HELLS and PRDM9 form a pioneer complex to open chromatin at meiotic recombination hot spots.

Chromatin barriers prevent spurious interactions between regulatory elements and DNA-binding proteins. One such barrier, whose mechanism for overcoming is poorly understood, is access to recombination hot spots during meiosis. Here we show that the chromatin remodeler HELLS and DNA-binding protein PRDM9 function together to open chromatin at hot spots and provide access for the DNA double-strand break (DSB) machinery. Recombination hot spots are decorated by a unique combination of histone modifications not found at other regulatory elements. HELLS is recruited to hot spots by PRDM9 and is necessary for both histone modifications and DNA accessibility at hot spots. In male mice lacking HELLS, DSBs are retargeted to other sites of open chromatin, leading to germ cell death and sterility. Together, these data provide a model for hot spot activation in which HELLS and PRDM9 form a pioneer complex to create a unique epigenomic environment of open chromatin, permitting correct placement and repair of DSBs.

Variation in histone configurations correlates with gene expression across nine inbred strains of mice.

The Diversity Outbred (DO) mice and their inbred founders are widely used models of human disease. However, although the genetic diversity of these mice has been well documented, their epigenetic diversity has not. Epigenetic modifications, such as histone modifications and DNA methylation, are important regulators of gene expression and, as such, are a critical mechanistic link between genotype and phenotype. Therefore, creating a map of epigenetic modifications in the DO mice and their founders is an important step toward understanding mechanisms of gene regulation and the link to disease in this widely used resource. To this end, we performed a strain survey of epigenetic modifications in hepatocytes of the DO founders. We surveyed four histone modifications (H3K4me1, H3K4me3, H3K27me3, and H3K27ac), as well as DNA methylation. We used ChromHMM to identify 14 chromatin states, each of which represents a distinct combination of the four histone modifications. We found that the epigenetic landscape is highly variable across the DO founders and is associated with variation in gene expression across strains. We found that epigenetic state imputed into a population of DO mice recapitulated the association with gene expression seen in the founders, suggesting that both histone modifications and DNA methylation are highly heritable mechanisms of gene expression regulation. We illustrate how DO gene expression can be aligned with inbred epigenetic states to identify putative cis-regulatory regions. Finally, we provide a data resource that documents strain-specific variation in the chromatin state and DNA methylation in hepatocytes across nine widely used strains of laboratory mice.

Identification of Arhgef12 and Prkci as genetic modifiers of retinal dysplasia in the Crb1rd8 mouse model.

Mutations in the apicobasal polarity gene CRB1 lead to diverse retinal diseases, such as Leber congenital amaurosis, cone-rod dystrophy, retinitis pigmentosa (with and without Coats-like vasculopathy), foveal retinoschisis, macular dystrophy, and pigmented paravenous chorioretinal atrophy. Limited correlation between disease phenotypes and CRB1 alleles, and evidence that patients sharing the same alleles often present with different disease features, suggest that genetic modifiers contribute to clinical variation. Similarly, the retinal phenotype of mice bearing the Crb1 retinal degeneration 8 (rd8) allele varies with genetic background. Here, we initiated a sensitized chemical mutagenesis screen in B6.Cg-Crb1rd8/Pjn, a strain with a mild clinical presentation, to identify genetic modifiers that cause a more severe disease phenotype. Two models from this screen, Tvrm266 and Tvrm323, exhibited increased retinal dysplasia. Genetic mapping with high-throughput exome and candidate-gene sequencing identified causative mutations in Arhgef12 and Prkci, respectively. Epistasis analysis of both strains indicated that the increased dysplastic phenotype required homozygosity of the Crb1rd8 allele. Retinal dysplastic lesions in Tvrm266 mice were smaller and caused less photoreceptor degeneration than those in Tvrm323 mice, which developed an early, large diffuse lesion phenotype. At one month of age, Müller glia and microglia mislocalization at dysplastic lesions in both modifier strains was similar to that in B6.Cg-Crb1rd8/Pjn mice but photoreceptor cell mislocalization was more extensive. External limiting membrane disruption was comparable in Tvrm266 and B6.Cg-Crb1rd8/Pjn mice but milder in Tvrm323 mice. Immunohistological analysis of mice at postnatal day 0 indicated a normal distribution of mitotic cells in Tvrm266 and Tvrm323 mice, suggesting normal early development. Aberrant electroretinography responses were observed in both models but functional decline was significant only in Tvrm323 mice. These results identify Arhgef12 and Prkci as modifier genes that differentially shape Crb1-associated retinal disease, which may be relevant to understanding clinical variability and underlying disease mechanisms in humans.

