Genetic risk converges on regulatory networks mediating early type 2 diabetes.

Type 2 diabetes mellitus (T2D), a major cause of worldwide morbidity and mortality, is characterized by dysfunction of insulin-producing pancreatic islet ß cells1,2. T2D genome-wide association studies (GWAS) have identified hundreds of signals in non-coding and ß cell regulatory genomic regions, but deciphering their biological mechanisms remains challenging3-5. Here, to identify early disease-driving events, we performed traditional and multiplexed pancreatic tissue imaging, sorted-islet cell transcriptomics and islet functional analysis of early-stage T2D and control donors. By integrating diverse modalities, we show that early-stage T2D is characterized by ß cell-intrinsic defects that can be proportioned into gene regulatory modules with enrichment in signals of genetic risk. After identifying the ß cell hub gene and transcription factor RFX6 within one such module, we demonstrated multiple layers of genetic risk that converge on an RFX6-mediated network to reduce insulin secretion by ß cells. RFX6 perturbation in primary human islet cells alters ß cell chromatin architecture at regions enriched for T2D GWAS signals, and population-scale genetic analyses causally link genetically predicted reduced RFX6 expression with increased T2D risk. Understanding the molecular mechanisms of complex, systemic diseases necessitates integration of signals from multiple molecules, cells, organs and individuals, and thus we anticipate that this approach will be a useful template to identify and validate key regulatory networks and master hub genes for other diseases or traits using GWAS data.

Genetic effects on liver chromatin accessibility identify disease regulatory variants.

Identifying the molecular mechanisms by which genome-wide association study (GWAS) loci influence traits remains challenging. Chromatin accessibility quantitative trait loci (caQTLs) help identify GWAS loci that may alter GWAS traits by modulating chromatin structure, but caQTLs have been identified in a limited set of human tissues. Here we mapped caQTLs in human liver tissue in 20 liver samples and identified 3,123 caQTLs. The caQTL variants are enriched in liver tissue promoter and enhancer states and frequently disrupt binding motifs of transcription factors expressed in liver. We predicted target genes for 861 caQTL peaks using proximity, chromatin interactions, correlation with promoter accessibility or gene expression, and colocalization with expression QTLs. Using GWAS signals for 19 liver function and/or cardiometabolic traits, we identified 110 colocalized caQTLs and GWAS signals, 56 of which contained a predicted caPeak target gene. At the LITAF LDL-cholesterol GWAS locus, we validated that a caQTL variant showed allelic differences in protein binding and transcriptional activity. These caQTLs contribute to the epigenomic characterization of human liver and help identify molecular mechanisms and genes at GWAS loci.

Human and rat skeletal muscle single-nuclei multi-omic integrative analyses nominate causal cell types, regulatory elements, and SNPs for complex traits.

Skeletal muscle accounts for the largest proportion of human body mass, on average, and is a key tissue in complex diseases and mobility. It is composed of several different cell and muscle fiber types. Here, we optimize single-nucleus ATAC-seq (snATAC-seq) to map skeletal muscle cell-specific chromatin accessibility landscapes in frozen human and rat samples, and single-nucleus RNA-seq (snRNA-seq) to map cell-specific transcriptomes in human. We additionally perform multi-omics profiling (gene expression and chromatin accessibility) on human and rat muscle samples. We capture type I and type II muscle fiber signatures, which are generally missed by existing single-cell RNA-seq methods. We perform cross-modality and cross-species integrative analyses on 33,862 nuclei and identify seven cell types ranging in abundance from 59.6% to 1.0% of all nuclei. We introduce a regression-based approach to infer cell types by comparing transcription start site-distal ATAC-seq peaks to reference enhancer maps and show consistency with RNA-based marker gene cell type assignments. We find heterogeneity in enrichment of genetic variants linked to complex phenotypes from the UK Biobank and diabetes genome-wide association studies in cell-specific ATAC-seq peaks, with the most striking enrichment patterns in muscle mesenchymal stem cells (∼3.5% of nuclei). Finally, we overlay these chromatin accessibility maps on GWAS data to nominate causal cell types, SNPs, transcription factor motifs, and target genes for type 2 diabetes signals. These chromatin accessibility profiles for human and rat skeletal muscle cell types are a useful resource for nominating causal GWAS SNPs and cell types.

