Decoding the transcriptomic signatures of psychological trauma in human cortex and amygdala.

Psychological trauma has profound effects on brain function and precipitates psychiatric disorders in vulnerable individuals, however, the molecular mechanisms linking trauma with psychiatric risk remain incompletely understood. Using RNA-seq data postmortem brain tissue of a cohort of 304 donors (N=136 with trauma exposure), we investigated transcriptional signatures of trauma exposures in two cortical regions (dorsolateral prefrontal cortex, and dorsal anterior cingulate cortex) and two amygdala regions (medial amygdala and basolateral amygdala) associated with stress processing and regulation. We focused on dissecting heterogeneity of traumatic experiences in these transcriptional signatures by investigating exposure to several trauma types (childhood, adulthood, complex, single acute, combat, and interpersonal traumas) and interactions with sex.

Discovery of F Labeled AZD5213 Derivatives as Novel Positron Emission Tomography (PET) Radioligands Targeting Histamine Subtype-3 Receptor.

The histamine subtype 3 (H) receptor is an important drug target in the central nervous system (CNS), and PET imaging offers a promising technique for the noninvasive evaluation of CNS disease related to the H receptor. In this study, we synthesized and evaluated the binding effects of [F]H3-2404 and [F]H3-2405 by modifying the structure of AZD5213, a selective H antagonist. These two radioligands were prepared in high radiochemical yields and displayed stability in serum.

Evaluating the evidence for genotype-informed Bayesian dosing of tacrolimus in children undergoing solid organ transplantation: A systematic literature review.

Tacrolimus, a calcineurin inhibitor, is a highly effective immunosuppressant used in solid organ transplantation (SOT). However, it is characterized by a narrow therapeutic range and high inter-patient variability in pharmacokinetics. Standard weight-based dosing followed by empiric dose titration is suboptimal in controlling drug concentrations, increasing risk of rejection or toxicity, particularly in the initial months post transplantation.

Electron Capture vs Transfer Dissociation for Site Determination of Tryptic Peptide Tyrosine Sulfation: Direct Detection of Fibrinogen Sulfation Sites and Identification of Novel Isobaric Interferences.

Tyrosine sulfation, an understudied but crucial post-translational modification, cannot be directly detected in conventional nanoflow liquid chromatography-tandem mass spectrometry (nanoLC-MS/MS) due to the extreme sulfate lability. Here, we report the detection of sulfate-retaining fragments from LC-electron capture dissociation (ECD) and nanoLC-electron transfer higher energy collision dissociation (EThcD). Sulfopeptide candidates were identified by Proteome Discoverer and MSFragger analysis of nanoLC-HCD MS/MS data and added to inclusion lists for LC-ECD or nanoLC-EThcD MS/MS.

The impact of chronic pain on brain gene expression.

Background: Chronic pain affects one fifth of American adults, contributing significant public health burden. Chronic pain mechanisms can be further understood through investigating brain gene expression.

Methods: We tested differentially expressed genes (DEGs) in chronic pain, migraine, lifetime fentanyl and oxymorphone use, and with chronic pain genetic risk in four brain regions (dACC, DLPFC, MeA, BLA) and imputed cell type expression data from 304 postmortem donors.

Minimising Adverse Drug Reactions and Verifying Economic Legitimacy-Pharmacogenomics Implementation in Children (MARVEL- PIC): protocol for a national randomised controlled trial of pharmacogenomics implementation.

Introduction: DNA-informed prescribing (termed pharmacogenomics, PGx) is the epitome of personalised medicine. Despite international guidelines existing, its implementation in paediatric oncology remains sparse.

Methods And Analysis: Minimising Adverse Drug Reactions and Verifying Economic Legitimacy-Pharmacogenomics Implementation in Children is a national prospective, multicentre, randomised controlled trial assessing the impact of pre-emptive PGx testing for actionable PGx variants on adverse drug reaction (ADR) incidence in patients with a new cancer diagnosis or proceeding to haematopoetic stem cell transplant.