Efficacy of a short message service brief contact intervention (SMS-SOS) in reducing repetition of hospital-treated self-harm: randomised controlled trial.

BACKGROUND: Hospital-treated self-harm is common and costly, and is associated with repeated self-harm and suicide. AIMS: To investigate the effectiveness of a brief contact intervention delivered via short message service (SMS) text messages in reducing hospital-treated self-harm re-presentations in three hospitals in Sydney (2017-2019), Australia. Trial registration number: ACTRN12617000607370. METHOD: A randomised controlled trial with parallel arms allocated 804 participants presenting with self-harm, stratified by previous self-harm, to a control condition of treatment as usual (TAU) (n = 431) or an intervention condition of nine automated SMS contacts (plus TAU) (n = 373), over 12 months following the index self-harm episode. The primary outcomes were (a) repeat self-harm event rate (number of self-harm events per person per year) at 6-, 12- and 24-month follow-up and (b) the time to first repeat at 24-month follow-up. RESULTS: The event rate for self-harm repetition was lower for the SMS compared with TAU group at 6 months (IRR = 0.79, 95% CI 0.61-1.01), 12 months (IRR = 0.78, 95% CI 0.64-0.95) and 24 months (IRR = 0.78, 95% CI 0.66-0.91). There was no difference between the SMS and TAU groups in the time to first repeat self-harm event over 24 months (HR = 0.96, 95% CI 0.72-1.26). There were four suicides in the TAU group and none in the SMS group. CONCLUSIONS: The 22% reduction in repetition of hospital-treated self-harm was clinically meaningful. SMS text messages are an inexpensive, scalable and universal intervention that can be used in hospital-treated self-harm populations but further work is needed to establish efficacy and cost-effectiveness across settings.

3D bioengineered neural tissue generated from patient-derived iPSCs mimics time-dependent phenotypes and transcriptional features of Alzheimer's disease.

Several iPSC-derived three-dimensional (3D) cultures have been generated to model Alzheimer's disease (AD). While some AD-related phenotypes have been identified across these cultures, none of them could recapitulate multiple AD-related hallmarks in one model. To date, the transcriptomic features of these 3D models have not been compared with those of human AD brains. However, these data are crucial to understanding the pertinency of these models for studying AD-related pathomechanisms over time. We developed a 3D bioengineered model of iPSC-derived neural tissue that combines a porous scaffold composed of silk fibroin protein with an intercalated collagen hydrogel to support the growth of neurons and glial cells into complex and functional networks for an extended time, a fundamental requisite for aging studies. Cultures were generated from iPSC lines obtained from two subjects carrying the familial AD (FAD) APP London mutation, two well-studied control lines, and an isogenic control. Cultures were analyzed at 2 and 4.5 months. At both time points, an elevated Aß42/40 ratio was detected in conditioned media from FAD cultures. However, extracellular Aß42 deposition and enhanced neuronal excitability were observed in FAD culture only at 4.5 months, suggesting that extracellular Aß deposition may trigger enhanced network activity. Remarkably, neuronal hyperexcitability has been described in AD patients early in the disease. Transcriptomic analysis revealed the deregulation of multiple gene sets in FAD samples. Such alterations were strikingly similar to those observed in human AD brains. These data provide evidence that our patient-derived FAD model develops time-dependent AD-related phenotypes and establishes a temporal relation among them. Furthermore, FAD iPSC-derived cultures recapitulate transcriptomic features of AD patients. Thus, our bioengineered neural tissue represents a unique tool to model AD in vitro over time.

Occupational nerve injuries.