BiVO4 Photoanodes Enhanced with Metal Phosphide Co-Catalysts: Relevant Properties to Boost Photoanode Performance.

Achieving highly performant photoanodes for oxygen evolution is key to developing photoelectrochemical devices for solar water splitting. In this work, BiVO4 photoanodes are enhanced with a series of core-shell structured bimetallic nickel-cobalt phosphides (MPs), and key insights into the role of co-catalysts are provided. The best BiVO4 /Ni1.5 Co0.5 P and BiVO4 /Ni0.5 Co1.5 P photoanodes achieve a 3.5-fold increase in photocurrent compared with bare BiVO4 . It is discovered that this enhanced performance arises from a synergy between work function, catalytic activity, and capacitive ability of the MPs. Distribution of relaxation times analysis reveals that the contact between the MPs, BiVO4 , and the electrolyte gives rise to three routes for hole injection into the electrolyte, all of which are significantly improved by the presence of a second metal cation in the co-catalyst. Kinetic studies demonstrate that the significantly improved interfacial charge injection is due to a lower charge-transfer resistance, enhanced oxygen-evolution reaction kinetics, and larger surface hole concentrations, providing deeper insights into the carrier dynamics in these photoanode/co-catalyst systems for their rational design.

Attitudes toward psychedelics and psychedelic-assisted therapy among potential mental health service users and the general population in Australia.

OBJECTIVE: Despite rapid advances in psychedelic sciences and the increasing number of countries legalizing psychedelics for the treatment of mental illnesses, the attitudes, knowledge and readiness of both mental health consumers and the general population remain largely unknown. METHODS: A cross-sectional survey was conducted among Australians, targeting individuals with mental illness as potential mental health service users. A sub-sample of individuals free of mental illness was also surveyed to assess attitudes in the general population. Participants completed the Attitudes on Psychedelics Questionnaire, the Basic Knowledge of Psychedelics Test and a questionnaire by Corrigan et al. to capture attitudes toward psychedelic therapy by mental health service users. RESULTS: Of the 502 respondents, 64.5% self-identified as having a mental illness. A significant proportion favored legalizing psychedelics for medical use (43%) and were open to their use (52.4%), yet fewer viewed their effects positively (24%) or considered them safe (33%). Most participants reported to be psychedelic naive (61%). Participants with mental illness had significantly more experience with psychedelics than participant free of mental illness (44.1% vs 29.7%). Experience, perceived knowledge and actual knowledge significantly predicted attitudes toward legalization, effects, risks and openness to psychedelics. CONCLUSIONS: While a large proportion of Australians are in favor of legalizing psychedelics for medical purposes, concerns about safety remain. People with self-identified mental illness, those with previous recreational psychedelic experience and those with greater knowledge of psychedelics were more likely to have positive attitudes toward psychedelics and psychedelic-assisted therapy.

Defining the passage of wisdom: A taxonomy of supervision for RANZCP trainees and Fellows.

OBJECTIVE: Trainees and Fellows of the Royal Australian and New Zealand College of Psychiatrists (RANZCP) work in complex interpersonal and organisational environments. Engagement in supervision can be a helpful way for trainees and Fellows to achieve interpersonal, professional, and organisational success. Supervision comes in many forms depending on the stage and state of one's career. An awareness of different supervision models is relevant to trainees' understanding of what is expected of them and their supervisors in their work and educational contexts. This paper explores the taxonomy of supervision models available to RANZCP trainees and Fellows in Australia and New Zealand. CONCLUSION: Supervision is a heterogeneous concept with multiple aims, outcomes, and processes that change with ones' stage of career.

A systematic review of modified electroconvulsive therapy (ECT) to treat delirium.

