Deficiency of factor-inhibiting HIF creates a tumor-promoting immune microenvironment.

Hypoxia signaling influences tumor development through both cell-intrinsic and -extrinsic pathways. Inhibiting hypoxia-inducible factor (HIF) function has recently been approved as a cancer treatment strategy. Hence, it is important to understand how regulators of HIF may affect tumor growth under physiological conditions. Here we report that in aging mice factor-inhibiting HIF (FIH), one of the most studied negative regulators of HIF, is a haploinsufficient suppressor of spontaneous B cell lymphomas, particular pulmonary B cell lymphomas. FIH deficiency alters immune composition in aged mice and creates a tumor-supportive immune environment demonstrated in syngeneic mouse tumor models. Mechanistically, FIH-defective myeloid cells acquire tumor-supportive properties in response to signals secreted by cancer cells or produced in the tumor microenvironment with enhanced arginase expression and cytokine-directed migration. Together, these data demonstrate that under physiological conditions, FIH plays a key role in maintaining immune homeostasis and can suppress tumorigenesis through a cell-extrinsic pathway.

Western Australia remote aeromedical substance use disorders outcomes.

INTRODUCTION: Substance use disorders (SUDs) cause significant harm to regional Australians, who are more likely to misuse alcohol and other drugs (AODs) and encounter difficulty in accessing treatment services. The primary aims of this study were to describe the demographics of patients aeromedically retrieved from regional locations and compare hospital outcomes with a metropolitan-based cohort. AIMS: Retrospective case-controlled cohort study. Participants were aeromedically retrieved within Western Australia for SUDs between 1 July 2014 and 30 June 2019. Retrieved patients were case-matched based on age and hospital discharge diagnosis. Descriptive statistics and χ2 analysis were used to summarise the findings. RESULTS: One hundred thirty-six (91.3%) aeromedical retrievals were found, with the majority being male (n = 95; 69.9%). These were case-matched to 427 metropolitan patients, the majority male (n = 321; 75.2%). Retrieved patients were more likely (all P < 0.05) Indigenous (odds ratio [OR], 9.35 [95% confidence interval (CI), 5.96-14.85]), unemployed (OR, 2.9 [95% CI, 1.41-6.80]), referred to a tertiary hospital (OR, 2.18 [95% CI, 1.24-3.86]) and to stay longer in hospital (OR, 1.08 [95% CI, 1.02-1.14]). DISCUSSION: Findings highlight that unmarried and/or unemployed males were overrepresented in the retrieval group, with over half identifying as Indigenous. Regional variation in retrievals was noted, while amphetamine-type stimulants featured prominently in the retrieval cohort, who experienced longer hospital stays and more restrictive treatment. CONCLUSIONS: Comparing clinical outcomes for retrieved regional patients experiencing SUDs, service design and delivery should focus on offering culturally safe care for Indigenous people, catering for regional health care catchment areas, while ideally adopting collaborative and integrated approaches between AODs and mental health services.

GP perspectives on a psychiatry phone line in Western Australia's Great Southern region: implications for addressing rural GP workload.

BACKGROUND: Mental illness is a public health challenge disproportionately affecting rural Australians. GPs provide most of the mental health care, and they report increasing levels of burnout and unsustainable workload in the context of increased patient complexity. This may be more salient in rural settings characterised by resource constraints. In this paper, we use evaluation data from a GP psychiatry phone line established in Western Australia's Great Southern region in 2021 to describe GPs' perspectives on the service and reflect on how it may help alleviate rural GP workload. METHODS: The sample was recruited among GPs practicing in the region. Data were collected through an online survey and semistructured interviews. Descriptive statistics were used to analyse the survey data. Interview data were subjected to thematic analysis; qualitative survey data were used for triangulation. RESULTS: A total of 45GPs completed the survey and 14 were interviewed. Interview data yielded three themes: the criticality of timeliness; the building blocks of confidence; and trust. GPs were highly satisfied with the service, and timeliness and trust were the characteristics underpinning its effectiveness. The service built GPs' confidence in managing mental health and alcohol and other drug use issues through strengthening knowledge and providing reassurance. CONCLUSIONS: Our results suggest that a telephone line operated by trusted, local psychiatrists with knowledge of the local mental health ecosystem of support can reduce rural GP workload through building confidence and strengthening personal agency, helping GPs navigate the ethical and clinical labyrinth of managing patient complexity in rural settings.

