Minimal extra-cardiac atherosclerosis present in young people with sudden cardiac death due to coronary artery disease.

Aim: To define the association between severe coronary artery disease and widespread atherosclerosis in younger individuals.

Methods: Individuals aged 1-50 years with sudden cardiac death (SCD) from 2019-23, autopsy-proven to be due to coronary artery disease, were identified using the state-wide EndUCD registry. Presence of extra-coronary atherosclerosis greater than modified American Heart Association class III was assessed in 5 arterial beds (intra-cerebral vessels, aorta, carotid, renal and femoral arteries).

Congenital Titinopathy: Comprehensive Characterization of the Most Severe End of the Disease Spectrum.

Unlabelled: Congenital titinopathy has recently emerged as one of the most common congenital muscle disorders.

Objective: To better understand the presentation and clinical needs of the under-characterized extreme end of the congenital titinopathy severity spectrum.

Methods: We comprehensively analyzed the clinical, imaging, pathology, autopsy, and genetic findings in 15 severely affected individuals from 11 families.

Sex-Specific Clinical and Genetic Factors Associated With Adverse Outcomes in Hypertrophic Cardiomyopathy.

Background: Females with hypertrophic cardiomyopathy present at a more advanced stage of the disease and have a higher risk of heart failure and death. The factors behind these differences are unclear. We aimed to investigate sex-related differences in clinical and genetic factors affecting adverse outcomes in the Sarcomeric Human Cardiomyopathy Registry.

Canagliflozin reduces oral loop diuretic intensification in patients with type 2 diabetes: A participant-level pooled analysis of the CANVAS and CREDENCE trials.

Aims: The sodium-glucose cotransporter 2 inhibitor canagliflozin reduces the risk of heart failure (HF) hospitalization or cardiovascular death and chronic kidney disease (CKD) progression among patients with type 2 diabetes at high cardiovascular risk or with CKD. Patients with type 2 diabetes commonly have coexisting HF or CKD that require treatment with loop diuretics; however, the prognostic implications of oral loop diuretic intensification are not well characterized.

Methods And Results: In this participant-level pooled analysis of the CREDENCE and CANVAS trials (not including CANVAS-R), 1454/8731 (16.

Association between anti-seizure medications and cardiac arrhythmias in patients undergoing ambulatory electroencephalographic and electrocardiographic monitoring.

Background Anti-seizure medications (ASMs) are commonly prescribed in epilepsy. However some have been associated with adverse cardiac outcomes including cardiac arrhythmias. Methods We conducted an observational study evaluating patients aged ≥16 years undergoing ambulatory video - electroencephalographic (EEG) - electrocardiographic (ECG) monitoring (AVEEM) between 2020 and 2023 in Australia.

Primary Antibody Deficiencies: Curation Of Gene-Disease Relationships Using A ClinGen Validation Framework.

Background: The Clinical Genome Resource (ClinGen) is an international collaborative effort between scientists and clinicians, diagnostic and research laboratories as well as the patient community. Using a standardized framework, ClinGen has established guidelines to classify gene-disease relationships as Definitive, Strong, Moderate, and Limited based on available scientific and clinical evidence. When the genetic and functional evidence for a gene-disease relationship has conflicting interpretations or contradictory evidence, they can be Disputed or Refuted.

Accelerating the Future of Oncology Drug Development: The Role of Consortia in the Delivery of Precision Oncology Early Phase Clinical Trials.

Purpose: Over the past 15 years, the landscape of early phase clinical trials (EPCTs) has undergone a remarkable expansion in both quantity and intricacy. The proliferation of sites, trials, sponsors, and contract research organizations has surged exponentially, marking a significant shift in research conduct. However, EPCT operations suffer from numerous inefficiencies, such as cumbersome start-up processes, which are particularly critical when drug safety and the recommended phase II dose need to be established in a timely manner.

