Verticillins: fungal epipolythiodioxopiperazine alkaloids with chemotherapeutic potential.

Covering: 1970 through June of 2023Verticillins are epipolythiodioxopiperazine (ETP) alkaloids, many of which possess potent, nanomolar-level cytotoxicity against a variety of cancer cell lines. Over the last decade, their in vivo activity and mode of action have been explored in detail. Notably, recent studies have indicated that these compounds may be selective inhibitors of histone methyltransferases (HMTases) that alter the epigenome and modify targets that play a crucial role in apoptosis, altering immune cell recognition, and generating reactive oxygen species. Verticillin A (1) was the first of 27 analogues reported from fungal cultures since 1970. Subsequent genome sequencing identified the biosynthetic gene cluster responsible for producing verticillins, allowing a putative pathway to be proposed. Further, molecular sequencing played a pivotal role in clarifying the taxonomic characterization of verticillin-producing fungi, suggesting that most producing strains belong to the genus Clonostachys (i.e., Bionectria), Bionectriaceae. Recent studies have explored the total synthesis of these molecules and the generation of analogues via both semisynthetic and precursor-directed biosynthetic approaches. In addition, nanoparticles have been used to deliver these molecules, which, like many natural products, possess challenging solubility profiles. This review summarizes over 50 years of chemical and biological research on this class of fungal metabolites and offers insights and suggestions on future opportunities to push these compounds into pre-clinical and clinical development.

Implementing global positioning system trackers for people with dementia who are at risk of wandering.

OBJECTIVE: The main aim of this study was to evaluate the feasibility and acceptability of using a GPS tracker to mitigate the risks associated with wandering for people with dementia and those caring for them and further evaluate the impact of trackers in delaying 24-hour care and the potential for reducing the involvement of support services, such as the police, in locating patients. METHODS: We recruited forty-five wearers-carers dyads, and a GPS tracker was issued to each participant. Dyads completed pre-and post-outcome questionnaires after six months, and a use-log of experiences was maintained through monthly monitoring calls. At six months, focus groups were conducted with 14 dyads where they shared ideas and learning. Data analyses were performed on outcome questionnaires, use-log analysis, and focus groups discussion. RESULTS: A 24% (N = 14) attrition rate was recorded, with 76% (N = 34) of the participants completing pre- and post-outcome questionnaires, of which 41% (N = 14) attended four focus group meetings. Participants reported enhanced independence for wearers as fewer restrictions were placed on their movements, peace of mind and reduced burden for the carers with less need to involve police or social services, and delays in 24-hour care. CONCLUSION: The results supported the feasibility of routine implementation of GPS trackers in dementia care with clear guidance, monitoring and support to family carers on safe use. This could delay admission into 24-hour care as wearers and carers have a greater sense of safety and are better connected should help be required. Studies with larger sample sizes, diverse participants and health economic analysis are needed to develop the evidence base further ahead of the routine implementation of GPS trackers in health and social care services.

The "cesium effect" magnified: exceptional chemoselectivity in cesium ion mediated nucleophilic reactions.

Chemodivergent construction of structurally distinct heterocycles from the same precursors by adjusting specific reaction parameters is an emergent area of organic synthesis; yet, understanding of the processes that underpin the reaction divergence is lacking, preventing the development of new synthetic methods by systematically harnessing key mechanistic effects. We describe herein cesium carbonate-promoted oxadiaza excision cross-coupling reactions of ß-ketoesters with 1,2,3-triazine 1-oxides that form pyridones in good to high yields, instead of the sole formation of pyridines when the same reaction is performed in the presence of other alkali metal carbonates or organic bases. The reaction can be further extended to the construction of synthetically challenging pyridylpyridones. A computational study comparing the effect of cesium and sodium ions in the oxadiaza excision cross-coupling reactions reveals that the cesium-coordinated species changes the reaction preference from attack at the ketone carbonyl to attack at the ester carbon due to metal ion-specific transition state conformational accommodation, revealing a previously unexplored role of cesium ions that may facilitate the development of chemodivergent approaches to other heterocyclic systems.

Somatic variants as a cause of drug-resistant epilepsy including mesial temporal lobe epilepsy with hippocampal sclerosis.

