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Background: Venous thromboembolism (VTE) diagnosis would greatly benefit from the identification of novel biomarkers to complement D-dimer, a marker limited by low specificity. Neutrophil extracellular traps (NETs) have been shown to promote thrombosis and could hypothetically be used for diagnosis of acute VTE. Objectives: To assess the levels of specific markers of neutrophil activation and NETs and compare their diagnostic accuracy to D-dimer. Methods: We measured plasma levels of neutrophil activation marker neutrophil elastase (NE), the NET marker nucleosomal citrullinated histone H3 (H3Cit-DNA) and cell-free DNA in patients (n = 294) with suspected VTE (pulmonary embolism and deep vein thrombosis) as well as healthy controls (n = 30). A total of 112 VTE positive and 182 VTE negative patients from two prospective cohort studies were included. Results: Higher levels of H3Cit-DNA and NE, but not cell-free DNA, were associated with VTE. Area under receiver operating curves (AUC) were 0.90 and 0.93 for D-dimer, 0.65 and 0.68 for NE and 0.60 and 0.67 for H3Cit-DNA in the respective cohorts. Adding NE and H3Cit-DNA to a D-dimer based risk model did not improve AUC. Conclusions: Our study demonstrates the presence of neutrophil activation and NET formation in VTE using specific markers. However, the addition of NE or H3Cit-DNA to D-dimer did not improve the discrimination compared to D-dimer alone. This study provides information on the feasibility of using markers of NETs as diagnostic tools in acute VTE. Based on our findings, we believe the potential of these markers are limited in this setting., QC 20230502

Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined but could be through direct cardiac infection and/or inflammation-induced dysfunction. To identify mechanisms and cardio-protective drugs, we use a state-of-the-art pipeline combining human cardiac organoids with phosphoproteomics and single nuclei RNA sequencing. We identify an inflammatory "cytokine-storm", a cocktail of interferon gamma, interleukin 1beta, and poly(I:C), induced diastolic dysfunction. Bromodomain-containing protein 4 is activated along with a viral response that is consistent in both human cardiac organoids (hCOs) and hearts of SARS-CoV-2-infected K18-hACE2 mice. Bromodomain and extraterminal family inhibitors (BETi) recover dysfunction in hCOs and completely prevent cardiac dysfunction and death in a mouse cytokine-storm model. Additionally, BETi decreases transcription of genes in the viral response, decreases ACE2 expression, and reduces SARS-CoV-2 infection of cardiomyocytes. Together, BETi, including the Food and Drug Administration (FDA) breakthrough designated drug, apabetalone, are promising candidates to prevent COVID-19 mediated cardiac damage.Copyright © 2021 Elsevier Inc.

Background/Purpose: Metabolic syndrome (MetS) is a chronic pro-inflammatory and pro-thrombotic state associated with increased atherosclerosis, cardiovascular events and type 2 diabetes. It is diagnosed in the presence of at least 3 of 5 metabolic risk factors (obesity, hypertension, hypertriglyceridemia, low high-density lipoproteins (HDL) and insulin resistance [1]). The pathophysiology of MetS remains incompletely understood, but may share mechanisms with inflammatory states such as SLE. Visceral adiposity is known as a source of pro-inflammatory cytokines by adipocytes, the so-called adipokines. The contribution of glucocorticoids to the development of MetS in SLE is not clear, even though their use is associated with cardiovascular comorbidities [2]. We aim to characterize the prevalence and associations of MetS, including serum levels of adipokines, in a multi-ethnic cohort of patients with SLE. Method(s): Using a standardised protocol, baseline demographics, per visit disease activity (SLEDAI2K) and treatment data, and annual recording of organ damage accrual (SLICC damage index (SDI)) were prospectively captured on SLE patients from a single tertiary centre. The presence of MetS,defined using the updated joint consensus criteria [1], was assessed retrospectively at the last recorded visit. Serum levels of adipokines (resistin, lipocalin-2, TNF, MCP-1) and insulin were measured by Quantibody. Result(s): 116 patients (median (IQR) age at enrolment 39.5 (31.4-51.1) years, median disease duration 6.1 (1.4-12) years) were followed for a median of 6.7 (4.1-8.1) years. 80% of patients were exposed to glucocorticoids (median time-adjusted mean dose 3.7 (0.5-7.0) mg/day and 50% accrued organ damage during follow-up. The prevalence of MetS in this cohort was 29%. The prevalence of the components of MetS included: hypertension (59%), low-HDL (51%), hypertriglyceridemia (32%), obesity (16%) and hyperglycaemia (22%). In univariable analysis, MetS was associated with base