Occupational nerve injuries span a broad array of pathologies and contribute toward functional limitation, disability, and economic impact. Early and accurate recognition, treatment, and management of workplace factors rely on a thorough understanding of the anatomic and biomechanical factors that drive nerve injury. This review explores the interplay between anatomy, biomechanics, and nerve pathology common to occupational nerve injury and provides the treating physician with a rational, evidence-based approach to diagnosis and to occupational aspects of management. Assessment of potential occupational nerve injury begins with a detailed understanding of the employee's work duties through a biomechanical lens. One must consider likelihood of occupational causation while accounting for predisposing conditions or preexisting symptoms. Beyond overt crush injury or laceration, potential mechanisms of nerve injury, with effects compounded over time, include compression, stretch, vibration, and repetitive or high-force movements of regional muscles and joints. Injury often occurs at nerve locations that experience higher pressures, changes in pressure over time, or abrupt changes in trajectory, often near a tethered point. This understanding, coupled with condition-specific knowledge presented in this review, equips managing physicians to diagnose occupational nerve injury and enhance treatment recommendations with rational activity modifications or equipment that can protect the nerve or decrease likelihood of continued injury. Long-term management often involves follow-up to assess effectiveness of interventions in the setting of the work environment, with gradual progression of the worker toward return to unrestricted duty or to a point of maximal medical improvement.

PrEP prescription in indiana 2017-2022: Implications for clinical practice.

The Ending the HIV Epidemic initiative is poised to eradicate HIV through increasing screening and linkage to care. Despite this, the rate of HIV testing remains inadequate, and effective preventive measures like pre-exposure prophylaxis (PrEP) are not adequately prescribed. A retrospective chart review was conducted to include 2017 through July 2022 from a large nonprofit health care system in the Midwest. Inclusion criteria included an HIV-negative diagnosis between 2017 and July 2022. Additional information includes gender, age, race/ethnicity, the primary payment method, the facility where screening occurred, history of PrEP prescription, and the provider who documented sexual health screening. Most patients were female (73%, n = 3366), followed by 27% (n = 1242) who identified as male. The majority identified as white (52.4%, n = 2415), and patients who identified as Black represented 45.3% (n = 2087) of the sample. Of the participants in the sample, n = 3030 (65.8%) did not have a documented sexual health assessment at the time of HIV screening. Black patients were 0.40 times less likely to report a PrEP prescription than their white counterparts. Patients screened by the provider and identified with infectious disease via a sexual mode of transmission demonstrated three times increased odds of being prescribed PrEP. This research highlights the importance of updating medical records systems to capture salient sexual health factors. Ongoing professional development should be made readily available so providers can conduct comprehensive sexual health assessments.

Gene replacement-Alzheimer's disease (GR-AD): Modeling the genetics of human dementias in mice.

INTRODUCTION: Genetic studies conducted over the past four decades have provided us with a detailed catalog of genes that play critical roles in the etiology of Alzheimer's disease (AD) and related dementias (ADRDs). Despite this progress, as a field we have had only limited success in incorporating this rich complexity of human AD/ADRD genetics findings into our animal models of these diseases. Our primary goal for the gene replacement (GR)-AD project is to develop mouse lines that model the genetics of AD/ADRD as closely as possible. METHODS: To do this, we are generating mouse lines in which the genes of interest are precisely and completely replaced in the mouse genome by their full human orthologs. RESULTS: Each model set consists of a control line with a wild-type human allele and variant lines that precisely match the human genomic sequence in the control line except for a high-impact pathogenic mutation or risk variant.

Metabolomics profiling reveals distinct, sex-specific signatures in serum and brain metabolomes in mouse models of Alzheimer's disease.

INTRODUCTION: Increasing evidence suggests that metabolic impairments contribute to early Alzheimer's disease (AD) mechanisms and subsequent dementia. Signals in metabolic pathways conserved across species can facilitate translation. METHODS: We investigated differences in serum and brain metabolites between the early-onset 5XFAD and late-onset LOAD1 (APOE4.Trem2*R47H) mouse models of AD to C57BL/6J controls at 6 months of age. RESULTS: We identified sex differences for several classes of metabolites, such as glycerophospholipids, sphingolipids, and amino acids. Metabolic signatures were notably different between brain and serum in both mouse models. The 5XFAD mice exhibited stronger differences in brain metabolites, whereas LOAD1 mice showed more pronounced differences in serum. DISCUSSION: Several of our findings were consistent with results in humans, showing glycerophospholipids reduction in serum of apolipoprotein E (apoE) ε4 carriers and replicating the serum metabolic imprint of the APOE ε4 genotype. Our work thus represents a significant step toward translating metabolic dysregulation from model organisms to human AD. HIGHLIGHTS: This was a metabolomic assessment of two mouse models relevant to Alzheimer's disease. Mouse models exhibit broad sex-specific metabolic differences, similar to human study cohorts. The early-onset 5XFAD mouse model primarily alters brain metabolites while the late-onset LOAD1 model primarily changes serum metabolites. Apolipoprotein E (apoE) ε4 mice recapitulate glycerophospolipid signatures of human APOE ε4 carriers in both brain and serum.