BACKGROUND: Delirium is costly for patients, carers, and healthcare systems. In addition, non-pharmacological and pharmacological management of delirium is challenging. Electroconvulsive therapy (ECT) has been proposed and used as an anecdotal treatment of delirium in clinical practice. However, the efficacy and safety of this approach are not well understood. OBJECTIVE: To synthesise and review the evidence relating to the safety and efficacy of ECT as a treatment for delirium. METHODS: A systematic review was completed according to PRISMA guidelines using the PubMed, CINAHL, Cochrane Library, and PsycINFO databases. Studies were eligible for inclusion if modified ECT was used to treat delirium symptoms. ECT for delirium in people with neuroleptic malignant syndrome, catatonia, or confusional states associated with acute primary psychiatric conditions were excluded. All included records were first ranked using the hierarchy of evidence-based medicine; quality was then assessed using the Joanna Briggs critical appraisal checklists. Pooled data across the cases identified were analysed using descriptive statistics. RESULTS: Of 1226 records screened, 10 studies met inclusion criteria: six case reports, three case series, and one quasi-experimental study. The literature base was of mixed quality. A single quasi-experimental study was assessed to be of 'fair' quality, the remainder of the case series and case reports were rated as 'poor' to 'fair' quality. A total of only 40 individual people with delirium who were treated with ECT were identified. In 33/40 cases, the aetiology of delirium was substance withdrawal. The number of ECT treatments administered ranged from 1 to 13. ECT was reported to positively contribute towards treatment of delirium in all cases, although objective measures of improvement were reported in only 6/13 patient cases from case reports and case series (46%). The singular quasi-experimental study reported a statistically significant decrease in duration of delirium, time spent in physical restraint, and in benzodiazepine requirement when ECT was used as an adjunct in benzodiazepine withdrawal delirium. When adverse events were described these included mild confusion and memory deficits; all were reported as time limited and reversible. Considerable limitations in the quality of the evidence base were identified, including the risk of selection, publication and reporting bias. Much data reporting on safety and efficacy of ECT in delirium was missing. CONCLUSION: There is insufficient literature to support modified ECT as a clinical treatment for delirium. The few studies identified were generally of weak evidence lacking important data on safety and objective outcome measures, and not including populations with broad delirium aetiologies. Further research using more robust methodologies and broader populations (age, aetiology) of people with delirium treated with ECT is needed.

Location of Artinite (Mg2CO3(OH)2·3H2O) within the MgO-CO2-H2O system using ab initio thermodynamics.

The MgO-CO2-H2O system have a variety of important industrial applications including in catalysis, immobilisation of radionuclides and heavy metals, construction, and mineralisation and permanent storage of anthropogenic CO2. Here, we develop a computational approach to generate phase stability plots for the MgO-CO2-H2O system that do not rely on traditional experimental corrections for the solid phases. We compare the predictions made by several dispersion-corrected density-functional theory schemes, and we include the temperature-dependent Gibbs free energy through the quasi-harmonic approximation. We locate the Artinite phase (Mg2CO3(OH)2·3H2O) within the MgO-CO2-H2O phase stability plot, and we demonstrate that this widely-overlooked hydrated and carbonated phase is metastable and can be stabilised by inhibiting the formation of fully-carbonated stable phases. Similar considerations may apply more broadly to other lesser known phases. These findings provide new insight to explain conflicting results from experimental studies, and demonstrate how this phase can potentially be stabilised by optimising the synthesis conditions.

Comparative Effectiveness of Integrated Peer Support and Clinical Staffing Models for Community-Based Residential Mental Health Rehabilitation: A Prospective Observational Study.

This observational study compared the outcomes of consumers receiving community-based residential mental health rehabilitation support in Australia under a clinical staffing model and an integrated staffing model where Peer Support Workers are the majority component of the staffing profile. Reliable and clinically significant (RCS) change between admission and discharge in functional and clinical assessment measures were compared for consumers receiving care under the clinical (n = 52) and integrated (n = 93) staffing models. Covariate analyses examined the impact of known confounders on the outcomes of the staffing model groups. No statistically significant differences in RCS improvement were identified between the staffing models. However, logistic regression modelling showed that consumers admitted under the integrated staffing model were more likely to experience reliable improvement in general psychiatric symptoms and social functioning. The findings support the clinical and integrated staffing models achieving at least equivalent outcomes for community-based residential rehabilitation services consumers.