Cardiovascular, kidney and safety outcomes with canagliflozin in older adults: A combined analysis from the CANVAS Program and CREDENCE trial.

Aim: SGLT2 inhibitors may be underused in older adults with type 2 diabetes due to concerns about safety and tolerability. This pooled analysis of the CANVAS Program and CREDENCE trial examined the efficacy and safety of canagliflozin according to age.

Methods: Pooled individual participant data from the CANVAS Program (n = 10 142) and CREDENCE trial (n = 4401) were analysed by baseline age (<65 years, 65 to <75 years, and ≥75 years).

Spatial mapping of the HCC landscape identifies unique intratumoral perivascular-immune neighborhoods.

Background: HCC develops in the context of chronic inflammation; however, the opposing roles the immune system plays in both the development and control of tumors are not fully understood. Mapping immune cell interactions across the distinct tissue regions could provide greater insight into the role individual immune populations have within tumors.

Methods: A 39-parameter imaging mass cytometry panel was optimized with markers targeting immune cells, stromal cells, endothelial cells, hepatocytes, and tumor cells.

Paracrine role of endothelial IGF-1 receptor in depot-specific adipose tissue adaptation in male mice.

During recent decades, changes in lifestyle have led to widespread nutritional obesity and its related complications. Remodelling adipose tissue as a therapeutic goal for obesity and its complications has attracted much attention and continues to be actively explored. The endothelium lines all blood vessels and is close to all cells, including adipocytes.

Affinity maturation endows potent activity onto class 6 SARS-CoV-2 broadly neutralizing antibodies.

The emergence of SARS-CoV-2 variants of concern (VOCs) has greatly diminished the neutralizing activity of previously FDA-approved monoclonal antibodies (mAbs), including that of antibody cocktails and of first-generation broadly neutralizing antibodies such as S309 (Sotrovimab). In contrast, antibodies targeting cryptic conformational epitopes of the receptor binding domain (RBD) have demonstrated broad activity against emerging variants, but exert only moderate neutralizing activity, which has so far hindered clinical development. Here, we utilize in vitro display technology to identify and affinity-mature antibodies targeting the cryptic class 6 epitope, accessible only in the "up" conformation of the SARS-CoV-2 spike trimer.

A mixed-methods assessment of the Australasian Society of Genetic Counselors (ASGC) Mentor Program.

Purpose: In Australia and New Zealand, one third of genetic counselors have less than 5 years' experience. Sharing experienced practitioners' professional knowledge is needed as the profession grows. Formal mentoring is an important facilitator of career progression and shared knowledge.

Genetic counseling workforce diversity, inclusion, and capacity in Australia and New Zealand.

Purpose: To understand diversity, inclusion, and capacity of genetic counselors (GCs) in Australasia (Australia and New Zealand).

Methods: Individuals with or working toward a GC qualification in Australasia were invited to complete an online survey, between November 2022 and March 2023. Quantitative data were analyzed using descriptive statistics, 1-sample proportion -tests, 2-sample -tests, and χ tests.

3-Month Melatonin Supplementation to Reduce Brain Oxidative Stress and Improve Sleep in Mild Cognitive Impairment: A Randomised Controlled Feasibility Trial.

Melatonin has multiple proposed therapeutic benefits including antioxidant properties, circadian rhythm synchronisation and sleep promotion. Since these areas are also recognised risk factors for dementia, melatonin has been hypothesised to slow cognitive decline in older adults. Participants with Mild Cognitive Impairment (MCI) were recruited from the community for a 12-week randomised placebo-controlled parallel, feasibility trial of 25 mg oral melatonin nightly.

Somatic mutation in autosomal dominant polycystic kidney disease revealed by deep sequencing human kidney cysts.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) results in progressive cysts that lead to kidney failure, and is caused by heterozygous germline variants in PKD1 or PKD2. Cyst pathogenesis is not definitively understood. Somatic second-hit mutations have been implicated in cyst pathogenesis, though technical sequencing challenges have limited investigation.