OBJECTIVE: The contribution of somatic variants to epilepsy has recently been demonstrated, particularly in the etiology of malformations of cortical development. The aim of this study was to determine the diagnostic yield of somatic variants in genes that have been previously associated with a somatic or germline epilepsy model, ascertained from resected brain tissue from patients with multidrug-resistant focal epilepsy. METHODS: Forty-two patients were recruited across three categories: (1) malformations of cortical development, (2) mesial temporal lobe epilepsy with hippocampal sclerosis, and (3) nonlesional focal epilepsy. Participants were subdivided based on histopathology of the resected brain. Paired blood- and brain-derived DNA samples were sequenced using high-coverage targeted next generation sequencing to high depth (585× and 1360×, respectively). Variants were identified using Genome Analysis ToolKit (GATK4) MuTect-2 and confirmed using high-coverage Amplicon-EZ sequencing. RESULTS: Sequence data on 41 patients passed quality control. Four somatic variants were validated following amplicon sequencing: within CBL, ALG13, MTOR, and FLNA. The diagnostic yield across 41 patients was 10%, 9% in mesial temporal lobe epilepsy with hippocampal sclerosis and 20% in malformations of cortical development. SIGNIFICANCE: This study provides novel insights into the etiology of mesial temporal lobe epilepsy with hippocampal sclerosis, highlighting a potential pathogenic role of somatic variants in CBL and ALG13. We also report candidate diagnostic somatic variants in FLNA in focal cortical dysplasia, while providing further insight into the importance of MTOR and related genes in focal cortical dysplasia. This work demonstrates the potential molecular diagnostic value of variants in both germline and somatic epilepsy genes.

Crimean-Congo Hemorrhagic Fever Survivors Elicit Protective Non-Neutralizing Antibodies that Target 11 Overlapping Regions on Viral Glycoprotein GP38.

Crimean-Congo hemorrhagic fever virus can cause lethal disease in humans yet there are no approved medical countermeasures. Viral glycoprotein GP38, unique to Nairoviridae, is a target of protective antibodies, but extensive mapping of the human antibody response to GP38 has not been previously performed. Here, we isolated 188 GP38-specific antibodies from human survivors of infection. Competition experiments showed that these antibodies bind across five distinct antigenic sites, encompassing eleven overlapping regions. Additionally, we reveal structures of GP38 bound with nine of these antibodies targeting different antigenic sites. Although GP38-specific antibodies were non-neutralizing, several antibodies were found to have protection equal to or better than murine antibody 13G8 in two highly stringent rodent models of infection. Together, these data expand our understanding regarding this important viral protein and inform the development of broadly effective CCHFV antibody therapeutics.

A practical guide for the preparation of C1-labeled α-amino acids using aldehyde catalysis with isotopically labeled CO2.

Isotopically carbon-labeled α-amino acids are valuable synthetic targets that are increasingly needed in pharmacology and medical imaging. Existing preparations rely on early stage introduction of the isotopic label, which leads to prohibitive synthetic costs and time-intensive preparations. Here we describe a protocol for the preparation of C1-labeled α-amino acids using simple aldehyde catalysts in conjunction with [*C]CO2 (* = 14, 13, 11). This late-stage labeling strategy is enabled by the one-pot carboxylate exchange of unprotected α-amino acids with [*C]CO2. The protocol consists of three separate procedures, describing the syntheses of (±)-[1-13C]phenylalanine, (±)-[1-11C]phenylalanine and (±)-[1-14C]phenylalanine from unlabeled phenylalanine. Although the delivery of [*C]CO2 is operationally distinct for each experiment, each procedure relies on the same fundamental chemistry and can be executed by heating the reaction components at 50-90 °C under basic conditions in dimethylsulfoxide. Performed on scales of up to 0.5 mmol, this methodology is amenable to C1-labeling of many proteinogenic α-amino acids and nonnatural derivatives, which is a breakthrough from existing methods. The synthesis of (±)-[1-13C]phenylalanine requires ~2 d, with product typically obtained in a 60-80% isolated yield (n = 3, µ = 71, σ = 8.3) with an isotopic incorporation of 70-88% (n = 18, µ = 72, σ = 9.0). Starting from the preformed imino acid (~3 h preparation time), rapid synthesis of (±)-[1-11C]phenylalanine can be completed in ~1 h with an isolated radiochemical yield of 13%. Finally, (±)-[1-14C]phenylalanine can be accessed in ~2 d with a 51% isolated yield and 11% radiochemical yield.

