quality RNA that have not been accessible using existing methodology., Significance: FUME-TCRseq is a TCR sequencing methodology that supports sensitive and spatially resolved detection of TCR clones in archival clinical specimens, which can facilitate longitudinal tracking of immune responses through disease course and treatment., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: Despite limited evidence, a high-flow nasal cannula (HFNC) is often used to treat mild to moderate (m/m) bronchiolitis. We aimed to decrease the rate of HFNC use in the pediatric emergency department (PED) for m/m bronchiolitis from a baseline of 37% to less than 18.5%., Methods: A multidisciplinary team created a bronchiolitis pathway and implemented it in December 2019. A respiratory score (RS) in the electronic medical record objectively classified bronchiolitis severity as mild, moderate, or severe. We tracked HFNC utilization in the PED among patients with m/m bronchiolitis as our primary outcome measure between December 2019 and December 2021. We monitored the percentage of patients with an RS as a process measure. Interventions through four plan-do-study-act cycles included updating the hospital oxygen therapy policy, applying the RS to all patients in respiratory distress, modifying the bronchiolitis order set, and developing a bronchiolitis-specific HFNC order., Results: Three hundred twenty-five patients were admitted from the PED with m/m bronchiolitis during the 11-month baseline period and 600 patients during the 25-month intervention period. The mean rate of HFNC utilization decreased from 37% to 17%. Despite a decrease in bronchiolitis encounters after the pandemic, in the spring of 2021, when volumes returned, we had a sustained HFNC utilization rate of 17%. RS entry increased from 60% to 73% in the intervention period., Conclusions: A clinical pathway for bronchiolitis can lead to decreased use of HFNC for m/m bronchiolitis. Consistent RS, order set development with decision support, and education led to sustained improvement despite pandemic-related volumes., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Primary cutaneous follicle center lymphoma (PCFCL) has an excellent prognosis using local treatment, whereas nodal follicular lymphoma (nFL), occasionally presenting with cutaneous spread, often requires systemic therapy. Distinction of the 2 diseases based on histopathology alone might be challenging. Copy number alterations (CNAs) have scarcely been explored on a genome-wide scale in PCFCL; however, they might serve as potential biomarkers during differential diagnosis and risk stratification. Low-coverage whole-genome sequencing is a robust, high-throughput method for genome-wide copy number profiling. In this study, we analyzed 28 PCFCL samples from 20 patients and compared the copy number profiles with a cohort of diagnostic samples of 64 nFL patients. Although the copy number profile of PCFCL was similar to that of nFL, PCFCL lacked amplifications of 18q, with the frequency peaking at 18q21.33 in nFL cases involving the BCL2 locus (PCFCL: 5.0% vs nFL: 31.3%, P = .018, Fisher exact test). Development of distant cutaneous spread was significantly associated with higher genomic instability including the proportion of genome altered (0.02 vs 0.13, P = .033) and number of CNAs (2 vs 9 P = .017), as well as the enrichment of 2p22.2-p15 amplification involving REL and XPO1 (6.3% vs 60.0%, P = .005), 3q23-q24 amplification (0.0% vs 50.0%, P = .004), 6q16.1-q23.3 deletion (6.3% vs 50.0%, P = .018), and 9p21.3 deletion covering CDKN2A and CDKN2B loci (0.0% vs 40.0%, P = .014, all Fisher exact test) in PCFCL. Analysis of sequential tumor samples in 2 cases harboring an unfavorable clinical course pointed to the acquisition of 2p amplification in the earliest common progenitor underlining its pivotal role in malignant transformation. By performing genome-wide copy number profiling on the largest patient cohort to date, we identified distinctive CNA alterations conceivably facilitating the differential diagnosis of PCFCL and secondary cutaneous involvement of nFL and potentially aiding the risk stratification of patients with PCFCL in the future., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The median age of patients with pancreatic ductal adenocarcinoma (PDAC) at diagnosis is 71 years; however, around 10% present with early-onset pancreatic