5-Substituted Pyridine-2,4-dicarboxylate Derivatives Have Potential for Selective Inhibition of Human Jumonji-C Domain-Containing Protein 5.

Jumonji-C domain-containing protein 5 (JMJD5) is a 2-oxoglutarate (2OG)-dependent oxygenase that plays important roles in development, circadian rhythm, and cancer through unclear mechanisms. JMJD5 has been reported to have activity as a histone protease, as an Nε-methyl lysine demethylase, and as an arginine residue hydroxylase. Small-molecule JMJD5-selective inhibitors will be useful for investigating its (patho)physiological roles. Following the observation that the broad-spectrum 2OG oxygenase inhibitor pyridine-2,4-dicarboxylic acid (2,4-PDCA) is a 2OG-competing JMJD5 inhibitor, we report that 5-aminoalkyl-substituted 2,4-PDCA derivatives are potent JMJD5 inhibitors manifesting selectivity for JMJD5 over other human 2OG oxygenases. Crystallographic analyses with five inhibitors imply induced fit binding and reveal that the 2,4-PDCA C5 substituent orients into the JMJD5 substrate-binding pocket. Cellular studies indicate that the lead compounds display similar phenotypes as reported for clinically observed JMJD5 variants, which have a reduced catalytic activity compared to wild-type JMJD5.

The impact of facilitators and rural immersion on medical student engagement during a child and adolescent mental health videoconference workshop.

OBJECTIVE: Child and adolescent mental health (CAMH) disorders are a major public health problem in Australia, especially outside metropolitan areas. The issue is compounded by a shortage of child and adolescent psychiatrists (CAPs). CAMH receives minimal coverage in health professional training, training opportunities are scarce, and support for generalist health professionals, who treat most cases, is lacking. Novel approaches to early medical education and teaching are required to strengthen the available skilled workforce in rural and remote settings. METHOD: This qualitative study explored the factors influencing medical student engagement in a CAMH videoconferencing workshop as part of the Rural Clinical School of WA. RESULTS: Our results confirm the priority of personal characteristics of medical educators, over clinical and subject matter expertise, on student learning. This research affirms that general practitioners are well-placed to facilitate recognition of learning experiences, especially given that students may not readily recognise exposure to CAMH cases. CONCLUSION: Our findings support the effectiveness, efficiencies, and benefits of utilising general medical educators in supporting child and adolescent psychiatry expertise in delivering subspecialty training within medical school curricula.

Inactivation of DRG1, encoding a translation factor GTPase, causes a recessive neurodevelopmental disorder.

PURPOSE: Developmentally regulated Guanosine-5'-triphosphate-binding protein 1 (DRG1) is a highly conserved member of a class of GTPases implicated in translation. Although the expression of mammalian DRG1 is elevated in the central nervous system during development, and its function has been implicated in fundamental cellular processes, no pathogenic germline variants have yet been identified. Here, we characterize the clinical and biochemical consequences of DRG1 variants. METHODS: We collate clinical information of 4 individuals with germline DRG1 variants and use in silico, in vitro, and cell-based studies to study the pathogenicity of these alleles. RESULTS: We identified private germline DRG1 variants, including 3 stop-gained p.Gly54∗, p.Arg140∗, p.Lys263∗, and a p.Asn248Phe missense variant. These alleles are recessively inherited in 4 affected individuals from 3 distinct families and cause a neurodevelopmental disorder with global developmental delay, primary microcephaly, short stature, and craniofacial anomalies. We show that these loss-of-function variants (1) severely disrupt DRG1 messenger RNA/protein stability in patient-derived fibroblasts, (2) impair its GTPase activity, and (3) compromise its binding to partner protein ZC3H15. Consistent with the importance of DRG1 in humans, targeted inactivation of mouse Drg1 resulted in preweaning lethality. CONCLUSION: Our work defines a new Mendelian disorder of DRG1 deficiency. This study highlights DRG1's importance for normal mammalian development and underscores the significance of translation factor GTPases in human physiology and homeostasis.

Developing fit-for-purpose funding models for rural settings: Lessons from the evaluation of a step-up/step-down service in regional Australia.