A phase III multisite randomised controlled trial to compare the efficacy of cannabidiol to placebo in the treatment of cannabis use disorder: the CBD-CUD study protocol.

BACKGROUND: Cannabis use disorder (CUD) is increasingly common and contributes to a range of health and social problems. Cannabidiol (CBD) is a non-intoxicating cannabinoid recognised for its anticonvulsant, anxiolytic and antipsychotic effects with no habit-forming qualities. Results from a Phase IIa randomised clinical trial suggest that treatment with CBD for four weeks reduced non-prescribed cannabis use in people with CUD. This study examines the efficacy, safety and quality of life of longer-term CBD treatment for patients with moderate-to-severe CUD. METHODS/DESIGN: A phase III multi-site, randomised, double-blinded, placebo controlled parallel design of a 12-week course of CBD to placebo, with follow-up at 24 weeks after enrolment. Two hundred and fifty adults with moderate-to-severe CUD (target 20% Aboriginal), with no significant medical, psychiatric or other substance use disorders from seven drug and alcohol clinics across NSW and VIC, Australia will be enrolled. Participants will be administered a daily dose of either 4 mL (100 mg/mL) of CBD or a placebo dispensed every 3-weeks. All participants will receive four-sessions of Cognitive Behavioural Therapy (CBT) based counselling. Primary endpoints are self-reported cannabis use days and analysis of cannabis metabolites in urine. Secondary endpoints include severity of CUD, withdrawal severity, cravings, quantity of use, motivation to stop and abstinence, medication safety, quality of life, physical/mental health, cognitive functioning, and patient treatment satisfaction. Qualitative research interviews will be conducted with Aboriginal participants to explore their perspectives on treatment. DISCUSSION: Current psychosocial and behavioural treatments for CUD indicate that over 80% of patients relapse within 1-6 months of treatment. Pharmacological treatments are highly effective with other substance use disorders but there are no approved pharmacological treatments for CUD. CBD is a promising candidate for CUD treatment due to its potential efficacy for this indication and excellent safety profile. The anxiolytic, antipsychotic and neuroprotective effects of CBD may have added benefits by reducing many of the mental health and cognitive impairments reported in people with regular cannabis use. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry: ACTRN12623000526673 (Registered 19 May 2023).

Development and evaluation of a de-escalation training intervention in adult acute and forensic units: the EDITION systematic review and feasibility trial.