Assessment of neurovascular uncoupling: APOE status is a key driver of early metabolic and vascular dysfunction.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia worldwide, with apolipoprotein Eε4 (APOEε4) being the strongest genetic risk factor. Current clinical diagnostic imaging focuses on amyloid and tau; however, new methods are needed for earlier detection. METHODS: PET imaging was used to assess metabolism-perfusion in both sexes of aging C57BL/6J, and hAPOE mice, and were verified by transcriptomics, and immunopathology. RESULTS: All hAPOE strains showed AD phenotype progression by 8 months, with females exhibiting the regional changes, which correlated with GO-term enrichments for glucose metabolism, perfusion, and immunity. Uncoupling analysis revealed APOEε4/ε4 exhibited significant Type-1 uncoupling (↓ glucose uptake, ↑ perfusion) at 8 and 12 months, while APOEε3/ε4 demonstrated Type-2 uncoupling (↑ glucose uptake, ↓ perfusion), while immunopathology confirmed cell specific contributions. DISCUSSION: This work highlights APOEε4 status in AD progression manifests as neurovascular uncoupling driven by immunological activation, and may serve as an early diagnostic biomarker. HIGHLIGHTS: We developed a novel analytical method to analyze PET imaging of 18F-FDG and 64Cu-PTSM data in both sexes of aging C57BL/6J, and hAPOEε3/ε3, hAPOEε4/ε4, and hAPOEε3/ε4 mice to assess metabolism-perfusion profiles termed neurovascular uncoupling. This analysis revealed APOEε4/ε4 exhibited significant Type-1 uncoupling (decreased glucose uptake, increased perfusion) at 8 and 12 months, while APOEε3/ε4 demonstrated significant Type-2 uncoupling (increased glucose uptake, decreased perfusion) by 8 months which aligns with immunopathology and transcriptomic signatures. This work highlights that there may be different mechanisms underlying age related changes in APOEε4/ε4 compared with APOEε3/ε4. We predict that these changes may be driven by immunological activation and response, and may serve as an early diagnostic biomarker.

In vivo validation of late-onset Alzheimer's disease genetic risk factors.

INTRODUCTION: Genome-wide association studies have identified over 70 genetic loci associated with late-onset Alzheimer's disease (LOAD), but few candidate polymorphisms have been functionally assessed for disease relevance and mechanism of action. METHODS: Candidate genetic risk variants were informatically prioritized and individually engineered into a LOAD-sensitized mouse model that carries the AD risk variants APOE ε4/ε4 and Trem2*R47H. The potential disease relevance of each model was assessed by comparing brain transcriptomes measured with the Nanostring Mouse AD Panel at 4 and 12 months of age with human study cohorts. RESULTS: We created new models for 11 coding and loss-of-function risk variants. Transcriptomic effects from multiple genetic variants recapitulated a variety of human gene expression patterns observed in LOAD study cohorts. Specific models matched to emerging molecular LOAD subtypes. DISCUSSION: These results provide an initial functionalization of 11 candidate risk variants and identify potential preclinical models for testing targeted therapeutics. HIGHLIGHTS: A novel approach to validate genetic risk factors for late-onset AD (LOAD) is presented. LOAD risk variants were knocked in to conserved mouse loci. Variant effects were assayed by transcriptional analysis. Risk variants in Abca7, Mthfr, Plcg2, and Sorl1 loci modeled molecular signatures of clinical disease. This approach should generate more translationally relevant animal models.

Genetic diversity promotes resilience in a mouse model of Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disorder with multifactorial etiology, including genetic factors that play a significant role in disease risk and resilience. However, the role of genetic diversity in preclinical AD studies has received limited attention. METHODS: We crossed five Collaborative Cross strains with 5xFAD C57BL/6J female mice to generate F1 mice with and without the 5xFAD transgene. Amyloid plaque pathology, microglial and astrocytic responses, neurofilament light chain levels, and gene expression were assessed at various ages. RESULTS: Genetic diversity significantly impacts AD-related pathology. Hybrid strains showed resistance to amyloid plaque formation and neuronal damage. Transcriptome diversity was maintained across ages and sexes, with observable strain-specific variations in AD-related phenotypes. Comparative gene expression analysis indicated correlations between mouse strains and human AD. DISCUSSION: Increasing genetic diversity promotes resilience to AD-related pathogenesis, relative to an inbred C57BL/6J background, reinforcing the importance of genetic diversity in uncovering resilience in the development of AD. HIGHLIGHTS: Genetic diversity's impact on AD in mice was explored. Diverse F1 mouse strains were used for AD study, via the Collaborative Cross. Strain-specific variations in AD pathology, glia, and transcription were found. Strains resilient to plaque formation and plasma neurofilament light chain (NfL) increases were identified. Correlations with human AD transcriptomics were observed.

