The impact of pubertal stress and adult hormone exposure on the transcriptome of the developing hypothalamus.

Why individuals suffer negative consequences following stress is a complex phenomenon that is dictated by individual factors, the timing of stress within the lifespan, and when in the lifespan the consequences are measured. Women who undergo adverse childhood experiences are at risk for lasting biological consequences, including affective and stress dysregulation. We have shown that pubertal adversity is associated with a blunted hypothalamic-pituitary-adrenal axis glucocorticoid response in peripartum humans and mice. In mice, our prior examination of the paraventricular nucleus (PVN) of the hypothalamus showed that pubertal stress led to an upregulation of baseline mRNA expression of six immediate early genes (IEGs) in the PVN of adult, pregnant mice. Separately, we showed that the pregnancy-associated hormone allopregnanolone is necessary and sufficient to produce the blunted stress response phenotype in pubertally stressed mice. In the current study, we further examined a potential mechanistic role for the IEGs in the PVN. We found that in pubertally stressed adult female, but not male, mice, intra-PVN allopregnanolone was sufficient to recapitulate the baseline IEG mRNA expression profile previously observed in pubertally stressed, pregnant mice. We also examined baseline IEG mRNA expression during adolescence, where we found that IEGs have developmental trajectories that showed sex-specific disruption by pubertal stress. Altogether, these data establish that IEGs may act as a key molecular switch involved in increased vulnerability to negative outcomes in adult, pubertally stressed animals. How the factors that produce vulnerability combine throughout the lifespan is key to our understanding of the etiology of stress-related disorders.

Immediate early genes as a molecular switch for lasting vulnerability following pubertal stress in mice.

Why individuals have negative consequences following stress is a complex phenomenon that is dictated by individual factors, the timing of stress within the lifespan, and when the consequences are measured. Women who undergo adverse childhood experiences are at risk for lasting biological consequences, including affective and stress dysregulation. We have shown that pubertal adversity is associated with a blunted glucocorticoid response within the hypothalamic-pituitary-adrenal axis in both peripartum humans and mice. In mice, we examined puberty-stress reprogramming in the paraventricular nucleus (PVN) of the hypothalamus, which initiates the HPA axis response. We found that pubertal stress led to an upregulation of six immediate early genes (IEGs) in the PVN of adult, pregnant mice. Separately, we showed that the pregnancy-associated hormone allopregnanolone is necessary and sufficient to produce the blunted stress response phenotype in pubertally stressed mice. Here, we examined the response of the IEGs in the PVN to the primary disruption of pubertal stress in early adolescence and to the secondary disruption of increased allopregnanolone in pregnancy. We found that in adult female, but not male, mice previously stressed during puberty, intra-PVN allopregnanolone was sufficient to recapitulate the pubertal stress associated baseline IEG expression profile. We also examined baseline IEG expression during adolescence, where we found that IEGs have sex-specific developmental trajectories that were disrupted by pubertal stress. Altogether, these data establish that IEGs can act as a key molecular switch that leads to increased vulnerability to negative outcomes in adult, pubertally stressed animals. Understanding how the factors that produce vulnerability combine throughout the lifespan will further our understanding of the etiology of negative outcomes and will help guide both the nature and timing of potential treatments.

Patterns of mental health care provision in urban areas: A comparative analysis for local policy in the ACT.

Urbanisation presents specific mental health challenges, requiring a better understanding of service availability in urban areas for mental health care planning. Our objective is to analyse patterns of urban mental healthcare provision in Australia, and compare these with relevant national and international regions to inform urban mental healthcare policy and planning. Following a health ecosystems approach, we use a standardised service classification instrument, the Description and Evaluation of Services and DirectoriEs (DESDE), and Mental Health Care Atlases, to compare the availability, bed capacity and diversity of services providing specialised mental health or psychosocial care that are universally accessible (ie provided at no or low cost only in all relevant care sectors in four Australian and three international urban regions. We used a heuristics approach and an homogeneity test. Applicability to local policy was assessed using the Adoption Impact Ladder. Community care was less developed in Australia than internationally, except in the case of residential care in Australian Capital Territory, our reference area. Alternatives to hospitalisation were scarce across all regions. The Atlas was applicable to regional and local mental health planning. Differences in pattern of care between regions has implications for planning, equality of access to care and prioritisation of resources. An ecosystems approach is relevant to service planning in mental healthcare at local level.