Background: Containment (e.g. physical restraint and seclusion) is used frequently in mental health inpatient settings. Containment is associated with serious psychological and physical harms. De-escalation (psychosocial techniques to manage distress without containment) is recommended to manage aggression and other unsafe behaviours, for example self-harm. All National Health Service staff are trained in de-escalation but there is little to no evidence supporting training's effectiveness. Objectives: Objectives were to: (1) qualitatively investigate de-escalation and identify barriers and facilitators to use across the range of adult acute and forensic mental health inpatient settings; (2) co-produce with relevant stakeholders an intervention to enhance de-escalation across these settings; (3) evaluate the intervention's preliminary effect on rates of conflict (e.g. violence, self-harm) and containment (e.g. seclusion and physical restraint) and understand barriers and facilitators to intervention effects. Design: Intervention development informed by Experience-based Co-design and uncontrolled pre and post feasibility evaluation. Systematic reviews and qualitative interviews investigated contextual variation in use and effects of de-escalation. Synthesis of this evidence informed co-design of an intervention to enhance de-escalation. An uncontrolled feasibility trial of the intervention followed. Clinical outcome data were collected over 24 weeks including an 8-week pre-intervention phase, an 8-week embedding and an 8-week post-intervention phase. Setting: Ten inpatient wards (including acute, psychiatric intensive care, low, medium and high secure forensic) in two United Kingdom mental health trusts. Participants: In-patients, clinical staff, managers, carers/relatives and training staff in the target settings. Interventions: Enhancing de-escalation techniques in adult acute and forensic units: Development and evaluation of an evidence-based training intervention (EDITION) interventions included de-escalation training, two novel models of reflective practice, post-incident debriefing and feedback on clinical practice, collaborative prescribing and ward rounds, practice changes around admission, shift handovers and the social and physical environment, and sensory modulation and support planning to reduce patient distress. Main outcome measures: Outcomes measured related to feasibility (recruitment and retention, completion of outcome measures), training outcomes and clinical and safety outcomes. Conflict and containment rates were measured via the Patient-Staff Conflict Checklist. Clinical outcomes were measured using the Attitudes to Containment Measures Questionnaire, Attitudes to Personality Disorder Questionnaire, Violence Prevention Climate Scale, Capabilities, Opportunities, and Motivation Scale, Coercion Experience Scale and Perceived Expressed Emotion in Staff Scale. Results: Completion rates of the proposed primary outcome were very good at 68% overall (excluding remote data collection), which increased to 76% (excluding remote data collection) in the post-intervention period. Secondary outcomes had high completion rates for both staff and patient respondents. Regression analyses indicated that reductions in conflict and containment were both predicted by study phase (pre, embedding, post intervention). There were no adverse events or serious adverse events related to the intervention. Conclusions: Intervention and data-collection procedures were feasible, and there was a signal of an effect on the proposed primary outcome. Limitations: Uncontrolled design and self-selecting sample. Future work: Definitive trial determining intervention effects. Trial registration: This trial is registered as ISRCTN12826685 (closed to recruitment). Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/101/02) and is published in full in Health Technology Assessment; Vol. 28, No. 3. See the NIHR Funding and Awards website for further award information. Context: Conflict (a term used to describe a range of potentially unsafe events including violence, self-harm, rule-breaking, medication refusal, illicit drug and alcohol use and absconding) in mental health settings causes serious physical and psychological harm. Containment interventions which are intended to minimise harm from violence (and other conflict behaviours) such as restraint, seclusion and rapid tranquilisation can result in serious injuries to patients and, occasionally, death. Involvement in physical restraint is the most common cause of serious physical injury to National Health Service mental health staff in the United Kingdom. Violence to staff results in substantial costs to the health service in sickness and litigation payments. Containment interventions are also expensive (e.g. physical restraint costs mental health services £6.1 million and enhanced observations £88 million per annum). Despite these harms, recent findings indicate containment interventions such as seclusion and physical restraint continue to be used frequently in mental health settings. Clinical trials have demonstrated that interventions can reduce containment without increasing violence and other conflict behaviours (e.g. verbal aggression, self-harm). Substantial cost-savings result from reducing containment use. De-escalation, as an intervention to manage aggression and potential violence without restrictive practices, is a core intervention. 'De-escalation' is a collective term for a range of psychosocial techniques designed to reduce distress and anger without the need to use 'containment' interventions (measures to prevent harm through restricting a person's ability to act independently, such as physical restraint and seclusion). Evidence indicates that de-escalation involves ensuring conditions for safe intervention and effective communication are established, clarifying and attempting to resolve the patient's concern, conveyance of respect and empathy and regulating unhelpful emotions such as anxiety and anger. Despite featuring prominently in clinical guidelines and training policy domestically and internationally and being a component of mandatory National Health Service training, there is no evidence-based model on which to base training. A systematic review of de-escalation training effectiveness and acceptability conducted in 2015 concluded: (1) no model of training has demonstrated effectiveness in a sufficiently rigorous evaluation, (2) the theoretical underpinning of evaluated models was often unclear and (3) there has been inadequate investigation of the characteristics of training likely to enhance acceptability and uptake. Despite all National Health Service staff being trained in de-escalation there have been no high-quality trials evaluating the effectiveness and cost-effectiveness of training. Feasibility studies are needed to establish whether it is possible to conduct a definitive trial that can determine the clinical, safety and cost-effectiveness of this intervention.

