Liver specification of human iPSC-derived endothelial cells transplanted into mouse liver.

Background & Aims: Liver sinusoidal endothelial cells (LSECs) are important in liver development, regeneration, and pathophysiology, but the differentiation process underlying their tissue-specific phenotype is poorly understood and difficult to study because primary human cells are scarce. The aim of this study was to use human induced pluripotent stem cell (hiPSC)-derived LSEC-like cells to investigate the differentiation process of LSECs.

Methods: hiPSC-derived endothelial cells (iECs) were transplanted into the livers of // mice and assessed over a 12-week period.

Treatment of immune thrombocytopenia in Australian adults: A multicenter retrospective observational study.

Background: In Australia, prescribing restrictions limit access to internationally recommended second-line therapies such as rituximab and thrombopoietin agonists (TPO-A) (eltrombopag and romiplostim). Subsequent lines of therapy include an array of immunosuppressive and immune-modulating agents directed by drug availability and physician and patient preference.

Objectives: The objective of the study was to describe the use of first and subsequent lines of treatment for adult immune thrombocytopenia (ITP) in Australia and to assess their effectiveness and tolerability.

A pilot study assessing the implementation of 96-well plate-based aggregometry (Optimul) in Australia.

Identification of disordered platelet function is important to guide peri-operative bleeding management as well as long term treatment and prognostic strategies in individuals with platelet bleeding disorders. Light transmission aggregometry (LTA), the current gold standard diagnostic test of platelet function is a time consuming technique almost exclusively performed in specialised laboratories and almost universally unavailable in regional centres in Australia, where there is an unmet need for access to specialised platelet function diagnostic services. 96-well plate-based aggregometry (Optimul, UK), has been utilised in research laboratories as a novel platform to investigate platelet function.

The utility of flow cytometric platelet forward scatter as an alternative to mean platelet volume.

The use of mean platelet diameter (MPD) to classify inherited thrombocytopenia (IT) has been demonstrated in several studies. Alternatively, the mean platelet volume (MPV) may be used, but in macrothrombocytopenia this may not be available. We hypothesized that platelet forward scatter (FSC) measurements using flow cytometry may be used for the size-based classification of IT.

Geriatric medicine and health care for older people in Australia.

Aged care coverage in Australia is universal but fragmented and has been challenged by government policy to deregulate aged care and open it up to market forces. A recent inquiry into aged care (Royal Commission into Aged Care Quality and Safety) documented the outcome of this policy-substandard care at most levels. The provision of services to older Aboriginal and Torres Strait Islander peoples, who have high prevalence of frailty and cognitive impairment, was also identified as inadequate.

Building platelet phenotypes: Diaphanous-related formin 1 (DIAPH1)-related disorder.

Variants of the Diaphanous-Related Formin 1 () gene have recently been reported causing inherited macrothrombocytopenia. The essential/"diagnostic" characteristics associated with the disorder are emerging; however, robust and complete criteria are not established. Here, we report the first cases of -related disorder in Australia caused by the autosomal dominant gain-of-function DIAPH1 R1213X variant formed by truncation of the protein within the diaphanous auto-regulatory domain (DAD) with loss of regulatory motifs responsible for autoinhibitory interactions within the DIAPH1 protein.

Risk Factors for Incident Falls and Fractures in Older Men With and Without Type 2 Diabetes Mellitus: The Concord Health and Ageing in Men Project.

Background: Type 2 diabetes mellitus (T2DM) increases falls and fracture risk. Our objective was to compare incidence and risk factors for falls and fractures in community-dwelling older men with and without T2DM.

Methods: A total of 1705 men (471 with T2DM; 1234 without T2DM) aged ≥70 years were assessed at baseline.

Higher-Impact Physical Activity Is Associated With Maintenance of Bone Mineral Density But Not Reduced Incident Falls or Fractures in Older Men: The Concord Health and Aging in Men Project.

High-impact physical activities with bone strains of high magnitude and frequency may benefit bone health. This study aimed to investigate the longitudinal associations between changes in loading intensities and application rates, estimated from self-reported physical activity, with bone mineral density (BMD) changes over 5 years and also with incident falls over 2 years and long-term incident fractures in community-dwelling older men. A total of 1599 men (mean age 76.

Branched chain amino acids, aging and age-related health.

Branched chain amino acids (BCAA: leucine, valine, isoleucine) have key physiological roles in the regulation of protein synthesis, metabolism, food intake and aging. Many studies report apparently inconsistent conclusions about the relationships between blood levels of BCAAs or dietary manipulation of BCAAs with age-related changes in body composition, sarcopenia, obesity, insulin and glucose metabolism, and aging biology itself. These divergent results can be resolved by consideration of the role of BCAAs as signalling molecules and the bidirectional mechanistic relationship between BCAAs and some aging phenotypes.