Staff Experiences of Integrating Peer Support Workers and Clinical Staff in Community-Based Residential Mental Health Rehabilitation: A Pragmatic Grounded Theory Analysis.

Mental health services are increasingly incorporating the views and expertise of people with a lived experience of mental illness in service delivery. A novel approach to this is the 'integrated staffing model' being trialled at two Australian public residential mental health rehabilitation services (Community Care Units, CCUs) where peer support workers (PSWs) occupy the majority of staff roles and work alongside clinicians. Semi-structured interviews were completed with fifteen staff 12-to-18-months after service commencement. Transcripts were analysed following principles of grounded theory analysis. Key emergent themes were: (1) recovery is a deeply personal and non-linear process; (2) The CCU as a transitional learning environment; (3) the integrated staffing model facilitates an effective rehabilitation team; and (4) coming together under the integrated staffing model required a steep learning curve. The findings suggest that the integrated staffing approach may provide a pathway to facilitate the meaningful inclusion of PSWs in rehabilitation settings.

A guide to support trainee's success in the psychotherapy written case submission.

OBJECTIVE: Many trainees find the Psychotherapy Written Case (PWC) requirement of the Royal Australian and New Zealand College of Psychiatrists training program challenging. The skills developed and assessed through this experience are critical to the competencies expected of a psychiatrist. However, the process of psychodynamic psychotherapy is often dramatically different from the expectations associated with early clinical placements in acute psychiatric settings. To support trainees in achieving success in the PWC, a guide to the written report was developed based on a review of existing resources and various stakeholder perspectives. CONCLUSIONS: The submission should reflect a training case rather than an idealised or fictionalised story attempting to demonstrate the therapist's competence. The PWC submission must meet the requirements of a general psychiatric report and provide a considered reflection on the experience of the novice therapist.

Examining the outcomes of the first one hundred residents in a community based residential rehabilitation unit for people affected by severe and persistent mental illness.

OBJECTIVE: Community-based residential rehabilitation for people experiencing severe and persistent mental illness (SPMI) is increasingly available as an alternative to psychiatric inpatient care. Understanding who accesses these services and their outcomes will inform the optimal allocation of limited public mental health resources. METHOD: This retrospective cohort study explored the outcomes of the first 100 consumers supported by a new Australian Community Care Unit (CCU). The primary outcome focus was acute mental health service use (emergency department presentations, acute mental health inpatient admission days), and secondary outcome foci were accommodation independence and substance use. RESULTS: When the 365 days before and after CCU support were compared, significant reductions in acute mental health bed days were observed (22 days, W = 3.373, p = .001); greater reductions were noted for those staying >182 days (31 days, W = 3.373, p = .001). Additionally, significant improvements in accommodation independence were found, (W = 3.373, p = .001). CONCLUSION: CCU consumers experienced reductions in acute mental health inpatient service use and improved accommodation independence. These observations are consistent with the intended functioning of the residential rehabilitation service.

Formulation in psychiatry - a guide to developing competence.

OBJECTIVE: This paper highlights the importance of psychiatric formulation and provides guidance to those learning the art of formulation. To achieve this, we explore the guidance on formulation that has been previously published in Australasian Psychiatry, identify the key components of psychiatric formulation, and outline an approach to comprehensive formulation in routine clinical practice. CONCLUSION: Formulation is the foundation of good psychiatric practice but presents a considerable challenge to the novice practitioner. Understanding the ingredients of formulation and a method for meaningfully putting these together will guide deliberate practice to learn the art of psychiatric formulation.

ACE2 expression in adipose tissue is associated with cardio-metabolic risk factors and cell type composition-implications for COVID-19.