Mental health hospitals are stressful places for patients and staff. Patients are often detained against their will, in places that are noisy, unfamiliar and frightening. Violence and self-injury happen quite frequently. Sometimes staff physically restrain patients or isolate patients in locked rooms (called seclusion). While these measures might sometimes be necessary to maintain safety, they are psychologically and physically harmful. To help reduce the use of these unsafe measures, staff are trained in communication skills designed to reduce anger and distress without using physical force. Professionals call these skills 'de-escalation'. Although training in de-escalation is mandatory, there is no good evidence to say whether it works or not, or what specific techniques staff should be trained in. The Enhancing de-escalation techniques in adult acute and forensic units: Development and evaluation of an evidence-based training intervention (EDITION) project aimed to develop and evaluate a de-escalation training programme informed by research evidence. We interviewed over one hundred people who either worked in or received treatment in a mental health hospital. These people were clear that the training should target key sources of interpersonal and environmental stress that prevent de-escalation from working. We also reviewed all the scientific studies on de-escalation and training, aiming to identify the elements of training that are most likely to increase use of de-escalation. Then, in partnership with current mental health service users and clinical staff, we developed the training programme. Training was delivered to more than 270 staff working in 10 different wards in mental health hospitals. We measured rates of violence, self-injury and use of physical restraint and seclusion 8 weeks before staff received training and 16 weeks after they received training (24 weeks of data collection in total). Analysis of these data showed that these unsafe events were occurring significantly less frequently after training than they were before training, which raised the possibility that the training was helping to reduce harm.

Whole-Genome sequencing in routine Mycobacterium bovis epidemiology - scoping the potential.

Mycobacterium bovis the main agent of bovine tuberculosis (bTB), presents as a series of spatially-localised micro-epidemics across landscapes. Classical molecular typing methods applied to these micro-epidemics, based on genotyping a few variable loci, have significantly improved our understanding of potential epidemiological links between outbreaks. However, they have limited utility owing to low resolution. Conversely, whole-genome sequencing (WGS) provides the highest resolution data available for molecular epidemiology, producing richer outbreak tracing, insights into phylogeography and epidemic evolutionary history. We illustrate these advantages by focusing on a common single lineage of M. bovis (1.140) from Northern Ireland. Specifically, we investigate the spatial sub-structure of 20 years of herd-level multi locus VNTR analysis (MLVA) surveillance data and WGS data from a down sampled subset of isolates of this MLVA type over the same time frame. We mapped 2108 isolate locations of MLVA type 1.140 over the years 2000-2022. We also mapped the locations of 148 contemporary WGS isolates from this lineage, over a similar geographic range, stratifying by single nucleotide polymorphism (SNP) relatedness cut-offs of 15 SNPs. We determined a putative core range for the 1.140 MLVA type and SNP-defined sequence clusters using a 50 % kernel density estimate, using cattle movement data to inform on likely sources of WGS isolates found outside of core ranges. Finally, we applied Bayesian phylogenetic methods to investigate past population history and reproductive number of the 1.140 M. bovis lineage. We demonstrate that WGS SNP-defined clusters exhibit smaller core ranges than the established MLVA type - facilitating superior disease tracing. We also demonstrate the superior functionality of WGS data in determining how this lineage was disseminated across the landscape, likely via cattle movement and to infer how its effective population size and reproductive number has been in flux since its emergence. These initial findings highlight the potential of WGS data for routine monitoring of bTB outbreaks.

Associations Between Supported Accommodation and Health and Re-offending Outcomes: a Retrospective Data Linkage Study.