Animal and translational models of SARS-CoV-2 infection and COVID-19.

COVID-19 is causing a major once-in-a-century global pandemic. The scientific and clinical community is in a race to define and develop effective preventions and treatments. The major features of disease are described but clinical trials have been hampered by competing interests, small scale, lack of defined patient cohorts and defined readouts.

Targeting miR-27a/VE-cadherin interactions rescues cerebral cavernous malformations in mice.

Cerebral cavernous malformations (CCMs) are vascular lesions predominantly developing in the central nervous system (CNS), with no effective treatments other than surgery. Loss-of-function mutation in CCM1/krev interaction trapped 1 (KRIT1), CCM2, or CCM3/programmed cell death 10 (PDCD10) causes lesions that are characterized by abnormal vascular integrity. Vascular endothelial cadherin (VE-cadherin), a major regulator of endothelial cell (EC) junctional integrity is strongly disorganized in ECs lining the CCM lesions.

An integrated approach to inherited platelet disorders: results from a research collaborative, the Sydney Platelet Group.

Inherited disorders of platelet function (IPFD) and/or number (IPND) are heterogeneous conditions that result in variable mucocutaneous bleeding symptoms as a result of deranged primary haemostasis caused by platelet dysfunction or thrombocytopenia. Diagnosis is important to guide post-operative bleeding prophylactic strategies, to avoid treatment with inappropriate medications, and inform prognosis. Achieving an accurate diagnosis has traditionally been hampered by the requirement of multiple, often complex, laboratory tests that are not always available at single centres.

Proinflammatory Diet Increases Circulating Inflammatory Biomarkers and Falls Risk in Community-Dwelling Older Men.

Background: The relations between diet, chronic inflammation, and musculoskeletal health are unclear, especially among older men.

Objective: This study aimed to determine associations of the Dietary Inflammatory Index (DII) with inflammatory biomarkers, musculoskeletal health, and falls risk in community-dwelling older men.

Methods: The cross-sectional analysis included 794 community-dwelling men, mean age 81.

Telephone call reminders did not increase screening uptake more than SMS reminders: a recruitment study within a trial.

Objectives: The aim of the study was to compare the response rates and costs of phone call vs. short message service (SMS) screening reminders to prospective randomized controlled trial (RCT) participants.

Study Design And Setting: This study was a randomized evaluation within a large Australian diabetes prevention RCT.

Loss of the Vitamin D Receptor in Human Breast Cancer Cells Promotes Epithelial to Mesenchymal Cell Transition and Skeletal Colonization.

Expression of the vitamin D receptor (VDR) is thought to be associated with neoplastic progression. However, the role of the VDR in breast cancer metastasis to bone and the molecular mechanisms underlying this process are unknown. Employing a rodent model (female Balb/c nu/nu mice) of systemic metastasis, we here demonstrate that knockdown of the VDR strongly increases the metastatic potential of MDA-MB-231 human breast cancer cells to bone, resulting in significantly greater skeletal tumor burden.

Testosterone therapy to prevent type 2 diabetes mellitus in at-risk men (T4DM): Design and implementation of a double-blind randomized controlled trial.

Background: Low circulating testosterone is associated with an increased risk of developing type 2 diabetes (T2DM) in overweight men with impaired glucose tolerance (IGT).

Aims: To determine in a multi-centre, double-blinded placebo-controlled randomized trial whether testosterone treatment combined with lifestyle intervention (Weight Watchers) relative to lifestyle intervention alone reduces T2DM incidence and improves glucose tolerance at 2 years.

Study Population: Overweight or obese men aged 50-74 years with a serum testosterone of ≤14 nmol/L and IGT or newly diagnosed T2DM established by an oral glucose tolerance test (OGTT).

Longitudinal Associations Between Vitamin D Metabolites and Sarcopenia in Older Australian men: The Concord Health and Aging in Men Project.

Background: To explore the associations between serum 25-hydroxyvitamin D (25D) and 1,25-dihydroxyvitamin D (1,25D) levels at baseline and incidence of sarcopenia over time in older Australian community-dwelling older men.

Methods: Of the 1,705 men aged ≥70 years (2005-2007) participating in the Concord Health and Ageing in Men Project, those without sarcopenia at baseline (n = 1,312 for 25D and n = 1,231 for 1,25D), 2 years (n = 1,024 for 25D and n = 956 for 1,25D), and 5-year follow-up (n = 709 for 25D and n = 663 for 1,25D) were included in the study. The main outcome measurement was the incidence of sarcopenia defined as appendicular lean mass adjusted for body mass index <0.

Non-alcoholic fatty liver disease, vascular inflammation and insulin resistance are exacerbated by TRAIL deletion in mice.