Patterns of service provision in child and adolescent mental health care in Australia.

Standard description of local care provision is essential for evidence-informed planning. This study aimed to map and compare the availability and diversity of current mental health service provision for children and adolescents in Australia. We used a standardised service classification instrument, the Description and Evaluation of Services and DirectoriEs (DESDE) tool, to describe service availability in eight urban and two rural health districts in Australia. The pattern of care was compared with that available for other age groups in Australia. Outpatient care was found to be the most common type of service provision, comprising 212 (81.2%) of all services identified. Hospital care (acute and non-acute) was more available in urban than in rural areas (20 services [9.7%] vs 1 [1.8%]). The level of diversity in the types of care available for children and adolescents was lower than that for the general adult population, but slightly higher than that for older people in the same areas. Standardised comparison of the pattern of care across regions reduces ambiguity in service description and classification, enables gap analysis and can inform policy and planning.

Missing in action: the right to the highest attainable standard of mental health care.

BACKGROUND: The right to the highest attainable standard of mental health remains a distant goal worldwide. The Report of the UN Special Rapporteur on the right of all people to enjoyment of the highest attainable standard of physical and mental health pleaded the urgent need for governments to act through appropriate laws and policies. We argue that Australia is in breach of international obligations, with inadequate access to mental health services, inconsistent mental health legislation across jurisdictions and ongoing structural (systematic) and individual discrimination. DISCUSSION: Inadequate access to mental health services is a worldwide phenomenon. Australia has committed to international law obligations under the Convention on the Rights of Persons with Disabilities (CRPD) to 'promote, protect and ensure the full and equal enjoyment of all human rights and fundamental freedoms by all persons with disability, with respect to their inherent dignity'. This includes people with mental health impairment and this convention includes the right to 'the highest attainable standard of mental health'. Under the Australian Constitution, ratification of this convention enables the national government to pass laws to implement the convention obligations, and such national laws would prevail over any inconsistent state (or territory) laws governing mental health service provision. The authors argue that enabling positive rights through legislation and legally binding mental health service standards may facilitate enhanced accountability and enforcement of such rights. These steps may support critical key stakeholders to improve the standards of mental health service provision supported by the implementation of international obligations, thereby accelerating mental health system reform. Improved legislation would encourage better governance and the evolution of better services, making mental health care more accessible, without structural or individual discrimination, enabling all people to enjoy the highest attainable standard of health.

Calidad de vida y sarcopenia en pacientes adultos con insuficiencia renal crónica / Quality of life and sarcopenia in adult patients with chronic renal failure

RESUMEN Introducción: la calidad de vida puede alterarse en los pacientes con insuficiencia renal crónica, sobre todo si sufren concomitantemente de sarcopenia. Objetivo: determinar la relación entre sarcopenia y calidad de vida en pacientes adultos con insuficiencia renal crónica del Hospital Nacional (Itauguá) y Hospital Militar (Asunción) entre abril y noviembre del 2021. Metodología: se utilizó un diseño observacional, descriptivo, transversal. Se incluyó a sujetos adultos de ambos sexos, portadores de insuficiencia renal crónica. Se midieron variables antropométricas, clínicas y laboratoriales. La calidad de vida se evaluó con el cuestionario EQ-5D y la sarcopenia con la fuerza de prensión palmar y el índice de masa muscular. Los datos se sometieron a estadística descriptiva y analítica con el programa Epi Info 7™. El estudio contó con la aprobación del Comité de Ética de la Universidad Privada del Este, Paraguay. Resultados: ingresaron al estudio 62 varones con edad media 56 ± 15 años y 57 mujeres con edad media 51 ± 16 años. La más frecuente de la insuficiencia renal fue la hipertensión arterial asociada a la diabetes mellitus (45,4 %). La sarcopenia se confirmó en 38,6 % de los pacientes. La calidad de vida fue buena en 30,25 %, regular en 39,5 % y mala en 30,25 %. Conclusión: en pacientes adultos con insuficiencia renal crónica, la sarcopenia predominó en los sujetos con regular y mala calidad de vida.