Introduction: Sub-acute mental health community services provide a bridging service between hospital and community care. There is limited understanding of the local factors that influence success, and of the funding implications of delivering services in rural areas. Methods: This paper draws from quantitative and qualitative evaluation data from a regional Western Australian service to explore these issues. Results: Consumers satisfaction with the service was high and, overall, admission to the service resulted in positive outcomes. High re-admission rates may be linked to limited community support services following discharge. Discussion: Our results suggest that outcomes may be enhanced by implementing flexible approaches that address the resource limitations of the rural context, and that the current funding model for sub-acute mental health services in rural Australian may not be fit for purpose. More needs to be understood about how these services can be better integrated with existing support services, and how they can be better funded.

Quality improvement through audit: Zuclopenthixol acetate prescribing, monitoring and patient outcomes in a regional health service.

OBJECTIVE: Prescribers' expectations of Zuclopethixol Acetate's (ZA) efficacy and tolerability are shaped by clinical experience and organisational culture; however, these expectations may not be consistent with current evidence and best practice. METHODS: Quality improvement project (QIP) through a process audit of ZA prescribing, monitoring and patient outcomes (adverse events) in order to identify issues requiring intervention to align with service standards and practices. RESULTS: QIP interventions resulted in a statistically significant shift in psychiatrist oversight, identifying high dose ZA with adverse outcomes and cessation of prescribing/administration within the Emergency Department. Clinically significant changes in patterns of prescribing were observed between pre-post intervention audits. CONCLUSION: Entrenching an evidence-based QIP approach to clinical practice can effect clinically significant patterns of practice change to improve safe prescribing and drug monitoring.

Using social network analysis approach in developing rural psychiatrist workforce.

OBJECTIVE: This study examines how rural and remote junior doctors career decisions are influenced by highly connected principles within a discipline. METHODS: Social network analysis was completed with data collected, by structured interview, with five psychiatry trainees and three early career psychiatrists in a rural location rated MM3 using the Modified Monash Model. UNICET software was used to determine the interactions between individual networks to look for overlap and common influencers. RESULTS: A single central, highly connected, psychiatrist was found at the core of the entire social network. This connector was instrumental in recruitment and retention in rural psychiatry workforce. CONCLUSION: Improving the understanding of human capital can encourage innovative solutions in developing sustainable strategies for recruiting and retaining rural psychiatry workforces.

Impaired protein hydroxylase activity causes replication stress and developmental abnormalities in humans.

Although protein hydroxylation is a relatively poorly characterized posttranslational modification, it has received significant recent attention following seminal work uncovering its role in oxygen sensing and hypoxia biology. Although the fundamental importance of protein hydroxylases in biology is becoming clear, the biochemical targets and cellular functions often remain enigmatic. JMJD5 is a "JmjC-only" protein hydroxylase that is essential for murine embryonic development and viability. However, no germline variants in JmjC-only hydroxylases, including JMJD5, have yet been described that are associated with any human pathology. Here we demonstrate that biallelic germline JMJD5 pathogenic variants are deleterious to JMJD5 mRNA splicing, protein stability, and hydroxylase activity, resulting in a human developmental disorder characterized by severe failure to thrive, intellectual disability, and facial dysmorphism. We show that the underlying cellular phenotype is associated with increased DNA replication stress and that this is critically dependent on the protein hydroxylase activity of JMJD5. This work contributes to our growing understanding of the role and importance of protein hydroxylases in human development and disease.

Rurality as a predictor of perinatal mental health and well-being in an Australian cohort.