Systemic lupus erythematosus (lupus) is an autoimmune disease characterized by autoantibodies that form immune complexes with self-antigens, which deposit in various tissues, leading to inflammation and disease. The etiology of disease is complex and still not completely elucidated. Dysregulated inflammation is an important disease feature, and the mainstay of lupus treatment still utilizes nonspecific anti-inflammatory drugs. Granulocyte colony-stimulating factor (G-CSF) is a growth, survival, and activation factor for neutrophils and a mobilizer of hematopoietic stem cells, both of which underlie inflammatory responses in lupus. To determine whether G-CSF has a causal role in lupus, we genetically deleted G-CSF from Lyn-deficient mice, an experimental model of lupus nephritis. Lyn-/-G-CSF-/- mice displayed many of the inflammatory features of Lyn-deficient mice; however, they had reduced bone marrow and tissue neutrophils, consistent with G-CSF's role in neutrophil development. Unexpectedly, in comparison to aged Lyn-deficient mice, matched Lyn-/-G-CSF-/- mice maintained neutrophil hyperactivation and exhibited exacerbated numbers of effector memory T cells, augmented autoantibody titers, and worsened lupus nephritis. In humans, serum G-CSF levels were not elevated in patients with lupus or with active renal disease. Thus, these studies suggest that G-CSF is not pathogenic in lupus, and therefore G-CSF blockade is an unsuitable therapeutic avenue.Copyright © 2021 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd

Introduction/Aim. A major cause of mortality and morbidity in COPD are acute exacerbations (AECOPD), most frequently triggered by infections, such as influenza A virus (IAV). However, the identity of key factors of the immune system which contribute to AECOPD remain ill-defined. Innate immune responses to pathogens depend on the activation of inflammasomes, which facilitate the maturation and release of proinflammatory cytokines such as IL-1beta. Recently, clinical studies and human in vitro data have demonstrated excessive activation of inflammasomes in AECOPD. The aim of this study was to investigate a novel functional link between inflammasome activation and IAV infection in the pathogenesis of AECOPD. Methods. We employed a murine COPD model with acute IAV infection. Specifically, 6-week-old mice were exposed to cigarette smoke (CS) for 8 weeks. After 8 weeks, mice were infected with IAV and culled 5 days post infection. We also used COPD patient serum during stable disease, with their own corresponding IAV-induced acute exacerbation. Results. We discovered excessive productions of genes and proteins encoding AIM2 which forms a cytoplasmic DNA-sensing inflammasome, and IL-1beta in a murine COPD model with acute IAV infection. Nevertheless, the first-line therapy for AECOPD is glucocorticosteroids, which is limited in its efficacy. In that respect, Pirfenidone (PFD) is clinically used anti-inflammatory therapeutic. Importantly, our compelling data supported that PFD can alleviate the mRNA expressions of Aim2, and Il1beta in COPD model following acute IAV infection. We also discovered an elevated IL-1beta protein levels in serum of AECOPD patients compared to their stable status. Conclusion. Collectively, we define for the first time that hyperactivation of AIM2/IL-1beta axis plays a role in AECOPD. Finally, our data inform the future clinical utility (repurposing) of PFD to target inflammasomes in AECOPD and this would represent an enormous change in the therapeu