ABSTRACT Introduction: the quality of life can be altered in patients with chronic renal failure, especially if they suffer concomitantly from sarcopenia. Objective: to determine the relationship between sarcopenia and quality of life in adult patients with chronic renal failure at the Hospital Nacional (Itauguá) and the Hospital Militar (Asunción) between April and November 2021. Methodology: an observational, descriptive, cross-sectional design was used. Adult subjects of both sexes, carriers of chronic renal failure were included. Anthropometric, clinical and laboratory variables were measured. Quality of life was evaluated with the EQ-5D questionnaire and sarcopenia with palm grip strength and muscle mass index. The data was submitted to descriptive and analytical statistics with the Epi Info 7™ program. The study was approved by the Ethics Committee of the Universidad Privada del Este, Paraguay. Results: 62 men with a mean age of 56 ± 15 years and 57 women with a mean age of 51 ± 16 years entered the study. The most frequent renal failure was arterial hypertension associated with diabetes mellitus (45.4 %). Sarcopenia was confirmed in 38.6 % of the patients. The quality of life was good in 30.25 %, regular in 39.5 % and bad in 30.25 %. Conclusion: in adult patients with chronic renal failure, sarcopenia prevailed in subjects with fair and poor quality of life.

Impact of Ed-LinQ: A Public Policy Strategy to Facilitate Engagement between Schools and the Mental Health Care System in Queensland, Australia.

Ed-LinQ is a mental health policy initiative to enhance the early detection and treatment of children with mental illness by improving the liaison between schools and health services in Queensland, Australia. We measured its impact from policy to practice to inform further program developments and public strategies. We followed a mixed quantitative/qualitative approach. The Adoption Impact Ladder (AIL) was used to analyse the adoption of this initiative by end-users (decision makers both in the health and education sectors) and the penetration of the initiative in the school sector. Survey respondents included representatives of schools (n = 186) and mental health providers (n = 78). In total, 63% of the school representative respondents were at least aware of the existence of the Ed-LinQ initiative, 74% were satisfied with the initiative and 28% of the respondent schools adopted the initiative to a significant extent. Adoption was higher in urban districts and in the health sector. The overall level of penetration in the school sector of Queensland was low (3%). The qualitative analysis indicated an improvement in the referral and communication processes between schools and the health sectors and the importance of funding in the implementation of the initiative. Mapping of existing programs is needed to assess the implementation of a new one as well as the design of different implementation strategies for urban and rural areas. Assessing the adoption of health policy strategies and their penetration in a target audience is critical to understand their proportional impacts across a defined ecosystem and constitutes a necessary preliminary step for the evaluation of their quality and efficiency.

Alcohol and Other Drug Service Availability, Capacity, and Diversity in Urban and Rural Australia: An Integrated Atlas.

OBJECTIVE: Variation exists in the patterns of alcohol and other drug (AOD) use and related impacts across geographic locations and over time. Understanding the existing AOD service system and the local context that it operates within is fundamental to optimize service provision. This article describes and compares the availability, placement capacity, and diversity of AOD services in urban and rural regions in Australia. METHOD: The Description and Evaluation of Services and DirectoriEs (DESDE) tool was used to categorize the service delivery system for AOD care in selected urban and rural regions in Australia. RESULTS: This study found that although AOD services (303 main types of care) were available across all study regions, there was consistently very limited availability of services targeting young people (n = 39, 13%) or older adults (n = 1, <1%). There were also very limited services addressing comorbidities. Availability and diversity of services varied across study areas. Outpatient and residential care were the most available services, whereas day care services were absent in most areas. CONCLUSIONS: By describing the capacity of identified available services within the study regions, this study provides baseline information to inform changes to policy and practice and a foundation for monitoring and modeling service changes over time. This information provides evidence useful for optimal planning. However, it should be combined with local knowledge and stakeholder expertise to ensure that local area service needs are addressed.