OBJECTIVE: Perinatal emotional well-being is more than the presence or absence of depressive and anxiety disorders; it encompasses a wide range of factors that contribute to emotional well-being. This study compares perinatal well-being between women living in metropolitan and rural regions. DESIGN: Prospective, longitudinal cohort. PARTICIPANTS/SETTING: Eight hundred and six women from Victoria and Western Australia recruited before 20 weeks of pregnancy and followed up to 12 months postpartum. MAIN OUTCOME MEASURES: Rurality was assessed using the Modified Monash Model (MM Model) with 578 in metropolitan cities MM1, 185 in regional and large rural towns MM2-MM3 and 43 in rural to remote MM4-MM7. The Structured Clinical Interview for DSM-IV (SCID-IV) was administered at recruitment to assess depression, and symptoms of depression and anxiety were measured using the Edinburgh Post-natal Depression Scale and the State and Trait Anxiety Scale, respectively. Other measures included stressful events, diet, exercise, partner support, parenting and sleep. RESULTS: The prevalence of depressive disorders did not differ across rurality. There was also no difference in breastfeeding cessation, exercise, sleep or partner support. Women living in rural communities and who also had depression reported significantly higher parenting stress than metropolitan women and lower access to parenting activities. CONCLUSIONS: Our study suggests while many of the challenges of the perinatal period were shared between women in all areas, there were important differences in parenting stress and access to activities. Furthermore, these findings suggest that guidelines and interventions designed for perinatal mental health should consider rurality.

Rural workforce challenges: Why not rural psychiatry?

OBJECTIVE: The Australian psychiatry workforce is under-subscribed and highly urbanised. Currently, 90% of psychiatrists work in the cities, and there are significant projected workforce shortages of psychiatrists throughout Australia, particularly in rural and remote locations. This qualitative study explores factors influencing medical students and junior doctors' decisions to pursue a career in rural psychiatry. METHOD: Using a phenomenological approach, data were collected through semi-structured interviews and focus groups and subjected to thematic analysis. RESULTS: Sixteen participants were interviewed, 11 interviewees and five participants from two focus groups. This study identified enablers and challenges in pursuing rural psychiatry training in Australia. Clinical exposure to rural psychiatry, personal factors, rural lifestyle and workforce shortage awareness were identified as enablers. The lack of rural infrastructure, the attractiveness of urban psychiatry and the stigma toward rural psychiatry were identified as barriers. CONCLUSIONS: Australian rural psychiatry workforce remains a complex issue. Reinforcing enablers and addressing barriers identified in this study would benefit future rural workforce initiatives.

Remoteness and socioeconomic status reduce access to specialist mental health care across Australia.

OBJECTIVE: Estimate impact of socioeconomic factors and remoteness from tertiary hospital on incidence/duration of Australian mental health admissions. METHODS: Retrospective analysis of incidence/duration of public mental health unit admissions (2018-19). Covariates included Indigenous population, potentially preventable hospitalisations (PPH) and socioeconomic disadvantage. RESULTS: Regional distance from hospital was correlated with socioeconomic disadvantage (ρ: p < 0.01). Population identifying as Aboriginal or Torres Strait Islander was associated with distance from hospital, socioeconomic disadvantage and PPH (ρ: p < 0.01). Bed days per capita was explained (R2adj: 0.48) by distance and socioeconomic disadvantage (p < 0.0001). A 1% increase in distance from hospital was associated with a 0.37% decrease in per capita bed days. Admission rate per capita across Queensland and WA was explained (R2adj: 0.36) by distance, education/occupation and state (p < 0.05). Across Queensland and WA a 1% increase in distance from hospital was associated with a 0.05% decreased incidence of admission. CONCLUSIONS: Rural Australians face high mental illness burden, socioeconomic disadvantage and limited service provision. Overcoming the additional disadvantages of reduced likelihood of admission to and reduced time in hospital with increasing distance from hospital will require increased outreach proportional to remoteness.

Remote supervision in psychiatry training: Unlocking capacity and technology.

OBJECTIVE: This paper explores the literature regarding remote supervision in the context of training in psychiatry with contemporary pedagogic theory and practice and utilising telephonic and videoconference technologies to enhance education outcomes. CONCLUSION: Remote supervision may provide psychiatry trainees with a balance between autonomy and support, promote clinical and professional independence in addition to developing a specific subset of telehealth skills whilst unlocking supervisory capacity to grow the psychiatry workforce, particularly in rural and remote settings.

An evaluation of junior doctors' experience in smoking cessation training in a rural mental health setting.