cancer (EOPC), i.e., before age 50. The molecular mechanisms underlying such an early onset are unknown. We assessed the role of common PDAC drivers (KRAS, TP53, CDKN2A and SMAD4) and determined their mutational status and protein expression in 90 formalin-fixed, paraffin-embedded tissues, including multiple primary and matched metastases, from 37 EOPC patients. KRAS was mutated in 88% of patients; p53 was altered in 94%, and p16 and SMAD4 were lost in 86% and 71% of patients, respectively. Meta-synthesis showed a higher rate of p53 alterations in EOPC than in late-onset PDAC (94% vs. 69%, P = 0.0009) and significantly higher loss of SMAD4 (71% vs. 44%, P = 0.0025). The majority of EOPC patients accumulated aberrations in all four drivers; in addition, high tumour heterogeneity was observed across all tissues. The cumulative effect of an exceptionally high rate of alterations in all common PDAC driver genes combined with high tumour heterogeneity suggests an important mechanism underlying the early onset of PDAC., (© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Introduction: Previous research indicates that population genomic screening can benefit individuals who act on the genetic results. However, there remains a significant gap between individuals receiving genetic information and acting on current risk management recommendations, prompting exploration of interventions to close this gap. This study aimed to determine the feasibility and acceptability and conduct a pilot implementation of existing evidence-based interventions (EBIs) for adherence to disease management for select genetic conditions among individuals ascertained through a population genomic screening program., Methods: Surveys of and interviews with individuals who received a genomic screening result were conducted to assess barriers to guideline-recommended care and assess the acceptability of problem-solving (PS) and motivational interviewing (MI) EBIs to facilitate adherence to recommendations. A design thinking workshop was conducted with clinicians to co-develop an MI- and PS-based intervention that would fit with current workflows to be piloted. Post-pilot engagement sessions with implementers determined acceptability and feasibility of the MI/PS pilot program for clinical implementation and elicited proposed adaptations for improvement., Results: PS and MI EBIs were reported to be acceptable and feasible to individuals with a result, and barriers to performing recommended management were identified. The pilot program included outreach by genetic counselors to individuals with a result, review of a checklist of barriers, and delivery of PS or MI as appropriate to facilitate care. The protocol as piloted was deemed acceptable and feasible for clinicians to deliver, with adaptations suggested., Conclusion: These results will inform an effectiveness trial to address gaps in adherence in patients who have received actionable genomic results., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Hydrogen fuel cells based on proton exchange membrane fuel cell (PEMFC) technology are promising as a source of clean energy to power a decarbonized future. However, PEMFCs are limited by a number of major inefficiencies; one of the most significant is hydrogen crossover. In this work, we comprehensively study the effects of two-dimensional (2D) materials applied to the anode side of the membrane as H 2 barrier coatings on Nafion to reduce crossover effects on hydrogen fuel cells, while studying adverse effects on conductivity and catalyst performance in the beginning of life testing. The barrier layers studied include graphene, hexagonal boron nitride (hBN), amorphous boron nitride (aBN), and varying thicknesses of molybdenum disulfide (MoS 2 ), all chosen due to their expected stability in a fuel cell environment. Crossover mitigation in the materials studied ranges from 4.4% (1 nm MoS 2 ) to 46.1% (graphene) as compared to Nafion 211. Effects on proton conductivity are also studied, suggesting high areal proton transport in materials previously thought to be effectively nonconductive, such as 2 nm MoS 2 and amorphous boron nitride under the conditions studied. The results indicate that a number of 2D materials are able to improve crossover effects, with those coated with 8 nm MoS 2 and 1 L graphene able to achieve greater crossover reduction while minimizing conductivity penalty.