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with few known risk factors and biomarkers. Several blood protein biomarkers have been linked to PDAC in previous studies, but these studies have assessed only a limited number of biomarkers, usually in small samples. In this study, we evaluated associations of circulating protein levels and PDAC risk using genetic instruments. Method(s): To identify novel circulating protein biomarkers of PDAC, we studied 8,280 cases and 6,728 controls of European descent from the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case-Control Consortium, using genetic instruments of protein quantitative trait loci. Result(s): We observed associations between predicted concentrations of 38 proteins and PDAC risk at an FDR of < 0.05, including 23 of those proteins that showed an association even after Bonferroni correction. These include the protein encoded by ABO, which has been implicated as a potential target gene of PDAC risk variant. Eight of the identified proteins (LMA2L, TM11D, IP-10, ADH1B, STOM, TENC1, DOCK9, and CRBB2) were associated with PDAC risk after adjusting for previously reported PDAC risk variants (OR ranged from 0.79 to 1.52). Pathway enrichment analysis showed that the encoding genes for implicated proteins were significantly enriched in cancer-related pathways, such as STAT3 and IL15 production. Conclusion(s): We identified 38 candidates of protein biomarkers for PDAC risk. Impact: This study identifies novel protein biomarker candidates for PDAC, which if validated by additional studies, may contribute to the etiologic understanding of PDAC development.Copyright © 2020 American Association for Cancer Research.

Objectives To characterise the prevalence and associations of metabolic syndrome (MetS) in a multiethnic cohort of patients with SLE. Methods Using a standardised protocol, baseline demographics, per visit disease activity (Systemic Lupus Erythematosus Disease Activity Index-2K) and treatment data, and annual recording of organ damage accrual (Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC-ACR) Damage Index) were captured on patients with SLE from a single tertiary centre. The presence of MetS, defined using modified updated joint consensus criteria, was assessed at the final visit from patient records. Serum concentrations of adipocytokines were measured by Quantibody. Results 116 patients, with median (Q1, Q3) age at enrolment of 39.5 (31.4-51.1) years and disease duration of 6.1 (1.4-12) years, were followed for a median of 6.7 (4.1-8.1) years. The prevalence of MetS was 29% (34/116), while the prevalence of MetS components varied: hypertension (59%), low high-density lipoproteins (HDLs) (51%), hypertriglyceridaemia (32%), obesity (16%) and hyperglycaemia (22%). In univariable analysis, MetS was associated with baseline organ damage (OR 4.34; 95% CI 1.80 to 10.48; p<0.01) and organ damage accrual (OR 2.34; 95% CI 1.02 to 5.36; p=0.04) but not with disease activity. In multivariable analysis, baseline organ damage remained significantly associated with MetS (adjusted OR 3.36; 95% CI 1.32 to 8.59; p=0.01). Glucocorticoid use was not associated with MetS or any of its five components. High serum concentrations of resistin were significantly negatively associated with MetS (OR 0.17; 95% CI 0.04 to 0.70; p=0.014). Conclusion MetS was common in a multiethnic cohort of patients with SLE, with the most frequent components being hypertension and low HDL. An independent association was found between MetS and organ damage but not glucocorticoid exposure or disease activity.Copyright ©

Background: Elevated copeptin, a marker for vasopressin release, has been associated with impaired prognosis in acute myocardial infarction (MI). The aim was to investigate whether this association extends beyond the acute phase and whether it is related to markers of stress (cortisol) and heart failure (NTproBNP). Methods: Copeptin, cortisol and NTproBNP were measured in 926 participants (age: 76.0; male: 48.5%) in the ICELAND MI study whereof 246 had a previous MI (91 recognizable (RMI) and 155 previously unrecognizable (UMI) detected by cardiac magnetic resonance imaging). The primary endpoint was cardiovascular events (CVEs), and secondary endpoints were total mortality, heart failure and MI (median follow-up was 9.1 years). The relation between copeptin and prognosis was assessed with the Cox proportional hazard regression (unadjusted, adjusted for cortisol and NTproBNP, respectively, and a multiple model: copeptin, cortisol, NTproBNP, age, sex, serum creatinine, heart failure). Results: Copeptin was higher in participants with MI (8.9 vs. 6.4 pmol/L; P <.01), with no difference between RMI vs. UMI. Increased copeptin correlated with evening cortisol (r =.11; P <.01) and NTproBNP (r =.07; P =.04). Copeptin was associated with CVE and total mortality after adjusting for cortisol and NTproBNP separately, and remained significantly associated with total mortality in the multiple model. Conclusions: Copeptin was higher in subjects with previous MI regardless whether previously recognized or not. Copeptin correlated weakly with cortisol and NTproBNP, and was independently associated with total mortality. This indicates that the prognostic implications of copeptin are not only mediated by heart failure or stress, supporting the assumption that copeptin is a marker of general vulnerability., QC 20211130