Characterizing molecular and synaptic signatures in mouse models of late-onset Alzheimer's disease independent of amyloid and tau pathology.

INTRODUCTION: MODEL-AD (Model Organism Development and Evaluation for Late-Onset Alzheimer's Disease) is creating and distributing novel mouse models with humanized, clinically relevant genetic risk factors to capture the trajectory and progression of late-onset Alzheimer's disease (LOAD) more accurately. METHODS: We created the LOAD2 model by combining apolipoprotein E4 (APOE4), Trem2*R47H, and humanized amyloid-beta (Aß). Mice were subjected to a control diet or a high-fat/high-sugar diet (LOAD2+HFD). We assessed disease-relevant outcome measures in plasma and brain including neuroinflammation, Aß, neurodegeneration, neuroimaging, and multi-omics. RESULTS: By 18 months, LOAD2+HFD mice exhibited sex-specific neuron loss, elevated insoluble brain Aß42, increased plasma neurofilament light chain (NfL), and altered gene/protein expression related to lipid metabolism and synaptic function. Imaging showed reductions in brain volume and neurovascular uncoupling. Deficits in acquiring touchscreen-based cognitive tasks were observed. DISCUSSION: The comprehensive characterization of LOAD2+HFD mice reveals that this model is important for preclinical studies seeking to understand disease trajectory and progression of LOAD prior to or independent of amyloid plaques and tau tangles. HIGHLIGHTS: By 18 months, unlike control mice (e.g., LOAD2 mice fed a control diet, CD), LOAD2+HFD mice presented subtle but significant loss of neurons in the cortex, elevated levels of insoluble Ab42 in the brain, and increased plasma neurofilament light chain (NfL). Transcriptomics and proteomics showed changes in gene/proteins relating to a variety of disease-relevant processes including lipid metabolism and synaptic function. In vivo imaging revealed an age-dependent reduction in brain region volume (MRI) and neurovascular uncoupling (PET/CT). LOAD2+HFD mice also demonstrated deficits in acquisition of touchscreen-based cognitive tasks.

Early molecular events of autosomal-dominant Alzheimer's disease in marmosets with PSEN1 mutations.

INTRODUCTION: Fundamental questions remain about the key mechanisms that initiate Alzheimer's disease (AD) and the factors that promote its progression. Here we report the successful generation of the first genetically engineered marmosets that carry knock-in (KI) point mutations in the presenilin 1 (PSEN1) gene that can be studied from birth throughout lifespan. METHODS: CRISPR/Cas9 was used to generate marmosets with C410Y or A426P point mutations in PSEN1. Founders and their germline offspring are comprehensively studied longitudinally using non-invasive measures including behavior, biomarkers, neuroimaging, and multiomics signatures. RESULTS: Prior to adulthood, increases in plasma amyloid beta were observed in PSEN1 mutation carriers relative to non-carriers. Analysis of brain revealed alterations in several enzyme-substrate interactions within the gamma secretase complex prior to adulthood. DISCUSSION: Marmosets carrying KI point mutations in PSEN1 provide the opportunity to study the earliest primate-specific mechanisms that contribute to the molecular and cellular root causes of AD onset and progression. HIGHLIGHTS: We report the successful generation of genetically engineered marmosets harboring knock-in point mutations in the PSEN1 gene. PSEN1 marmosets and their germline offspring recapitulate the early emergence of AD-related biomarkers. Studies as early in life as possible in PSEN1 marmosets will enable the identification of primate-specific mechanisms that drive disease progression.

A community-based participatory research approach to evaluating and improving hepatitis C risk, knowledge, and stigma associations among people who inject substances in Indiana.