Many of Australias smaller marsupial species have been taxonomically described in just the past 50 years, and the Dasyuridae, a speciose family of carnivores, is known to harbour many cryptic taxa. Evidence from molecular studies is being increasingly utilised to help revise species boundaries and focus taxonomic efforts, and research over the past two decades has identified several undescribed genetic lineages within the dasyurid genus Planigale. Here, we describe two new species, Planigale kendricki sp. nov. (formerly known as Planigale 1) and P. tealei sp. nov. (formerly known as Planigale sp. Mt Tom Price). The two new species have broadly overlapping distributions in the Pilbara region of Western Australia. The new species are genetically distinct from each other and from all other members of the genus, at both mitochondrial and nuclear loci, and morphologically, in both external and craniodental characters. The new species are found in regional sympatry within the Pilbara but occupy different habitat types at local scales. This work makes a start at resolving the cryptic diversity within Planigale at a time when small mammals are continuing to decline throughout Australia.

Interest in spatial omics is on the rise, but generation of highly multiplexed images remains challenging, due to cost, expertise, methodical constraints, and access to technology. An alternative approach is to register collections of whole slide images (WSI), generating spatially aligned datasets. WSI registration is a two-part problem, the first being the alignment itself and the second the application of transformations to huge multi-gigapixel images. To address both challenges, we developed Virtual Alignment of pathoLogy Image Series (VALIS), software which enables generation of highly multiplexed images by aligning any number of brightfield and/or immunofluorescent WSI, the results of which can be saved in the ome.tiff format. Benchmarking using publicly available datasets indicates VALIS provides state-of-the-art accuracy in WSI registration and 3D reconstruction. Leveraging existing open-source software tools, VALIS is written in Python, providing a free, fast, scalable, robust, and easy-to-use pipeline for registering multi-gigapixel WSI, facilitating downstream spatial analyses., (© 2023. The Author(s).)

Purpose: College students with chronic illnesses are vulnerable to poor adjustment, but it remains unclear how these students differ from healthy peers. This study compares psychosocial adjustment and risky behavior between students with and without chronic illnesses. Participants: Participants ( N  = 629, 78% Caucasian, 77% Female) were recruited from universities. Methods : Participants completed measures of illness history, anxiety, depression, stressful life events, social support, and risky behavior. Results: College students with chronic illnesses demonstrated significantly greater symptoms of anxiety F(1,620) = 8.742, p < .003, depression F(1,614) = 26.947, p < .001, more stressful life events F(1,476) = 23.671, p < .001, and lower social support F(1,613) = 15.645, p < .001. No differences in risky behaviors between groups emerged F(1,601) = 3.432, p = .064. An indirect effect of health status on risk-taking behavior was observed [b = .677, 95% CI (.351, 1.072)] partially mediated by depression. Conclusion: College students with chronic illnesses demonstrated worse psychosocial outcomes than healthy students, warranting programs to support these students. Depressive symptoms partially mediated risky behavior.

The signature of early cancer dynamics on the spatial arrangement of tumour cells is poorly understood, and yet could encode information about how sub-clones grew within the expanding tumour. Novel methods of quantifying spatial tumour data at the cellular scale are required to link evolutionary dynamics to the resulting spatial architecture of the tumour. Here, we propose a framework using first passage times of random walks to quantify the complex spatial patterns of tumour cell population mixing. First, using a simple model of cell mixing we demonstrate how first passage time statistics can distinguish between different pattern structures. We then apply our method to simulated patterns of mutated and non-mutated tumour cell population mixing, generated using an agent-based model of expanding tumours, to explore how first passage times reflect mutant cell replicative advantage, time of emergence and strength of cell pushing. Finally, we explore applications to experimentally measured human colorectal cancer, and estimate parameters of early sub-clonal dynamics using our spatial computational model. We infer a wide range of sub-clonal dynamics, with mutant cell division rates varying between 1 and 4 times the rate of non-mutated cells across our sample set. Some mutated sub-clones emerged after as few as 100 non-mutant cell divisions, and others only after 50,000 divisions. The majority were consistent with boundary driven growth or short-range cell pushing. By analysing multiple sub-sampled regions in a small number of samples, we explore how the distribution of inferred dynamics could inform about the initial mutational event. Our results demonstrate the efficacy of first passage time analysis as a new methodology in spatial analysis of solid tumour tissue, and suggest that patterns of sub-clonal mixing can provide insights into early cancer