Following release from prison, housing and health issues form a complex and mutually reinforcing dynamic, increasing reincarceration risk. Supported accommodation aims to mitigate these post-release challenges. We describe the impact of attending Rainbow Lodge (RL), a post-release supported accommodation service for men in Sydney, Australia, on criminal justice and emergency health outcomes. Our retrospective cohort study using linked administrative data includes 415 individuals referred to RL between January 2015 and October 2020. Outcomes of interest were rates of criminal charges, emergency department (ED) presentations and ambulance attendance; and time to first reincarceration, criminal charge, ED presentation and ambulance attendance. The exposure of interest was attending RL; covariates included demographic characteristics, release year and prior criminal justice and emergency health contact. Those who attended RL (n = 170, 41%) more commonly identified as Aboriginal or Torres Strait Islander (52% vs 41%; p = 0.025). There was strong evidence that attending RL reduced the incidence criminal charges (adjusted rate ratio [ARR] = 0.56; 95% confidence interval [CI] 0.340.86; p = 0.009). Absolute rates indicate a weak protective effect of RL attendance on ED presentation and ambulance attendance; however, adjusted analyses indicated no evidence of an association between attending RL and rates of ED presentations (ARR = 0.88; 95% CI = 0.65-1.21), or ambulance attendance (ARR = 0.82; 95% CI = 0.57-1.18). There was no evidence of an association between attending RL and time to first reincarceration, charge, ED presentation or ambulance attendance. Greater detail about reasons for emergency health service contact and other self-report outcome measures may better inform how supported accommodation is meeting its intended aims.

Care Plan Templates in Adult Community Mental Health Teams in England and Wales: An Evaluation.

Adults accessing community mental health services are required to have a care plan, developed in collaboration with the person accessing the service. The variation in care plan templates in use in England and Wales, and their impact on care planning, is unknown. This study evaluates the community mental health care plan templates in use across England and Wales. Data were obtained from a Freedom of Information request to 50 NHS Mental Health Trusts. An evaluation tool was designed and used to extract data. Data were rated red, amber, or green against clinical and design standards. Forty-seven care plan templates were obtained. The clinical aspect of the care plan template had 60% adherence to the national standards, and the design aspects had 87% adherence. A 'high/low' typology is proposed against the design/clinical standards. The study identifies priority areas for improvement in the care plan templates as space to record the actions that service users and carers will take to contribute to their care plan, space to record the name and contact details for their care coordinator or lead professional, plus others involved in the person's care. This study was not registered.

Developing a web-based app for non-mental health nurses to assess the mental health needs and risks of children and young people.

There is high demand for specialist mental health services for children and young people in the UK. Non-mental health nurses are well-placed to assess the mental health needs and risks of children and young people to maximise opportunities for early intervention and relieve the pressure on child and adolescent mental health services. This article provides an overview of a service development project to develop a web-based application (app) to support non-mental health nurses when assessing the mental health needs and risks of children and young people. The article describes the development, testing and evaluation process, which involved consultation with children and young people as well as interviews, focus groups and an online survey with a range of professionals working with children and young people. Overall, the findings suggest that the app is appropriate for use by non-mental health nurses in terms of quality, functionality and acceptability.

Learnings from a prison-based drug treatment program on planning for release: A qualitative study.

INTRODUCTION: Prison-based drug and alcohol group treatment programs operate in all Australian jurisdictions. With more than two-thirds of people in prison having a history of substance use prior to incarceration, such programs are needed. There have been few published papers on the impact of attending group treatment programs in Australian prisons, and the research published to date has been predominately quantitative. We aim to report the experiences of males in prison who completed and those who did not complete a group-based drug and alcohol program, to gain insight into their strategies for reducing harm from drug and alcohol post-release. METHODS: Qualitative thematic analysis of in-depth interviews with 12 males who completed or were about to complete and 10 males who discontinued a prison-based group drug and alcohol treatment program. RESULTS: Program completers were more likely to have well-developed plans to reduce drug and alcohol harms and maintain abstinence upon return to the community, which included creating healthier social networks. They also showed stronger insights into the factors that led to offending. Those who did not complete the drug and alcohol program appeared to rely on self-will as the main way to reduce drug and alcohol harms, with less awareness of options for support services to reduce or stop drug and alcohol use. DISCUSSION AND CONCLUSIONS: Prison-based drug and alcohol program engagement imparted useful information for program completers. Controlled trials are needed to examine whether such differences equate to improved outcomes after release.

Interaction between Macrophages and Adipose Stromal Cells Increases the Angiogenic and Proliferative Potential of Pregnancy-Associated Breast Cancers.