Comparative regulomics supports pervasive selection on gene dosage following whole genome duplication.

BACKGROUND: Whole genome duplication (WGD) events have played a major role in eukaryotic genome evolution, but the consequence of these extreme events in adaptive genome evolution is still not well understood. To address this knowledge gap, we used a comparative phylogenetic model and transcriptomic data from seven species to infer selection on gene expression in duplicated genes (ohnologs) following the salmonid WGD 80-100 million years ago. RESULTS: We find rare cases of tissue-specific expression evolution but pervasive expression evolution affecting many tissues, reflecting strong selection on maintenance of genome stability following genome doubling. Ohnolog expression levels have evolved mostly asymmetrically, by diverting one ohnolog copy down a path towards lower expression and possible pseudogenization. Loss of expression in one ohnolog is significantly associated with transposable element insertions in promoters and likely driven by selection on gene dosage including selection on stoichiometric balance. We also find symmetric expression shifts, and these are associated with genes under strong evolutionary constraints such as ribosome subunit genes. This possibly reflects selection operating to achieve a gene dose reduction while avoiding accumulation of "toxic mutations". Mechanistically, ohnolog regulatory divergence is dictated by the number of bound transcription factors in promoters, with transposable elements being one likely source of novel binding sites driving tissue-specific gains in expression. CONCLUSIONS: Our results imply pervasive adaptive expression evolution following WGD to overcome the immediate challenges posed by genome doubling and to exploit the long-term genetic opportunities for novel phenotype evolution.

Patterns of Service Provision in Older People's Mental Health Care in Australia.

Australia has a population of around 4 million people aged 65 years and over, many of whom are at risk of developing cognitive decline, mental illness, and/or psychological problems associated with physical illnesses. The aim of this study was to describe the pattern of specialised mental healthcare provision (availability, placement capacity, balance of care and diversity) for this age group in urban and rural health districts in Australia. The Description and Evaluation of Services and DirectoriEs for Long Term Care (DESDE-LTC) tool was used in nine urban and two rural health districts of the thirty-one Primary Health Networks across Australia. For the most part service provision was limited to hospital and outpatient care across all study areas. The latter was mainly restricted to health-related outpatient care, and there was a relative lack of social outpatient care. While both acute and non-acute hospital care were available in urban areas, in rural areas hospital care was limited to acute care. Limited access to comprehensive mental health care, and the uniformity in provision across areas in spite of differences in demographic, socioeconomic and health characteristics raises issues of equity in regard to psychogeriatric care in this country. Comparing patterns of mental health service provision across the age span using the same classification method allows for a better understanding of care provision and gap analysis for evidence-informed policy.

International experiences of the active period of COVID-19 - Mental health care.

AIM: To summarise commonalities and variations in the mental health response to COVID-19 across different sites and countries, with a view to better understanding key steps not only in crisis management, but for future systemic reform of mental health care. METHOD: We conducted a Rapid Synthesis and Translation Process of lessons learned from an international panel of experts, collecting on the ground experiences of the pandemic as it evolved in real time. Digital conferencing and individual interviews were used to rapidly acquire knowledge on the COVID-19 outbreak across 16 locations in Australia, Denmark, Italy, Spain, Taiwan, the UK, and the USA. RESULTS: COVID-19 has had massive impacts on mental health care internationally. Most systems were under-resourced and under-prepared, struggling to manage both existing and new clients. There were significant differences between sites, depending on the explosivity the pandemic and the readiness of the mental health system. Integrated, community mental health systems exhibited greater adaptability in contrast to services which depended on face-to-face and hospital-based care. COVID-19 has demonstrated the need for a new approach to rapid response to crisis in mental health. New decision support system tools are necessary to ensure local decision-makers can effectively respond to the enormous practical challenges posed in these circumstances. CONCLUSIONS: The process we have undertaken has generated clear lessons for mental health policymakers worldwide, beyond pandemic planning and response to guide next steps in systemic mental health reform. Key here is achieving some balance between national leadership and local context adaptation of evidence.