dynamics., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Haughey et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Oxytocin protocols are employed to induce uterine contractions and progressive cervical changes, but they are associated with adverse maternal and neonatal outcomes. The aim of this study was to determine whether compliance with a checklist-based protocol for oxytocin administration was associated with changes in neonatal and maternal outcomes., Methods: A retrospective cohort study of 86,786 pregnant women undergoing term (> 37 weeks) induction of labor between January 2015 and December 2017 was performed. Systemwide training in the use of an oxytocin administration protocol was provided to obstetricians and nurses. Pre-use and in-use oxytocin checklists were incorporated into each unit's policies and procedures. Subsequently, charts were reviewed and individually audited by an obstetric nurse who scored each record based on the documentation of variables in an oxytocin administration protocol and ranked adherence as complete or absent. Primary outcomes were postpartum hemorrhage, neonatal ICU (NICU) admission, and delivery by cesarean section. Bivariate analyses (t-tests) were performed on adherent and nonadherent groups for comparison of selected demographic variables and the primary outcome variables. Logistic regression was completed on the primary outcome variable with eight covariates., Results: Among patients with complete adherence to the oxytocin administration protocol, the rate of cesarean section in the unadjusted analysis was 16.20%, compared to 18.54% for those with incomplete adherence; the rates of postpartum hemorrhage were 2.64% vs. 3.14%, respectively, and the rates of NICU admission were 3.03% vs. 3.86%, respectively. In the multivariable logistic regression, complete protocol adherence was associated with significantly lower odds of postpartum hemorrhage (adjusted odds ratio [OR] 0.85, 95% confidence interval [CI] 0.76-0.94) but higher odds of Cesarean section (adjusted OR 1.07, 95% CI 1.01-1.13); the adjusted OR for NICU admission was 0.90, which did not reach statistical significance (95% CI 0.81-1.00). Among the covariates, nulliparity and elective induction were the strongest predictors of the primary outcomes of cesarean section, postpartum hemorrhage, and NICU admission., Conclusion: Adherence to the oxytocin administration protocol was associated with a decrease in postpartum hemorrhage but an increased risk of delivery by cesarean section., (Copyright © 2022. Published by Elsevier Inc.)

Although the overall suicide rate worldwide has changed minimally over the past 100 years, different trends have been observed over time in the USA, Australia, and New Zealand (NZ). However, few studies have focused on suicides in children (< 18 years), making evaluation of possible trends difficult. The last 20 years has also seen an increase in childhood obesity, eating disorders, and body image issues for children in many developed nations; however, few studies have shown whether a significant proportion of child suicides have an abnormal BMI. The current study evaluates child suicides (from 2008 to 2017) in South Australia (Australia), compared with the jurisdictions of Auckland (NZ) and Hennepin County (USA). Demographic data (age, sex, ethnicity), body mass index (BMI), the number of cases of youth suicide, and the method of suicide from these three regions were collected and analyzed. Across the 10-year period, the jurisdiction of Auckland had a downward trend, while Hennepin County and South Australia had increasing numbers of cases. The most common method of child suicide in all centers was hanging, occurring in > 80% of cases in South Australia and Auckland and 56% in Hennepin County. Hennepin County had a greater proportion of suicides using firearms (28%), compared to 1.9% in Auckland and 5.1% in South Australia. Unusual means of suicide were used less frequently by youth than previously., (© 2022. The Author(s).)

Genetic and epigenetic variation, together with transcriptional plasticity, contribute to intratumour heterogeneity 1 . The interplay of these biological processes and their respective contributions to tumour evolution remain unknown. Here we show that intratumour genetic ancestry only infrequently affects gene expression traits and subclonal evolution in colorectal cancer (CRC). Using spatially resolved paired whole-genome and transcriptome sequencing, we find that the majority of intratumour variation in gene expression is not strongly heritable but rather 'plastic'. Somatic expression quantitative trait loci analysis identified a number of putative genetic controls of expression by cis-acting coding and non-coding mutations, the majority of which were clonal within a tumour, alongside frequent structural alterations. Consistently, computational inference on the spatial patterning of tumour phylogenies finds that a considerable proportion of CRCs did not show evidence of subclonal selection, with only a subset of putative genetic drivers associated with subclone expansions. Spatial intermixing of clones is common, with some tumours growing exponentially and others only at the periphery. Together, our data suggest that most genetic intratumour variation in CRC has no major phenotypic consequence and that transcriptional plasticity is, instead, widespread within a tumour., (© 2022. The Author(s).)