BACKGROUND: COVID-19 severity varies widely. Although some demographic and cardio-metabolic factors, including age and obesity, are associated with increasing risk of severe illness, the underlying mechanism(s) are uncertain. SUBJECTS/METHODS: In a meta-analysis of three independent studies of 1471 participants in total, we investigated phenotypic and genetic factors associated with subcutaneous adipose tissue expression of Angiotensin I Converting Enzyme 2 (ACE2), measured by RNA-Seq, which acts as a receptor for SARS-CoV-2 cellular entry. RESULTS: Lower adipose tissue ACE2 expression was associated with multiple adverse cardio-metabolic health indices, including type 2 diabetes (T2D) (P = 9.14 × 10-6), obesity status (P = 4.81 × 10-5), higher serum fasting insulin (P = 5.32 × 10-4), BMI (P = 3.94 × 10-4), and lower serum HDL levels (P = 1.92 × 10-7). ACE2 expression was also associated with estimated proportions of cell types in adipose tissue: lower expression was associated with a lower proportion of microvascular endothelial cells (P = 4.25 × 10-4) and higher proportion of macrophages (P = 2.74 × 10-5). Despite an estimated heritability of 32%, we did not identify any proximal or distal expression quantitative trait loci (eQTLs) associated with adipose tissue ACE2 expression. CONCLUSIONS: Our results demonstrate that individuals with cardio-metabolic features known to increase risk of severe COVID-19 have lower background ACE2 levels in this highly relevant tissue. Reduced adipose tissue ACE2 expression may contribute to the pathophysiology of cardio-metabolic diseases, as well as the associated increased risk of severe COVID-19.

The genetic architecture of type 2 diabetes.

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.

Characteristics of people on community treatment orders in Australia: Data from the 2010 National Survey of High Impact Psychosis.

OBJECTIVE: Existing evidence on factors associated with community treatment order placement is largely restricted to administrative data. We utilised the data from a large nationally representative sample to compare the demographic, clinical, social functioning, substance use and service utilisation profiles of people living with psychosis under community treatment orders with those who were not. METHODS: Participants were grouped based on whether they had been subject to a community treatment order in the past 12 months or not. We conducted logistic regressions to examine demographic, clinical, social functioning, substance use and service utilisation profiles associated with the two groups. RESULTS: People who had recently been subject to community treatment orders were more likely to be treated with long-acting injectable antipsychotics and lacked insight but were less likely to report suicidal ideation. They also had higher psychiatric inpatient admission rates but a lower frequency of general practitioner visits. CONCLUSION: People on community treatment orders in Australia may differ from those who are not under a community treatment order in their treatment needs. Resources and care provision must match the needs of this particularly vulnerable group.

Guidance for providing effective feedback in clinical supervision in postgraduate medical education: a systematic review.

The primary aim was to systematically review the empirical evidence relating to models and guidance for providing effective feedback in clinical supervision occurring in postgraduate medical education contexts. A secondary aim was to identify the common and differentiating components of models and guidance for providing effective feedback in this context. A systematic review was conducted. Fifty-one records met the inclusion criteria, including 12 empirical studies. Empirical records meeting inclusion criteria were critically appraised. Qualitative content analysis was applied to the guidance on effective and ineffective feedback provision to identify key principles. A composite model was created synthesising the guidance identified for providing effective feedback. The evidence supporting specific models and guidance in postgraduate medical education was limited. However, there is evidence to support all of the commonly identified principles. In addition, a consensus about the principles of effective feedback in clinical supervision in postgraduate medical education was found.

Integrative analysis of gene expression, DNA methylation, physiological traits, and genetic variation in human skeletal muscle.