We report a pilot study on the feasibility of determinations of circulating levels of paraoxonase-1 (PON1) and compounds related to energy metabolism as biomarkers for the evaluation of patients with rectal cancer (RC), and the effects produced by neoadjuvant radiochemotherapy (NRCT). We studied 32 patients treated with radiotherapy plus capecitabine concomitant chemotherapy and 48 control subjects. We identified pre-NRCT PON1 and alpha-ketoglutarate as the parameters that best discriminated between RC patients and the control group. Receiver operating characteristics analysis of the combination of the two parameters showed an area under the curve (AUC) of 0.918. Moreover, patients who presented a pathological complete response (pCR) to treatment had lower plasma pre-NRCT valine concentrations (AUC of 0.826). Patients who had a relapse had lower concentrations of succinate (AUC of 0.833). The results of the present study illustrate the usefulness of investigating alterations in oxidative stress and metabolism in RC. Due to the small number of patients studied, our results must be considered preliminary, but they suggest that the determination of circulating levels of PON1 and alpha-ketoglutarate might be a valuable tool for the early diagnosis of RC, while the determination of valine and succinate might effectively predict pCR and the appearance of relapse.

Background: There is a paucity of information on the role of microvascular and inflammatory biomarkers in cognitive dysfunction. Objective: This study sought to evaluate the relationships between established and a number of peripheral biomarkers on cognitive patterns in 108 older adults with memory complaints. Methods: Participants in the AIBL Active study aged 60 years and older with at least one vascular risk factor and memory complaints completed a neuropsychological test battery and provided cross-sectional health data. Linear regression models adjusted for covariates examined associations between cognitive performance and a panel of vascular risk factors (Framingham cardiovascular scores, hs-CRP, homocysteine, fasting glucose, LDL-cholesterol) and peripheral biomarkers (TNF-α, BDNF, VCAM-1, ICAM-1, PAI-1, CD40L). Results: Higher fasting glucose and homocysteine levels were independent factors associated with poorer performance in Trail Making Test (TMT) B (adjusted β = 0.40 ± 0.10 and 0.43 ± 0.09, respectively). Increasing homocysteine levels were weakly associated with poorer global cognition and delayed recall (adjusted β = 0.23 ± 0.10 and -0.20 ± 0.10 respectively). Increasing Framingham cardiovascular scores were related to poorer performance in TMT B (β = 0.42 ± 0.19). There was early evidence of associations between increasing plasma TNF-α and poorer TMT B (adjusted β = 0.21 ± 0.10) and between increasing BDNF and better global cognition (β = -0.20 ± 0.09). Conclusion: This study provides evidence to support the associations between vascular risk factors (Framingham scores, fasting glucose, and homocysteine) and poorer cognitive functions. Additionally, we measured several peripheral biomarkers to further investigate their associations with cognition. The relationship between TNF-α, BDNF, and cognitive performance in various domains may offer new insights into potential mechanisms in vascular cognitive impairment. © 2020 - IOS Press and the authors. All r