OBJECTIVES: To explore hepatitis C risk, knowledge, and stigma among individuals who inject substances in South Central Indiana. DESIGN: A cross-sectional study design was employed using a community-based participatory research approach. The community partner was a grassroots harm reduction organization. SAMPLE: Participants in this study were at least 18 years of age, current residents of Indiana, and self-identified as injection substance users (n = 179). MEASUREMENTS: The survey measured hepatitis C risk, knowledge, and stigma, as well as differences in hepatitis C risk scores among key demographic characteristics. RESULTS: Most participants identified as male (n = 106, 59%), White (n = 139, 78%), and straight (n = 143, 80%). People of color reported lower hepatitis C knowledge than White participants. Women had significantly lower hepatitis C knowledge compared with men. LGBTQ participants reported increased hepatitis C risk compared with straight participants. Increased frequency of substance use was associated with decreased stigma. Unhoused participants demonstrated significantly lower hepatitis C knowledge compared with housing-secure participants. CONCLUSIONS: Our findings increase understanding that knowledge and risk around hepatitis C are associated with demographic characteristics. Results underscore the need for tailored public health interventions to increase hepatitis C knowledge, reduce stigma, and improve testing and treatment among vulnerable populations.

Differential splicing of neuronal genes in a Trem2*R47H mouse model mimics alterations associated with Alzheimer's disease.

BACKGROUND: Molecular characterization of late-onset Alzheimer's disease (LOAD), the leading cause of age-related dementia, has revealed transcripts, proteins, and pathway alterations associated with disease. Assessing these postmortem signatures of LOAD in experimental model systems can further elucidate their relevance to disease origins and progression. Model organisms engineered with human genetic factors further link these signatures to disease-associated variants, especially when studies are designed to leverage homology across species. Here we assess differential gene splicing patterns in aging mouse models carrying humanized APOE4 and/or the Trem2*R47H variant on a C57BL/6J background. We performed a differential expression of gene (DEG) and differential splicing analyses on whole brain transcriptomes at multiple ages. To better understand the difference between differentially expressed and differentially spliced genes, we evaluated enrichment of KEGG pathways and cell-type specific gene signatures of the adult brain from each alteration type. To determine LOAD relevance, we compared differential splicing results from mouse models with multiple human AD splicing studies. RESULTS: We found that differentially expressed genes in Trem2*R47H mice were significantly enriched in multiple AD-related pathways, including immune response, osteoclast differentiation, and metabolism, whereas differentially spliced genes were enriched for neuronal related functions, including GABAergic synapse and glutamatergic synapse. These results were reinforced by the enrichment of microglial genes in DEGs and neuronal genes in differentially spliced genes in Trem2*R47H mice. We observed significant overlap between differentially spliced genes in Trem2*R47H mice and brains from human AD subjects. These effects were absent in APOE4 mice and suppressed in APOE4.Trem2*R47H double mutant mice relative to Trem2*R47H mice. CONCLUSIONS: The cross-species observation that alternative splicing observed in LOAD are present in Trem2*R47H mouse models suggests a novel link between this candidate risk gene and molecular signatures of LOAD in neurons and demonstrates how deep molecular analysis of new genetic models links molecular disease outcomes to a human candidate gene.

Efficacy and safety of a 4-week course of repeated subcutaneous ketamine injections for treatment-resistant depression (KADS study): randomised double-blind active-controlled trial.

BACKGROUND: Prior trials suggest that intravenous racemic ketamine is a highly effective for treatment-resistant depression (TRD), but phase 3 trials of racemic ketamine are needed. AIMS: To assess the acute efficacy and safety of a 4-week course of subcutaneous racemic ketamine in participants with TRD. Trial registration: ACTRN12616001096448 at www.anzctr.org.au. METHOD: This phase 3, double-blind, randomised, active-controlled multicentre trial was conducted at seven mood disorders centres in Australia and New Zealand. Participants received twice-weekly subcutaneous racemic ketamine or midazolam for 4 weeks. Initially, the trial tested fixed-dose ketamine 0.5 mg/kg versus midazolam 0.025 mg/kg (cohort 1). Dosing was revised, after a Data Safety Monitoring Board recommendation, to flexible-dose ketamine 0.5-0.9 mg/kg or midazolam 0.025-0.045 mg/kg, with response-guided dosing increments (cohort 2). The primary outcome was remission (Montgomery-Åsberg Rating Scale for Depression score ≤10) at the end of week 4. RESULTS: The final analysis (those who received at least one treatment) comprised 68 in cohort 1 (fixed-dose), 106 in cohort 2 (flexible-dose). Ketamine was more efficacious than midazolam in cohort 2 (remission rate 19.6% v. 2.0%; OR = 12.1, 95% CI 2.1-69.2, P = 0.005), but not different in cohort 1 (remission rate 6.3% v. 8.8%; OR = 1.3, 95% CI 0.2-8.2, P = 0.76). Ketamine was well tolerated. Acute adverse effects (psychotomimetic, blood pressure increases) resolved within 2 h. CONCLUSIONS: Adequately dosed subcutaneous racemic ketamine was efficacious and safe in treating TRD over a 4-week treatment period. The subcutaneous route is practical and feasible.