We integrate comeasured gene expression and DNA methylation (DNAme) in 265 human skeletal muscle biopsies from the FUSION study with >7 million genetic variants and eight physiological traits: height, waist, weight, waist-hip ratio, body mass index, fasting serum insulin, fasting plasma glucose, and type 2 diabetes. We find hundreds of genes and DNAme sites associated with fasting insulin, waist, and body mass index, as well as thousands of DNAme sites associated with gene expression (eQTM). We find that controlling for heterogeneity in tissue/muscle fiber type reduces the number of physiological trait associations, and that long-range eQTMs (>1 Mb) are reduced when controlling for tissue/muscle fiber type or latent factors. We map genetic regulators (quantitative trait loci; QTLs) of expression (eQTLs) and DNAme (mQTLs). Using Mendelian randomization (MR) and mediation techniques, we leverage these genetic maps to predict 213 causal relationships between expression and DNAme, approximately two-thirds of which predict methylation to causally influence expression. We use MR to integrate FUSION mQTLs, FUSION eQTLs, and GTEx eQTLs for 48 tissues with genetic associations for 534 diseases and quantitative traits. We identify hundreds of genes and thousands of DNAme sites that may drive the reported disease/quantitative trait genetic associations. We identify 300 gene expression MR associations that are present in both FUSION and GTEx skeletal muscle and that show stronger evidence of MR association in skeletal muscle than other tissues, which may partially reflect differences in power across tissues. As one example, we find that increased RXRA muscle expression may decrease lean tissue mass.

Multi-omic profiling of pituitary thyrotropic cells and progenitors.

BACKGROUND: The pituitary gland is a neuroendocrine organ containing diverse cell types specialized in secreting hormones that regulate physiology. Pituitary thyrotropes produce thyroid-stimulating hormone (TSH), a critical factor for growth and maintenance of metabolism. The transcription factors POU1F1 and GATA2 have been implicated in thyrotrope fate, but the transcriptomic and epigenomic landscapes of these neuroendocrine cells have not been characterized. The goal of this work was to discover transcriptional regulatory elements that drive thyrotrope fate. RESULTS: We identified the transcription factors and epigenomic changes in chromatin that are associated with differentiation of POU1F1-expressing progenitors into thyrotropes using cell lines that represent an undifferentiated Pou1f1 lineage progenitor (GHF-T1) and a committed thyrotrope line that produces TSH (TαT1). We compared RNA-seq, ATAC-seq, histone modification (H3K27Ac, H3K4Me1, and H3K27Me3), and POU1F1 binding in these cell lines. POU1F1 binding sites are commonly associated with bZIP transcription factor consensus binding sites in GHF-T1 cells and Helix-Turn-Helix (HTH) or basic Helix-Loop-Helix (bHLH) factors in TαT1 cells, suggesting that these classes of transcription factors may recruit or cooperate with POU1F1 binding at unique sites. We validated enhancer function of novel elements we mapped near Cga, Pitx1, Gata2, and Tshb by transfection in TαT1 cells. Finally, we confirmed that an enhancer element near Tshb can drive expression in thyrotropes of transgenic mice, and we demonstrate that GATA2 enhances Tshb expression through this element. CONCLUSION: These results extend the ENCODE multi-omic profiling approach to the pituitary gland, which should be valuable for understanding pituitary development and disease pathogenesis.

Estimated Reduction in the Burden of Nontyphoidal Salmonella Illness in Canada Circa 2019.

Nontyphoidal Salmonella (NTS) is a leading cause of acute gastrointestinal illness in Canada, and reported cases have been on the rise since the early 2000s. To address this trend, agri-food industry partners and government have worked to identify and implement interventions, guided by the enhanced information provided by whole-genome sequencing, to reduce the incidence of NTS. A substantial reduction in the number of NTS cases reported occurred in 2019. Due to underreporting and underdiagnosis factors, the observed decrease in the number of reported cases represents a fraction of the true number of illnesses averted in the community. The objective of this study was to: (1) use burden of illness estimation methodologies to estimate the true number of NTS illnesses, hospitalizations, and deaths prevented, and (2) estimate the economic savings associated with the prevention of these cases. Compared with the previous 5 years, there were an estimated 25,821 fewer illnesses, 213 fewer hospitalizations, and 2 fewer deaths attributable to NTS in 2019. This corresponds to an estimated reduction of 26.9 million Canadian dollars in the economic burden of NTS. Although causality cannot be proven by this study, the findings are suggestive that the strategically implemented suite of public health actions, including genomic-based surveillance, policy changes, and interventions by the government and industry, were successful in reducing the economic and health burden of NTS infections in Canada.