Preclinical Evaluation of Azabenzimidazole-Based PET Radioligands for γ-8 Dependent Transmembrane AMPA Receptor Regulatory Protein Imaging.

AMPA glutamate receptors (AMPARs) play a pivotal role in excitatory neurotransmission, particularly in the hippocampus where the TARP γ-8 subunit is enriched and serves as a target for emerging anti-epileptic drugs. To enable in vivo visualization of TARP γ-8 distribution and expression by positron emission tomography (PET), this study focuses on the development of novel F-labeled TARP γ-8 inhibitors and their corresponding precursors, stemming from the azabenzimidazole scaffold. The resulting radioligands [ F]TARP-2204 and [ F]TARP-2205 were successfully synthesized with acceptable radiochemical yield, high molar activity, and excellent radiochemical purity.

Potential roles of FGF5 as a candidate therapeutic target in prostate cancer.

Fibroblast growth factor (FGF) is a secreted ligand that is widely expressed in embryonic tissues but its expression decreases with age. In the developing prostate, FGF5 has been proposed to interact with the Hedgehog (Hh) signaling pathway to guide mitogenic processes. In the adult prostate, the FGF/FGFR signaling axis has been implicated in prostate carcinogenesis, but focused studies on FGF5 functions in the prostate are limited.

Lessons learnt in the first year of an Australian pediatric cardio oncology clinic.

Background: Modern oncological therapies together with chemotherapy and radiotherapy have broadened the agents that can cause cardiac sequelae, which can manifest for pediatric oncology patients while on active treatment. Recommendations for high-risk patients who should be monitored in a pediatric cardio-oncology clinic have previously been developed by expert Delphi consensus by our group. In 2022 we opened our first multidisciplinary pediatric cardio-oncology clinic adhering to these recommendations in surveillance and management.

Evaluation of thiadiazine-based PET radioligands for imaging the AMPA receptor.

As a subclass of ionotropic glutamate receptors (iGluRs), α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) receptors have been implicated in various neurological disorders and neurodegenerative diseases. To further our understanding of AMPA receptor-related disorders in the central nervous system (CNS), it is important to be able to image and quantify AMPA receptors in vivo. In this study, we identified a novel F-containing AMPA positive allosteric modulator (PAM) 6 as a potential lead compound.

Primary health care service utilisation before and after entry into long-term care in Australia.

Objectives: To examine utilisation of primary health care services (subsidised by the Australian Government, Medicare Benefits Schedule, MBS) before and after entry into long-term care (LTC) in Australia.

Methods: A retrospective cohort study of older people (aged ≥65 years) who entered LTC in Australia between 2012 and 2016 using the Historical Cohort of the Registry of Senior Australians. MBS-subsidised general attendances (general practitioner (GP), medical and nurse practitioners), health assessment and management plans, allied health, mental health services and selected specialist attendances accessed in 91-day periods 12 months before and after LTC entry were examined.

Evaluation of a Telehealth-Based Pharmacist Led Chronic Care Management Program.

Clinical pharmacy services improve several patient chronic disease outcomes. This review evaluates a pharmacist-led chronic care management (CCM) program partnered with a health system for patient outcomes and sustainability. A mixed methods evaluation based on the Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) framework was completed.

Knowledge, attitudes, and practices of registered dietitians and nutritionists regarding enteral and parenteral nutrition support in Ghana: a needs assessment study.

Background: There is a paucity of data on enteral and parenteral (EN and PN) nutrition support (NS) provided by nutrition and dietetic practitioners in adult acute care settings in Ghana. Furthermore, gray literature suggests that Ghanaian clinical nutrition professionals (CNPs) are seldom involved in advanced nutrition care teams.

Objectives: To assess the knowledge, attitudes, and practices of Ghanaian CNPs regarding EN and PN.

Primary, allied health, geriatric, pain and palliative healthcare service utilisation by aged care residents, 2012-2017.

Objectives: To examine the incidence and trends in primary care, allied health, geriatric, pain and palliative care service use by permanent residential aged care (PRAC) residents and the older Australian population.