Introduction: Smoking prevalence remains high amongst people with mental illness, however, they are less likely to be screened for tobacco dependence and offered treatment to quit. Smoking cessation and education training are insufficient in medical schools, despite a positive relationship between training and practice once qualified. However, the question as to whether there is adequate skill and expertise to address smoking in people with mental illness within Australian mental health settings is unclear. Furthermore, people living in rural and remote areas smoke at higher rates, quit at lower rates than those in urban areas, and experience limitations in their ability to access smoking cessation supports. The Smokers' Clinic is an initiative established in a rural Australian mental health service offering a smoking cessation service to patients and staff employed by the service. Aim: This study aims to assess the change in the knowledge and confidence of resident medical officers in their understanding of nicotine dependence, smoking cessation strategies and prescribing nicotine replacement therapy in a community mental health setting. It was hypothesized that providing education and supervised clinical experience would improve knowledge, increasing confidence and motivation in managing smoking cessation in mental health patients. The research was undertaken using data collected through a questionnaire obtained from surveying resident medical officers administering the Smokers' Clinic following a 10-week rural community mental health rotation. Materials and methods: Twenty resident medical officers completed the 10-week rotation, with 14 completing the questionnaire. Knowledge of tobacco smoking, nicotine dependence and smoking cessation interventions improved with the experience of the Smokers' Clinic during the clinical rotation. Resident medical officers were motivated to spend additional time engaged in self-directed learning and all reported continued use of acquired experience and information in their clinical work after the rotation. Conclusion: This study indicates the utility of a novel approach in delivering education, training, building clinical expertise, and facilitating sustained clinical capacity amongst junior medical staff for smoking cessation in a rural community mental health setting. It offers an efficient approach for mental health services to deliver smoking cessation services to reduce the morbidity and mortality burden associated with tobacco smoking.

Megahertz pulse trains enable multi-hit serial femtosecond crystallography experiments at X-ray free electron lasers.

The European X-ray Free Electron Laser (XFEL) and Linac Coherent Light Source (LCLS) II are extremely intense sources of X-rays capable of generating Serial Femtosecond Crystallography (SFX) data at megahertz (MHz) repetition rates. Previous work has shown that it is possible to use consecutive X-ray pulses to collect diffraction patterns from individual crystals. Here, we exploit the MHz pulse structure of the European XFEL to obtain two complete datasets from the same lysozyme crystal, first hit and the second hit, before it exits the beam. The two datasets, separated by <1 µs, yield up to 2.1 Å resolution structures. Comparisons between the two structures reveal no indications of radiation damage or significant changes within the active site, consistent with the calculated dose estimates. This demonstrates MHz SFX can be used as a tool for tracking sub-microsecond structural changes in individual single crystals, a technique we refer to as multi-hit SFX.

Rethinking Accessibility in Light of the Orange Declaration: Applying a Socio-Ecological Lens to Rural Mental Health Commissioning.

The prevalence of mental illness is a critical public health issue. In Australia, the prevalence of mental illness is similar across all settings, however, people living in rural and remote areas experience worse outcomes than their urban counterparts. Access to mental health services is critical, however, the notion of accessibility needs to be understood in the context of the uniqueness and variability of the rural experience. The Orange Declaration on Rural and Remote Mental Health recognized that rural areas face a series of interconnected challenges and called for place-specific responses and new funding models that reward collaboration and local partnerships. In this paper, we argue that recent mental health planning, policy and service development uses a narrow interpretation of the notion of accessibility that is out of step with current thinking on the heterogeneity of the rural experience. We use some examples of our own research and experience in rural Western Australia to argue that the current commissioning model is not aligned with the Orange Declaration, and remains largely metro-centric and reliant on a narrow conceptualization of service accessibility. We argue that what is needed is a dynamic, responsive, context-sensitive understanding of accessibility that is informed by the distinctiveness of rural adversity, and recognizes the heterogeneity and variability of the rural experience whilst acknowledging rural agency and social capital, and we suggest that applying a socio-ecological approach to the development of new commissioning models provides a way forward.

Cohort study comparison of Mental Health and Wellbeing Services delivered by The Royal Flying Doctor Service, across Far North and Central West Queensland.