Colorectal malignancies are a leading cause of cancer-related death 1  and have undergone extensive genomic study 2,3 . However, DNA mutations alone do not fully explain malignant transformation 4-7 . Here we investigate the co-evolution of the genome and epigenome of colorectal tumours at single-clone resolution using spatial multi-omic profiling of individual glands. We collected 1,370 samples from 30 primary cancers and 8 concomitant adenomas and generated 1,207 chromatin accessibility profiles, 527 whole genomes and 297 whole transcriptomes. We found positive selection for DNA mutations in chromatin modifier genes and recurrent somatic chromatin accessibility alterations, including in regulatory regions of cancer driver genes that were otherwise devoid of genetic mutations. Genome-wide alterations in accessibility for transcription factor binding involved CTCF, downregulation of interferon and increased accessibility for SOX and HOX transcription factor families, suggesting the involvement of developmental genes during tumourigenesis. Somatic chromatin accessibility alterations were heritable and distinguished adenomas from cancers. Mutational signature analysis showed that the epigenome in turn influences the accumulation of DNA mutations. This study provides a map of genetic and epigenetic tumour heterogeneity, with fundamental implications for understanding colorectal cancer biology., (© 2022. The Author(s).)

Background: Melanoma genetic testing reportedly increases preventative behaviour without causing psychological harm. Genetic testing for familial melanoma risk is now available, yet little is known about dermatologists' perceptions regarding the utility of testing and genetic testing ordering behaviours. Objectives: To survey Australasian Dermatologists on the perceived utility of genetic testing, current use in practice, as well as their confidence and preferences for the delivery of genomics education. Methods: A 37-item survey, based on previously validated instruments, was sent to accredited members of the Australasian College of Dermatologists in March 2021. Quantitative items were analysed statistically, with one open-ended question analysed qualitatively. Results: The response rate was 56% (256/461), with 60% (153/253) of respondents between 11 and 30 years post-graduation. While 44% (112/252) of respondents agreed, or strongly agreed, that genetic testing was relevant to their practice today, relevance to future practice was reported significantly higher at 84% (212/251) ( t = -9.82, p < 0.001). Ninety three percent (235/254) of respondents reported rarely or never ordering genetic testing. Dermatologists who viewed genetic testing as relevant to current practice were more likely to have discussed ( p < 0.001) and/or offered testing ( p < 0.001). Respondents indicated high confidence in discussing family history of melanoma, but lower confidence in ordering genetic tests and interpreting results. Eighty four percent (207/247) believed that genetic testing could negatively impact life insurance, while only 26% (63/244) were aware of the moratorium on using genetic test results in underwriting in Australia. A minority (22%, 55/254) reported prior continuing education in genetics. Face-to-face courses were the preferred learning modality for upskilling. Conclusion: Australian Dermatologists widely recognise the relevance of genetic testing to future practice, yet few currently order genetic tests. Future educational interventions could focus on how to order appropriate genetic tests and interpret results, as well as potential implications on insurance., Competing Interests: HS is a shareholder of MoleMap NZ Limited and e-derm consult GmbH, and undertakes regular teledermatological reporting for both companies. HS is a Medical Consultant for Canfield Scientific Inc., MoleMap Australia Pty Ltd., Blaze Bioscience Inc., Revenio Research Oy and a Medical Advisor for First Derm. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Primiero, Baker, Wallingford, Maas, Yanes, Fowles, Janda, Young, Nisselle, Terrill, Lodge, Tiller, Lacaze, Andersen, McErlean, Turbitt, Soyer and McInerney-Leo.)