Reduction in GABAB on glia induce Alzheimer's disease related changes.

Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by beta-amyloid plaques (Aß), neurofibrillary tangles (NFT), and neuroinflammation. Data have demonstrated that neuroinflammation contributes to Aß and NFT onset and progression, indicating inflammation and glial signaling is vital to understanding AD. A previous investigation demonstrated a significant decrease of the GABAB receptor (GABABR) in APP/PS1 mice (Salazar et al., 2021). To determine if changes in GABABR restricted to glia serve a role in AD, we developed a mouse model with a reduction of GABABR restricted to macrophages, GAB/CX3ert. This model exhibits changes in gene expression and electrophysiological alterations similar to amyloid mouse models of AD. Crossing the GAB/CX3ert mouse with APP/PS1 resulted in significant increases in Aß pathology. Our data demonstrates that decreased GABABR on macrophages leads to several changes observed in AD mouse models, as well as exacerbation of AD pathology when crossed with existing models. These data suggest a novel mechanism in AD pathogenesis.

Transcriptomic stratification of late-onset Alzheimer's cases reveals novel genetic modifiers of disease pathology.

Late-Onset Alzheimer's disease (LOAD) is a common, complex genetic disorder well-known for its heterogeneous pathology. The genetic heterogeneity underlying common, complex diseases poses a major challenge for targeted therapies and the identification of novel disease-associated variants. Case-control approaches are often limited to examining a specific outcome in a group of heterogenous patients with different clinical characteristics. Here, we developed a novel approach to define relevant transcriptomic endophenotypes and stratify decedents based on molecular profiles in three independent human LOAD cohorts. By integrating post-mortem brain gene co-expression data from 2114 human samples with LOAD, we developed a novel quantitative, composite phenotype that can better account for the heterogeneity in genetic architecture underlying the disease. We used iterative weighted gene co-expression network analysis (WGCNA) to reduce data dimensionality and to isolate gene sets that are highly co-expressed within disease subtypes and represent specific molecular pathways. We then performed single variant association testing using whole genome-sequencing data for the novel composite phenotype in order to identify genetic loci that contribute to disease heterogeneity. Distinct LOAD subtypes were identified for all three study cohorts (two in ROSMAP, three in Mayo Clinic, and two in Mount Sinai Brain Bank). Single variant association analysis identified a genome-wide significant variant in TMEM106B (p-value < 5×10-8, rs1990620G) in the ROSMAP cohort that confers protection from the inflammatory LOAD subtype. Taken together, our novel approach can be used to stratify LOAD into distinct molecular subtypes based on affected disease pathways.

Use of Medicare Benefit Scheme mental health services in young people who experienced self-harm and/or suicidal behaviours: Data from the Young Minds Matter survey.

OBJECTIVES: To examine healthcare utilisation patterns in a sample of young people with self-reported experiences of self-harm and/or suicidal behaviours. METHODS: A national survey examining mental health in a nationally representative sample of young Australians aged 12-17 years, linked to routinely collected healthcare and dispensing data. For respondents that self-reported experience of self-harm, suicidal ideation, suicidal plan and/or suicide attempt, we assessed attendance at a Medicare Benefits Scheme (MBS) subsidised MH service or non-MH general practitioner (GP) attendance at three time periods: 1) ever, 2) in the 12 months prior to completing the survey and 3) after completing the survey until 31 Dec 2015. We also assessed correlates associated with attendance and non-attendance at a MH service. RESULTS: The study included 311 young people. MH services were attended in the 12 months before the survey by 38.3% with attempted suicide, 28.7% with a suicidal plan, 28.9% with suicidal ideation and 29.4% with self-harm. MH treatment administered by a GP was the most common MH service (25%); followed treatment by psychologist (15%) and psychiatrist (5%). Attendance at a MH service was observed highest alongside more severe self-reported depression. CONCLUSIONS: Potential underutilisation of MBS MH services by young people with self-harm and/or suicidal behaviours.