Methods: Repeated cross-sectional analyses on PRAC residents (N = 318,484) and the older (≥65 years) Australian population (N ~ 3.5 million).

Regulator of G Protein Signaling Proteins Control Growth, Development and Cellulase Production in .

Heterotrimeric (αβγ) G protein signaling pathways are critical environmental sensing systems found in eukaryotic cells. Exchange of GDP for GTP on the Gα subunit leads to its activation. In contrast, GTP hydrolysis on the Gα is accelerated by Regulator of G protein Signaling (RGS) proteins, resulting in a return to the GDP-bound, inactive state.

Imaging Leucine-Rich Repeat Kinase 2 In Vivo with F-Labeled Positron Emission Tomography Ligand.

Leucine-rich repeat kinase 2 (LRRK2) has been demonstrated to be closely involved in the pathogenesis of Parkinson's disease (PD), and pharmacological blockade of LRRK2 represents a new opportunity for therapeutical treatment of PD and other related neurodegenerative conditions. The development of an LRRK2-specific positron emission tomography (PET) ligand would enable a target occupancy study in vivo and greatly facilitate LRRK2 drug discovery and clinical translation as well as provide a molecular imaging tool for studying physiopathological changes in neurodegenerative diseases. In this work, we present the design and development of compound (PF-06455943) as a promising PET radioligand through a PET-specific structure-activity relationship optimization, followed by comprehensive pharmacology and ADME/neuroPK characterization.

Continuing professional development in the COVID-19 era: evolution of the Pegasus Health Small Group model.

Background and context This paper outlines the process of moving a continuing education programme for primary healthcare professionals from a fully in-person model to fully online so it could continue during coronavirus disease 2019 (COVID-19) lockdowns. The programme uses a peer-led Small Group model with the leader facilitating interactive discussion based on background content researched by a team from Pegasus Health. Assessment of problem When the COVID-19 restrictions were implemented in March 2020, the usual in-person Small Group meetings could not continue.

Loss of forebrain BIN1 attenuates hippocampal pathology and neuroinflammation in a tauopathy model.

Bridging integrator 1 (BIN1) is the second most prevalent genetic risk factor identified by genome-wide association studies (GWAS) for late-onset Alzheimer's disease. BIN1 encodes an adaptor protein that regulates membrane dynamics in the context of endocytosis and neurotransmitter vesicle release. In vitro evidence suggests that BIN1 can directly bind to tau in the cytosol.

Trends in mental health service utilisation by Australia's older population.

Objectives: To examine the incidence, trends, and differences between age groups and sex in Medicare Benefits Schedule (MBS)-subsidised mental health service utilisation by older Australians over the past 10 years.

Methods: A cross-sectional cohort study between 1 July 2009 and 30 June 2019 was conducted using publicly available MBS data for older individuals aged ≥65 years. Age- and sex-standardised yearly incidence rates of psychological therapy (MBS M06), GP mental health treatments (MBS A20), focussed psychological strategy (MBS M07), and psychiatric attendances (MBS A08) and incidence rate ratios (IRR) estimated using Poisson regression were calculated.

Government-subsidised mental health services are underused in Australian residential aged care facilities.

Objective To describe patterns of use of the available Government-subsidised mental health services among people living in Australian residential aged care facilities. Methods A retrospective population-based trend analysis was conducted, including all non-Indigenous people living in an Australian facility between 2012 and 2017. Adjusted incidence proportions and trends were estimated for four groups of mental health services.

BIN1 is a key regulator of proinflammatory and neurodegeneration-related activation in microglia.

Background: The BIN1 locus contains the second-most significant genetic risk factor for late-onset Alzheimer's disease. BIN1 undergoes alternate splicing to generate tissue- and cell-type-specific BIN1 isoforms, which regulate membrane dynamics in a range of crucial cellular processes. Whilst the expression of BIN1 in the brain has been characterized in neurons and oligodendrocytes in detail, information regarding microglial BIN1 expression is mainly limited to large-scale transcriptomic and proteomic data.