Background: Understanding cultural differences between geographical regions is essential in delivering culturally appropriate healthcare. We aimed to describe the characteristics and outcomes of diverse clients using the Far North Mental Health and Wellbeing Service (FNS) and the Central West Health and Wellbeing Service (CWS). Methods: We conducted a cohort study within Queensland, Australia, on all clients who received a mental health therapy session at either the FNS or the CWS. Patient data was prospective data collected form July 2019 to December 2020. Findings: There were1202 clients, with a median number of individual contacts per-client of 3.0 (IQR 2.0-6.0). There was 428 (35.6% 95% CI 32.90-38.39) males and 772 (64.2% 95% CI 61.44-66.94) females with a median age across the genders of 38.0 (IQR 28.0-51.0). There was 505 (42.0% 95% CI 39.20-44.86) identifying as Indigenous and 697 (58.0% 95% CI 55.14-60.80) as non-Indigenous Australians. The FNS had a significantly higher proportion of Indigenous clients (n=484; 54.8% 95% CI 51.46-58.13) as compared to the CWS (n=21; 6.6% 95% CI 4.12-9.89). Of the 1202 clients, 946 (78.7% 95% CI 76.28-80.99) had a socio-economic classification of 'most disadvantaged', consisting of 740 (83.8%) clients from the FNS and 206 (64.6%) clients from the CWS. The majority of presentations were for neurotic, stress-related and somatoform disorders (n=568; 47.3%), followed by mood affective disorders (n=310; 25.8%). The overall number of treatments strategies employed was 10798, equalling a median of 6.0 (IQR 4.0-9.0) strategies per-client, with the leading strategies being counselling/psychosocial (n=1394; 12.9%), reflective listening (n=1191; 11.0%), and strengths based reasoning (n=1116; 10.3%). There were 511 (42.5%) clients who completed the Kessler Psychological Distress Scale (K10/K5), with 493 (41.0%) clients not offered as deemed not culturally appropriate by the treating team. The mean initial K10/K5 score was 23.7 (SD 9.4) which significantly decreased (p<0.001) to 18.0 (SD 10.0) at final consultation. Interpretation: This study highlighted client socioeconomic differences between two geographically remote mental health services. It is essential that services are regionally co-designed to ensure cultural appropriateness. Funding: No funding to declare.

Factor inhibiting HIF can catalyze two asparaginyl hydroxylations in VNVN motifs of ankyrin fold proteins.

The aspariginyl hydroxylase human factor inhibiting hypoxia-inducible factor (FIH) is an important regulator of the transcriptional activity of hypoxia-inducible factor. FIH also catalyzes the hydroxylation of asparaginyl and other residues in ankyrin repeat domain-containing proteins, including apoptosis stimulating of p53 protein (ASPP) family members. ASPP2 is reported to undergo a single FIH-catalyzed hydroxylation at Asn-986. We report biochemical and crystallographic evidence showing that FIH catalyzes the unprecedented post-translational hydroxylation of both asparaginyl residues in "VNVN" and related motifs of ankyrin repeat domains in ASPPs (i.e., ASPP1, ASPP2, and iASPP) and the related ASB11 and p18-INK4C proteins. Our biochemical results extend the substrate scope of FIH catalysis and may have implications for its biological roles, including in the hypoxic response and ASPP family function.

A rural ecosystem of recovery: Lessons from substance users' experiences of accessing services in Western Australia's South West.

INTRODUCTION: Substance use is a public health issue with a greater burden in rural areas. Barriers to accessing services are exacerbated for rural substance users, with confidentiality concerns, longer travel distances, workforce issues and limited availability of services. This paper presents results from a study exploring substance users' experiences of accessing services in Western Australia's South West. METHODS: This qualitative study was informed by phenomenology, and drew from social determinants and socio-ecological theories. Data were collected through 22 semi-structured telephone interviews with current and past substance users residing in the South West. Interviews were audio-recorded and transcripts were subjected to thematic analysis. RESULTS: Two themes were identified: readiness to engage as a three-way street; and building an ecosystem of recovery networks. Effective engagement with services required multi-level readiness. Individual readiness was strongly influenced by the social environment, while service readiness required trustworthiness and responsiveness. A number of local access barriers were identified that hindered broader system readiness. Participants experienced recovery as on-going and require an ecosystem of support with peer support at the centre and a network of healthy relationships established through meaningful connections. DISCUSSION AND CONCLUSIONS: An effective ecosystem of support for alcohol and other drugs users in the South West should include expanded access to health, community and welfare services, with an emphasis on peer-led support programs, and strong cross-sector collaboration to mitigate the access barriers operating at the broader community level. Lessons from our study can inform the development of rural ecosystems of support for alcohol and other drugs users.