Pregnancy associated breast cancers (PABCs) exhibit increased aggressiveness and overall poorer survival. During lactation, changes take place in the breast tissue microenvironment that lead to increased macrophage recruitment and alterations in adipose stromal cells (ASC-Ls). The interaction of these cells in PABCs could play a role in the increased aggressiveness of these cancers. We utilized an in vitro co-culture model to recreate the interactions of ASC-Ls and macrophages in vivo. We performed qRT-PCR to observe changes in gene expression and cytokine arrays to identify transcriptional changes that result in an altered microenvironment. Additionally, functional assays were performed to further elicit how these changes affect tumorigenesis. The co-culture of ASC-Ls and macrophages altered both mRNA expression and cytokine secretion in a tumor promoting manner. Tumorigenic cytokines, such as IL-6, CXCL1, CXCL5, and MMP-9 secretion levels, were enhanced in the co-culture. Additionally, conditioned media from the co-culture elevated the tumor cell proliferation and angiogenic potential of endothelial cells. These finds indicate that the changes seen in the microenvironment of PABC, specifically the secretion of cytokines, play a role in the increased tumorigenesis of PABCs by altering the microenvironment to become more favorable to tumor progression.

Yarning as a method for building sexual wellbeing among urban Aboriginal young people in Australia.

This paper describes the strategies used by Aboriginal young people to build positive relationships and sexual wellbeing. It does so to counter the risk-focussed narratives present in much existing research and to showcase the resourcefulness of Aboriginal young people. We used peer-interview methods to collect qualitative data from 52 Aboriginal young people living in western Sydney, Australia. Participants reported a strong desire to stay safe and healthy in their sexual relationships and to achieve this they relied heavily on oral communication and yarning strategies. Participants viewed communication as a way to gain or give advice (about bodies, infections, pregnancy, relationships); to assess the acceptability and safety of potential partners; to negotiate consent with partners; to build positive relationships; and to get themselves out of unhealthy relationships. Participants also discussed 'self-talk' as a strategy for building sexual wellbeing, referring to narratives of self-respect and pride in culture as important in establishing Aboriginal young people's positive views of self and as deserving of respectful and safe sexual relationships. These findings suggest that future programmes and interventions based on yarning could be well-regarded, given it is a cultural form of pedagogy and a strategy Aboriginal young people already use to build positive relationships and identities.

Fetal alcohol spectrum disorder and Aboriginal and Torres Strait Islander men: A discussion to be had.

Fetal alcohol spectrum disorder (FASD) is a lifelong disability of varying severity that occurs among individuals prenatally exposed to alcohol. Among Aboriginal and Torres Strait Islander (Indigenous) Australians, the effects of colonisation and ongoing racism could increase the risk of alcohol consumption during pregnancy. Much of the research and the effort towards prevention of and caring for people with FASD in Indigenous communities has been targeted towards women and children. More support and effort towards prevention of FASD is needed across the whole Indigenous community. In this paper, we discuss several areas for increased involvement by Indigenous men in future FASD research, prevention, care and support.

Alcohol relapse prevention health care after alcohol withdrawal in New South Wales prisons, Australia: A patient file review.

INTRODUCTION: People who enter custody have complex health issues and comorbidities may include alcohol use disorders. We investigated clinical service provision and comorbidities recorded among individuals with a likely alcohol withdrawal syndrome within prison in New South Wales, Australia. METHODS: For this clinical case series review, electronic medical data were used to identify 50 people entering custody between August and November 2018 who likely had a treated alcohol withdrawal syndrome. We aimed for a 3:2 ratio of men and women, and a 1:1 ratio of Aboriginal and non-Aboriginal individuals. Data were extracted using a purposefully designed tool which included current alcohol withdrawal management, comorbidities and alcohol relapse prevention approaches used or recommended. RESULTS: Thirty-eight men and 12 women, of whom 22 were Aboriginal, were included. Twenty-nine individuals (58%) reported a history of medical comorbidities. Thirty-five (70%) reported using other substances and over half (60%) had a diagnosis of mental health disorders. Fourteen (28%) individuals had a record of receiving brief intervention and five (10%) of motivational interviewing. Twenty-three individuals (46%) were referred to and seen by drug and alcohol clinicians. Only seven (14%) of the sample had pre-release community care plans. DISCUSSION AND CONCLUSIONS: Individuals treated for an alcohol withdrawal syndrome in New South Wales prisons have a high prevalence of medical comorbidities and other substance use. Clinical interventions focused on alcohol withdrawal management, and relapse prevention interventions were not recorded for most individuals. Service innovation and expansion are needed to increase the provision of post-withdrawal management.