Introduction: The molecular mechanisms responsible for ICU Acquired Weakness (ICUAW) are poorly understood. Novel biomarkers may provide potential therapeutic targets, and assist in the identification of patients at risk of ICUAW. Activin A is a strong negative regulator of muscle mass, is elevated in sepsis and predicts mortality in acute respiratory failure. It is unclear whether muscle wasting in critically ill humans is related to elevated activin A levels. Objective(s): To investigate the relationship between serum activin A levels and physical function at ICU and hospital discharge. Method(s): This study was a prospective longitudinal observational cohort study. To date, 16 participants have been recruited from 2 tertiary ICUs from metropolitan hospitals in Melbourne, Australia. Participants were included if they were mechanically ventilated > 48 hours and were expected to have a total ICU stay of > 5 days. Total serum activin A levels were measured daily in ICU by specific assays. Grip strength and Medical Research Council Sum Score (MRC-SS) were completed daily in ICU. Physical Function in ICU Test Scored, Six-Minute Walk Test and Timed Up and Go Test were completed on ICU discharge and hospital discharge. Result(s): Nine of the sixteen participants survived to complete at least one physical outcome measure. Median serum activin A levels were lower in the participants who survived to ICU discharge (pseudo-R2 0.0822, p=0.021) but were not related to in hospital mortality (pseudo-R2 0.0422, p=0.078). Initial activin A levels were lower in participants who survived to hospital discharge (pseudo-R2 0.0614, p=0.048). Serum activin A levels were not related to any of the physical outcome measures at any time point. Conclusion(s): High serum activin A levels were associated with increased mortality but not worse physical function in critically ill patients.

Objectives: To describe the first isolation and sequencing of SARS-CoV-2 in Australia and rapid sharing of the isolate. Setting(s): SARS-CoV-2 was isolated from a 58-year-old man from Wuhan, China who arrived in Melbourne on 19 January 2020 and was admitted to the Monash Medical Centre, Melbourne from the emergency department on 24 January 2020 with fever, cough, and progressive dyspnoea. Major outcomes: Clinical course and laboratory features of the first reported case of COVID-19 (the illness caused by SARS-CoV-2) in Australia; isolation, whole genome sequencing, imaging, and rapid sharing of virus from the patient. Result(s): A nasopharyngeal swab and sputum collected when the patient presented to hospital were each positive for SARS-CoV-2 (reverse transcription polymerase chain reaction). Inoculation of Vero/hSLAM cells with material from the nasopharyngeal swab led to the isolation of SARS-CoV-2 virus in culture. Electron microscopy of the supernatant confirmed the presence of virus particles with morphology characteristic of viruses of the family Coronaviridae. Whole genome sequencing of the viral isolate and phylogenetic analysis indicated the isolate exhibited greater than 99.99% sequence identity with other publicly available SARS-CoV-2 genomes. Within 24 hours of isolation, the first Australian SARS-CoV-2 isolate was shared with local and overseas reference laboratories and major North American and European culture collections. Conclusion(s): The ability to rapidly identify, propagate, and internationally share our SARS-CoV-2 isolate is an important step in collaborative scientific efforts to deal effectively with this international public health emergency by developing better diagnostic procedures, vaccine candidates, and antiviral agents.Copyright © 2020 AMPCo Pty Ltd

Background: Competing risk models used for midpregnancy prediction of preterm pre-eclampsia have shown detection rates (DR) of 85%, at fixed false-positive rate (FPR) of 10%. The full algorithm used between 19+0 and 24+6 weeks includes maternal factors, mean arterial pressure (MAP), mean uterine artery pulsatility index (UtAPI), serum placental growth factor (PlGF) level in multiples of the median (MoM), and soluble Fms-like tyrosine kinase-1 (sFlt-1) level in MoM. Aim(s): To assess performance of the Fetal Medicine Foundation (FMF) algorithm at midpregnancy to screen for preterm (<37 weeks) pre-eclampsia. The outcome measured was preterm pre-eclampsia. Material(s) and Method(s): This is a prospective study including singleton pregnancies at 19-22 weeks gestation. Maternal bloods were collected and analysed using three different immunoassay platforms. Maternal characteristics, medical history, MAP, mean UtAPI, serum PlGF MoM and serum sFlt-1 MoM were used for risk assessment. DR and FPR were calculated, and receiver operating characteristic curves produced. Result(s): Five hundred and twelve patients were included. Incidence of preterm pre-eclampsia was 1.6%. Using predicted risk of pre-eclampsia of one in 60 or more and one in 100 or higher, as given by the FMF predictive algorithm, the combination with the best predictive performance for preterm pre-eclampsia included maternal factors, MAP, UtAPI and PlGF MoM, giving DRs of 100% and 100%, respectively, and FPRs of 9.3 for all platforms and 12.9-13.5, respectively. Addition of sFlt-1 to the algorithm did not appear to improve performance. sFlt-1 MoM and PlGF MoM values obtained on the different platforms performed very similarly. Conclusion(s): Second trimester combined screening for preterm pre-eclampsia by maternal history, MAP, mean UtAPI and PlGF MoM using the FMF algorithm performed very well in this patient population.Copyright © 2020 The Royal Australian and New Zealand College of Obstetricians and Gynaecolo