A Meta-Analysis of Levofloxacin for Contacts of Multidrug-Resistant Tuberculosis.

Background: Data from randomized trials evaluating the effectiveness of tuberculosis (TB) preventive treatment for contacts of multidrug-resistant (MDR)-TB are lacking. Two recently published randomized trials that did not achieve statistical significance provide the opportunity for a meta-analysis.

Methods: We conducted combined analyses of two phase 3 trials of levofloxacin MDR-TB preventive treatment - Levofloxacin for the Prevention of Multidrug-Resistant Tuberculosis (VQUIN) trial and the Levofloxacin preventive treatment in children exposed to MDR-TB (TB-CHAMP) trial.

Levofloxacin for the Prevention of Multidrug-Resistant Tuberculosis in Vietnam.

Background: Prevention of drug-resistant tuberculosis is a global health priority. However, trials evaluating the effectiveness of treating infection among contacts of persons with drug-resistant tuberculosis are lacking.

Methods: We conducted a double-blind, randomized, controlled trial comparing 6 months of daily levofloxacin (weight-based doses) with placebo to treat infection.

Evolocumab in metastatic castration-resistant prostate cancer: study protocol for a single-arm, phase II trial, and initial experience with use of a validated lipid biomarker to direct therapy.

Background: Despite advances in the treatment of metastatic castration-resistant prostate cancer (mCRPC), primary and secondary resistance to current therapies remains. Elevated circulating sphingolipids are associated with poor outcomes in patients with mCRPC, including therapeutic resistance and shorter overall survival. PCPro is a clinically accessible, regulatory compliant plasma lipid biomarker of poor prognosis in mCRPC, which incorporates prognostic sphingolipids.

The design and evaluation of a bone health teaching module for secondary school students in NSW, Australia.

Issue Addressed: The growing prevalence of osteoporosis requires preventative management starting from an early age as peak bone mass is typically reached by age 30. However, current Australian adolescents are not adequately addressing key osteoprotective factors. Alarmingly, around 17% have insufficient vitamin D levels, 55% consume insufficient dietary calcium, and 79% are insufficiently active.

Designing and Validating a Hereditary Spastic Paraplegia-Specific Quality of Life Rating Scale (HSPQoL).

Patients with Hereditary Spastic Paraplegia (HSP) report reduced quality of life (QoL) compared to the general population. Generic QoL measures do not address disease-specific aspects such as spasticity, access to specialty HSP clinics, and bladder symptoms. We designed and validated a HSP-specific QoL scale (HSPQoL), intended for use in standard clinical settings and clinical trials.

Cognitive and behavioural therapy for insomnia in the treatment of adolescent insomnia: A systematic review and meta-analysis of randomised controlled trials.

Insomnia is common in adolescents with associated negative health consequences. This systematic review and meta-analysis assessed the effect of cognitive behavioural therapy for insomnia interventions on insomnia symptoms and subjective sleep quality in adolescents aged 10-19 years. Key electronic databases, including CINAHL, Embase, MEDLINE, PsycINFO and Scopus, were systematically searched from inception to October 2024, and five randomised controlled trials met inclusion criteria for qualitative synthesis.

A common form of dominant human IFNAR1 deficiency impairs IFN-α and -ω but not IFN-β-dependent immunity.

Autosomal recessive deficiency of the IFNAR1 or IFNAR2 chain of the human type I IFN receptor abolishes cellular responses to IFN-α, -β, and -ω, underlies severe viral diseases, and is globally very rare, except for IFNAR1 and IFNAR2 deficiency in Western Polynesia and the Arctic, respectively. We report 11 human IFNAR1 alleles, the products of which impair but do not abolish responses to IFN-α and -ω without affecting responses to IFN-β. Ten of these alleles are rare in all populations studied, but the remaining allele (P335del) is common in Southern China (minor allele frequency ≈2%).