Non-alcoholic fatty liver disease (NAFLD) incorporates steatosis, non-alcoholic steato-hepatitis (NASH) and liver cirrhosis, associating with diabetes and cardiovascular disease (CVD). TNF-related apoptosis-inducing ligand (TRAIL) is protective of CVD. We aimed to determine whether TRAIL protects against insulin resistance, NAFLD and vascular injury.

SIRT1 Polymorphisms and Serum-Induced SIRT1 Protein Expression in Aging and Frailty: The CHAMP Study.

The nutrient sensing protein, SIRT1 influences aging and nutritional interventions such as caloric restriction in animals, however, the role of SIRT1 in human aging remains unclear. Here, the role of SIRT1 single-nucleotide polymorphisms (SNPs) and serum-induced SIRT1 protein expression (a novel assay that detects circulating factors that influence SIRT1 expression in vitro) were studied in the Concord Health and Ageing in Men Project (CHAMP), a prospective cohort of community dwelling men aged 70 years and older. Serum-induced SIRT1 expression was not associated with age or mortality, however participants within the lowest quintile were less likely to be frail (odds ratio (OR) 0.

Quantitative muscle ultrasound as a biomarker in Charcot-Marie-Tooth neuropathy.

Objective: The utility of quantitative muscle ultrasound as a marker of disease severity in Charcot-Marie-Tooth (CMT) disease subtypes was investigated.

Methods: Muscle ultrasound was prospectively performed on 252 individual muscles from 21 CMT patients (9 CMT1A, 8 CMTX1, 4 CMT2A) and compared to 120 muscles from 10 age and gender-matched controls. Muscle ultrasound recorded echogenicity and thickness in representative muscles including first dorsal interosseus (FDI) and tibialis anterior (TA).

Sarcopenic Obesity and Its Temporal Associations With Changes in Bone Mineral Density, Incident Falls, and Fractures in Older Men: The Concord Health and Ageing in Men Project.

Body composition and muscle function have important implications for falls and fractures in older adults. We aimed to investigate longitudinal associations between sarcopenic obesity and its components with bone mineral density (BMD) and incident falls and fractures in Australian community-dwelling older men. A total of 1486 men aged ≥70 years from the Concord Health and Ageing in Men Project (CHAMP) study were assessed at baseline (2005-2007), 2-year follow-up (2007-2009; n = 1238), and 5-year follow-up (2010-2013; n = 861).

Low Hemoglobin Concentrations Are Associated With Sarcopenia, Physical Performance, and Disability in Older Australian Men in Cross-sectional and Longitudinal Analysis: The Concord Health and Ageing in Men Project.

Background: The objective of this study is to examine associations between Hb levels and sarcopenia, low muscle strength, functional measures, and activities of daily living (ADL) and instrumental ADL (IADL) disabilities in older Australian men.

Methods: Men aged 70 years and older (2005-2007) from the Concord Health and Ageing in Men Project were assessed at baseline (n = 1,705), 2 years (n = 1,367), and 5 years (n = 958). The main outcome measurements were walking speed, muscle strength, ADL and IADL disabilities, and sarcopenia using the Foundation for the National Institutes of Health criteria (low appendicular lean mass adjusted for body mass index < 0.

Use of Whole-Exome Sequencing for Diagnosis of Limb-Girdle Muscular Dystrophy: Outcomes and Lessons Learned.

Importance: To our knowledge, the efficacy of transferring next-generation sequencing from a research setting to neuromuscular clinics has never been evaluated.

Objective: To translate whole-exome sequencing (WES) to clinical practice for the genetic diagnosis of a large cohort of patients with limb-girdle muscular dystrophy (LGMD) for whom protein-based analyses and targeted Sanger sequencing failed to identify the genetic cause of their disorder.

Design, Setting, And Participants: We performed WES on 60 families with LGMDs (100 exomes).

Cross-Sectional and Longitudinal Associations Between Anemia and Frailty in Older Australian Men: The Concord Health and Aging in Men Project.

Background: Anemia and frailty are both common in older people and are associated with adverse health outcomes. There have been some cross-sectional studies of anemia and frailty but no longitudinal studies. The objectives of this study were to examine cross-sectional and longitudinal associations between anemia and frailty in older Australian men.

Sarcopenia Is Associated With Incident Disability, Institutionalization, and Mortality in Community-Dwelling Older Men: The Concord Health and Ageing in Men Project.

Introduction: Sarcopenia is associated with an increased risk of adverse outcomes. The aim of this study was to explore the relationship between severity of sarcopenia and incident activities of daily living (ADL) disability, institutionalization, and all-cause mortality among community-dwelling older men participating in the Concord Health and Ageing in Men Project (CHAMP).

Methods: Longitudinal analysis of 1705 participants aged 70 years or older at baseline (2005-2007) living in the community in Sydney, Australia.