Importance: The conventional model of atherosclerosis presumes that the mass of cholesterol within very low-density lipoprotein particles, low-density lipoprotein particles, chylomicron, and lipoprotein (a) particles in plasma is the principal determinant of the mass of cholesterol that will be deposited within the arterial wall and will drive atherogenesis. However, each of these particles contains one molecule of apolipoprotein B (apoB) and there is now substantial evidence that apoB more accurately measures the atherogenic risk owing to the apoB lipoproteins than does low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol. Observations: Cholesterol can only enter the arterial wall within apoB particles. However, the mass of cholesterol per apoB particle is variable. Therefore, the mass of cholesterol that will be deposited within the arterial wall is determined by the number of apoB particles that are trapped within the arterial wall. The number of apoB particles that enter the arterial wall is determined primarily by the number of apoB particles within the arterial lumen. However, once within the arterial wall, smaller cholesterol-depleted apoB particles have a greater tendency to be trapped than larger cholesterol-enriched apoB particles because they bind more avidly to the glycosaminoglycans within the subintimal space of the arterial wall. Thus, a cholesterol-enriched particle would deposit more cholesterol than a cholesterol-depleted apoB particle whereas more, smaller apoB particles that enter the arterial wall will be trapped than larger apoB particles. The net result is, with the exceptions of the abnormal chylomicron remnants in type III hyperlipoproteinemia and lipoprotein (a), all apoB particles are equally atherogenic. Conclusions and Relevance: Apolipoprotein B unifies, amplifies, and simplifies the information from the conventional lipid markers as to the atherogenic risk attributable to the apoB lipoproteins..Copyright © 20

Background: The prognostic value of asymptomatic perioperative troponin rise in vascular surgery is unclear. We conducted this systematic review and meta-analysis to determine the significance of clinical and subclinical troponin elevation after vascular surgery. Method(s): We searched MEDLINE (Ovid), Embase (Ovid), and the Cochrane Library, without language restriction, from inception to May 2019 and included studies that reported associations between elevated postoperative troponin and short-term mortality, major adverse cardiac events (MACEs), or long-term mortality in a vascular surgery cohort. We synthesized study-level data on the maximally adjusted estimates using mixed effects modeling to generate summary odds ratios (ORs) for fixed-interval outcomes and summary hazard ratios for long-term mortality. Between-study heterogeneity was assessed with meta-regression. Methodologic quality and publication bias were formally assessed. Result(s): We included 24 studies involving 11,657 participants. Postoperative troponin was found to have a strong, positive association with short-term mortality (OR, 4.95; 95% confidence interval [CI], 2.87-8.52; 7 studies; 2661 people) and MACEs (OR, 5.33; 95% CI, 1.59-17.82; 12 studies; 5047 people) independent of meeting the criteria for myocardial infarction. Subclinical postoperative troponin elevation was further demonstrated to be associated with greater long-term mortality (hazard ratio, 1.94; 95% CI, 1.56-2.42; 13 studies; 7630 people; median follow-up, 24 months). Time to troponin sampling, hypertension, and type of surgery partially accounted for between-study heterogeneity. The methodologic quality of included studies was variable, and publication bias was not detected. Conclusion(s): Elevated postoperative troponin is strongly prognostic of worse survival and greater likelihood of MACEs after vascular surgery, regardless of whether symptoms of myocardial ischemia are present. These data support the benefit of postoperati