Rapid response to crisis: Health system lessons from the active period of COVID-19.

BACKGROUND: This paper outlines the need for a health systems approach and rapid response strategy for gathering information necessary for policy decisions during pandemics and similar crises. It suggests a new framework for assessing the phases of the pandemic. METHOD: The paper draws its information and conclusions from a rapid synthesis and translation process (RSTP) of a series of webinars and online discussions from the Pandemic-Mental Health International Network (Pan-MHIN) - policy experts from across 16 locations in Australia, Denmark, Italy, Spain, Taiwan, the UK and the USA. While the initial focus of this research was on mental health, COVID-19 has raised much broader issues and questions for health planners. RESULTS: We identified gaps affecting the capacity to respond effectively and quickly, including in relation to system indicators, the inadequacy of the prior classification of the phases of the pandemic, the absences of a healthcare ecosystem approach, and the quick shift to digital technologies. The strengths and weaknesses of COVID-19 responses across different systems, services, sites and countries been identified and compared, including both low and high impacted areas. CONCLUSIONS: There is an urgent need for managerial epidemiology based on healthcare ecosystem research encompassing multidisciplinary teams, visualization tools and decision analytics for rapid response. Policy and healthcare context played a key role in the response to COVID-19. Its severity, the containment measures and the societal response varied greatly across sites and countries. Understanding this variation is vital to assess the impact of COVID-19 in specific areas such as ageing or mental health.

Patterns of Mental Health Care in Remote Areas: Kimberley (Australia), Nunavik (Canada), and Lapland (Finland): Modèles de soins de santé mentale dans les régions éloignées: Kimberley (Australie), Nunavik (Canada) et Laponie (Finlande).

OBJECTIVE: Mental health (MH) care in remote areas is frequently scarce and fragmented and difficult to compare objectively with other areas even in the same country. This study aimed to analyze the adult MH service provision in 3 remote areas of Organization for Economic Cooperation and Development countries in the world. METHODS: We used an internationally agreed set of systems indicators, terminology, and classification of services (Description and Evaluation of Services and DirectoriEs for Long Term Care). This instrument provided a standard description of MH care provision in the Kimberley region (Australia), Nunavik (Canada), and Lapland (Finland), areas characterized by an extremely low population density and high relative rates of Indigenous peoples. RESULTS: All areas showed high rates of deprivation within their national contexts. MH services were mostly provided by the public sector supplemented by nonprofit organizations. This study found a higher provision per inhabitant of community residential care in Nunavik in relation to the other areas; higher provision of community outreach services in the Kimberley; and a lack of day services except in Lapland. Specific cultural-based services for the Indigenous population were identified only in the Kimberley. MH care in Lapland was self-sufficient, and its care pattern was similar to other Finnish areas, while the Kimberley and Nunavik differed from the standard pattern of care in their respective countries and relied partly on services located outside their boundaries for treating severe cases. CONCLUSION: We found common challenges in these remote areas but a huge diversity in the patterns of MH care. The implementation of care interventions should be locally tailored considering both the environmental characteristics and the existing pattern of service provision.

Project Synergy: co-designing technology-enabled solutions for Australian mental health services reform.

Project Synergy aims to test the potential of new and emerging technologies to enhance the quality of mental health care provided by traditional face-to-face services. Specifically, it seeks to ensure that consumers get the right care, first time (delivery of effective mental health care early in the course of illness). Using co-design with affected individuals, Project Synergy has built, implemented and evaluated an online platform to assist the assessment, feedback, management and monitoring of people with mental disorders. It also promotes the maintenance of wellbeing by collating health and social information from consumers, their supportive others and health professionals. This information is reported back openly to consumers and their service providers to promote genuine collaborative care. The online platform does not provide stand-alone medical or health advice, risk assessment, clinical diagnosis or treatment; instead, it supports users to decide what may be suitable care options. Using an iterative cycle of research and development, the first four studies of Project Synergy (2014-2016) involved the development of different types of online prototypes for young people (i) attending university; (ii) in three disadvantaged communities in New South Wales; (iii) at risk of suicide; and (iv) attending five headspace centres. These contributed valuable information concerning the co-design, build, user testing and evaluation of prototypes, as well as staff experiences during development and service quality improvements following implementation. Through ongoing research and development (2017-2020), these prototypes underpin one online platform that aims to support better multidimensional mental health outcomes for consumers; more efficient, effective and appropriate use of health professional knowledge and clinical skills; and quality improvements in mental health service delivery.