Aboriginal and Torres Strait Islander Human Research Ethics Committees (HRECs) are essential in promoting our health and wellbeing.

The history of unethical and inhumane research conducted on Aboriginal and Torres Strait Islander people since colonisation highlights the critical need for specific Human Research Ethics for research involving Aboriginal and Torres Strait Islander peoples in Australia. The development of Aboriginal Human Research Ethics Committees (AHRECs) has played a vital role in ensuring research is safe and delivered for Aboriginal and Torres Strait Islander people in a way that protects and promotes their health and wellbeing. However, there remains a lack of appropriate and critical ethical governance for such research in areas without specific Aboriginal HRECs in each jurisdiction. This perspective argues that greater investment in state-based AHRECs and consideration of a national AHREC are essential to ensure the ongoing health and wellbeing of Aboriginal and Torres Strait Islander people in the research process -the ultimate aim of any research that involves them.

Interactive Volume Visualization Via Multi-Resolution Hash Encoding Based Neural Representation.

Implicit neural networks have demonstrated immense potential in compressing volume data for visualization. However, despite their advantages, the high costs of training and inference have thus far limited their application to offline data processing and non-interactive rendering. In this paper, we present a novel solution that leverages modern GPU tensor cores, a well-implemented CUDA machine learning framework, an optimized global-illumination-capable volume rendering algorithm, and a suitable acceleration data structure to enable real-time direct ray tracing of volumetric neural representations. Our approach produces high-fidelity neural representations with a peak signal-to-noise ratio (PSNR) exceeding 30 dB, while reducing their size by up to three orders of magnitude. Remarkably, we show that the entire training step can fit within a rendering loop, bypassing the need for pre-training. Additionally, we introduce an efficient out-of-core training strategy to support extreme-scale volume data, making it possible for our volumetric neural representation training to scale up to terascale on a workstation with an NVIDIA RTX 3090 GPU. Our method significantly outperforms state-of-the-art techniques in terms of training time, reconstruction quality, and rendering performance, making it an ideal choice for applications where fast and accurate visualization of large-scale volume data is paramount.

Site Reversal in Nucleophilic Addition to 1,2,3-Triazine 1-Oxides.

One of the most important reactions of 1,2,3-triazines with a dienophile is inverse electron demand Diels-Alder (IEDDA) cycloaddition, which occurs through nucleophilic addition to the triazine followed by N2 loss and cyclization to generate a heterocycle. The site of addition is either at the 4- or 6-position of the symmetrically substituted triazine core. Although specific examples of the addition of nucleophiles to triazines are known, a comprehensive understanding has not been reported, and the preferred site for nucleophilic addition is unknown and unexplored. With access to unsymmetrical 1,2,3-triazine-1-oxides and their deoxygenated 1,2,3-triazine compounds, we report C-, N-, H-, O-, and S-nucleophilic additions on 1,2,3-triazine and 1,2,3-triazine-1-oxide frameworks where the 4- and 6-positions could be differentiated. In the IEDDA cycloadditions using C- and N-nucleophiles, the site of addition is at C-6 for both heterocyclic systems, but product formation with 1,2,3-triazine-1-oxides is faster. Other N-nucleophile reactions with triazine 1-oxides show addition at either the 4- or 6-position of the triazine 1-oxide ring, but nucleophilic attack only occurs at the 6-position on the triazine. Hydride from NaBH4 undergoes addition at the 6-position on the triazine and the triazine 1-oxide core. Alkoxides show a high nucleophilic selectivity for the 4-position of the triazine 1-oxide. Thiophenoxide, cysteine, and glutathione undergo nucleophilic addition on the triazine core at the 6-position, while addition occurs at the 4-position of the triazine 1-oxide. These nucleophilic additions proceed under mild reaction conditions and show high functional group tolerance. Computational studies clarified the roles of the nucleophilic addition and nitrogen extrusion steps and the influence of steric and electronic factors in determining the outcomes of the reactions with different nucleophiles.