Brain-derived neurotrophic factor (BDNF) has been implicated in cognition and the effects of chronic stress. We have previously shown in mice that chronic adolescent treatment with corticosterone (CORT), to simulate stress, resulted in spatial memory deficits and markedly elevated levels of the N-methyl-D-aspartate (NMDA) receptor subunit NR2B in adult male BDNF heterozygous mice (BDNF+/-), but not in wildtype controls (WT) or females. The aim of the present study was to further characterize this 'two hit' model, including whether these effects are long-lasting. CORT treatment was delivered in the drinking water from 6 to 9 weeks of age. As previously demonstrated, male BDNF+/- mice treated with CORT presented with a deficit in spatial memory at 11 weeks of age. However, this deficit was not maintained at 15 weeks of age. Conversely, male WT treated with CORT developed a deficit only at 15 weeks of age. There were no significant gene-environment interactions in female mice at any time point. CORT treatment caused a modest, but significant increase in NR2B levels which was independent of genotype. These results show marked age-dependent and sex-dependent effects of CORT on behaviour which are different in BDNF+/- mice than in controls.Copyright © 2019 Elsevier B.V.

Background: Repeat transarterial chemoembolisation (rTACE) is often required for hepatocellular carcinoma (HCC) to achieve disease control, however, current practice guidelines regarding treatment allocation vary significantly. This study aims to identify key factors associated with patient survival following rTACE to facilitate treatment allocation and prognostic discussion. Method(s): Patients with HCC undergoing rTACE at six Australian tertiary centers from 2009 to 2014 were included. Variables encompassing clinical, tumour, treatment type and response factors were analysed against the primary outcome of overall survival. Univariate analysis and multivariate Cox regression modelling were used to identify factors pre- and post-TACE therapy significantly associated with survival. Result(s): Total of 292 consecutive patients underwent rTACE with mainly Child Pugh A cirrhosis (61%) and BCLC stage A (57%) disease. Median overall survival (OS) was 30 months (IQR 15.2-50.2) from initial TACE. On multivariate analysis greater tumour number (p = 0.02), higher serum bilirubin (p = 0.007) post initial TACE, and hepatic decompensation (p = 0.001) post second TACE were associated with reduced survival. Patients with serum AFP >= 200 ng/ml following initial TACE had lower survival (p = 0.001), compared to patients with serum AFP level that remained < 200 ng/ml post-initial TACE, with an overall survival of 19.4 months versus 34.7 months (p = 0.0001) respectively. Conclusion(s): Serum AFP level following initial treatment in patients undergoing repeat TACE for HCC is a simple and useful clinical prognostic marker. Moreover, it has the potential to facilitate appropriate patient selection for rTACE particularly when used in conjunction with baseline tumour burden and severity of hepatic dysfunction post-initial TACE.Copyright © 2020 The Author(s).

Background: AK112 is a humanized IgG1 bispecific anti-PD-1/VEGF antibody. VEGF blockade potentiates PD-1 inhibition by, inter alia, opposing the immunosuppressive effects of VEGF-A, which include suppression of dendritic cell activity and enhancement of checkpoint molecule expression on CD8+ T cells and proliferation of regulatory T cells. Combination therapies involving PD-(L)1 and VEGF inhibitors have been approved for the treatment of selected patients with metastatic non-small cell lung carcinoma, advanced renal cell carcinoma and advanced endometrial carcinoma. A supplemental Biologics License Application has been submitted for an anti-PD-L1 + anti-VEGF combination for the firstline treatment of unresectable hepatocellular carcinoma. Given the strong correlation between VEGF and PD-1 expression in the tumor microenvironment, the simultaneous blockade of these 2 targets by AK112 as a single agent might achieve higher target binding specificities and synergistically produce enhanced antitumor activity compared to co-administration of anti-PD-(L)1 and anti-VEGF therapies. Method(s): This is a Phase 1a/1b, first-in-human, multicenter, open-label study in patients with advanced or metastatic solid tumor that is refractory/relapsed to standard therapies. The primary objective is to assess safety, tolerability and DLTs; and to determine the Maximum Tolerated Dose (MTD) or Maximum Administered Dose of AK112. Antitumor activity, PK and immunogenicity of AK112 will be studied as secondary objectives. As exploratory endpoints, tumor tissue samples may be evaluated for PD-L1 expression, mRNA expression profile and biomarkers (e.g. CD8+, FoxP3, Granzyme B, apelin and EPHB4). PD-1 receptor occupancy on circulating T-cells and serum VEGF level may also be measured as indications of target engagement. The dose-escalation phase will evaluate 5 dose levels of AK112 (up to 20 mg/kg Q2W IV) using a 3+3+3 study design. Additional subjects (up to 18 subjects) may be enrolled at any