Service availability and capacity in rural mental health in Australia: Analysing gaps using an Integrated Mental Health Atlas.

OBJECTIVE: Access to services and workforce shortages are major challenges in rural areas worldwide. In order to improve access to mental health care, it is imperative to understand what services are available, what their capacity is and where existing funds might be spent to increase availability and accessibility. The aim of this study is to investigate mental health service provision in a selection of rural and remote areas across Australia by analysing service availability, placement capacity and diversity. METHOD: This research studies the health regions of Western New South Wales and Country Western Australia and their nine health areas. Service provision was analysed using the DESDE-LTC system for long-term care service description and classification that allows international comparison. Rates per 100,000 inhabitants were calculated to compare the care availability and placement capacity for children and adolescents, adults and older adults. RESULTS: The lowest diversity was found in northern Western Australia. Overall, Western New South Wales had a higher availability of non-acute outpatient services for adults, but hardly any acute outpatient services. In Country Western Australia, substantially fewer non-acute outpatient services were found, while acute services were much more common. Acute inpatient care services were more common in Western New South Wales, while sub-acute inpatient services and non-acute day care services were only found in Western New South Wales. CONCLUSION: The number and span of services in the two regions showed discrepancies both within and between regions, raising issues on the equity of access to mental health care in Australia. The standard description of the local pattern of rural mental health care and its comparison across jurisdictions is critical for evidence-informed policy planning and resource allocation.

Rice Galaxy: an open resource for plant science.

BACKGROUND: Rice molecular genetics, breeding, genetic diversity, and allied research (such as rice-pathogen interaction) have adopted sequencing technologies and high-density genotyping platforms for genome variation analysis and gene discovery. Germplasm collections representing rice diversity, improved varieties, and elite breeding materials are accessible through rice gene banks for use in research and breeding, with many having genome sequences and high-density genotype data available. Combining phenotypic and genotypic information on these accessions enables genome-wide association analysis, which is driving quantitative trait loci discovery and molecular marker development. Comparative sequence analyses across quantitative trait loci regions facilitate the discovery of novel alleles. Analyses involving DNA sequences and large genotyping matrices for thousands of samples, however, pose a challenge to non-computer savvy rice researchers. FINDINGS: The Rice Galaxy resource has shared datasets that include high-density genotypes from the 3,000 Rice Genomes project and sequences with corresponding annotations from 9 published rice genomes. The Rice Galaxy web server and deployment installer includes tools for designing single-nucleotide polymorphism assays, analyzing genome-wide association studies, population diversity, rice-bacterial pathogen diagnostics, and a suite of published genomic prediction methods. A prototype Rice Galaxy compliant to Open Access, Open Data, and Findable, Accessible, Interoperable, and Reproducible principles is also presented. CONCLUSIONS: Rice Galaxy is a freely available resource that empowers the plant research community to perform state-of-the-art analyses and utilize publicly available big datasets for both fundamental and applied science.

Genomic variation in 3,010 diverse accessions of Asian cultivated rice.

Here we analyse genetic variation, population structure and diversity among 3,010 diverse Asian cultivated rice (Oryza sativa L.) genomes from the 3,000 Rice Genomes Project. Our results are consistent with the five major groups previously recognized, but also suggest several unreported subpopulations that correlate with geographic location. We identified 29 million single nucleotide polymorphisms, 2.4 million small indels and over 90,000 structural variations that contribute to within- and between-population variation. Using pan-genome analyses, we identified more than 10,000 novel full-length protein-coding genes and a high number of presence-absence variations. The complex patterns of introgression observed in domestication genes are consistent with multiple independent rice domestication events. The public availability of data from the 3,000 Rice Genomes Project provides a resource for rice genomics research and breeding.