Aims/hypothesis: We aimed to assess associations between cord blood metabolic markers and fetal overgrowth, and whether cord markers mediated the impact of maternal adiposity on neonatal anthropometric outcomes among children born to Indigenous and Non-Indigenous Australian women with normal glucose tolerance (NGT), gestational diabetes mellitus (GDM) and pregestational type 2 diabetes mellitus. Method(s): From the Pregnancy and Neonatal Outcomes in Remote Australia (PANDORA) study, an observational cohort of 1135 mother-baby pairs, venous cord blood was available for 645 singleton babies (49% Indigenous Australian) of women with NGT (n = 129), GDM (n = 419) and type 2 diabetes (n = 97). Cord glucose, triacylglycerol, HDL-cholesterol, C-reactive protein (CRP) and C-peptide were measured. Multivariable logistic and linear regression were used to assess the associations between cord blood metabolic markers and the outcomes of birthweight z score, sum of skinfold thickness (SSF), being large for gestational age (LGA) and percentage of body fat. Pathway analysis assessed whether cord markers mediated the associations between maternal and neonatal adiposity. Result(s): Elevated cord C-peptide was significantly associated with increasing birthweight z score (beta 0.57 [95% CI 0.42, 0.71]), SSF (beta 0.83 [95% CI 0.41, 1.25]), percentage of body fat (beta 1.20 [95% CI 0.69, 1.71]) and risk for LGA [OR 3.14 [95% CI 2.11, 4.68]), after adjusting for age, ethnicity and diabetes type. Cord triacylglycerol was negatively associated with birthweight z score for Indigenous Australian women only. No associations between cord glucose, HDL-cholesterol and CRP >0.3 mg/l (2.9 nmol/l) with neonatal outcomes were observed. C-peptide mediated 18% (95% CI 13, 36) of the association of maternal BMI with LGA and 11% (95% CI 8, 17) of the association with per cent neonatal fat. Conclusions/interpretation: Cord blood C-peptide is an important mediator of the association between maternal and i

Background & Aims: Human studies examining associations between circulating levels of insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) and colorectal cancer risk have reported inconsistent results. We conducted complementary serologic and Mendelian randomization (MR) analyses to determine whether alterations in circulating levels of IGF1 or IGFBP3 are associated with colorectal cancer development. Method(s): Serum levels of IGF1 were measured in blood samples collected from 397,380 participants from the UK Biobank, from 2006 through 2010. Incident cancer cases and cancer cases recorded first in death certificates were identified through linkage to national cancer and death registries. Complete follow-up was available through March 31, 2016. For the MR analyses, we identified genetic variants associated with circulating levels of IGF1 and IGFBP3. The association of these genetic variants with colorectal cancer was examined with 2-sample MR methods using genome-wide association study consortia data (52,865 cases with colorectal cancer and 46,287 individuals without [controls]) Results: After a median follow-up period of 7.1 years, 2665 cases of colorectal cancer were recorded. In a multivariable-adjusted model, circulating level of IGF1 associated with colorectal cancer risk (hazard ratio per 1 standard deviation increment of IGF1, 1.11; 95% confidence interval [CI] 1.05-1.17). Similar associations were found by sex, follow-up time, and tumor subsite. In the MR analyses, a 1 standard deviation increment in IGF1 level, predicted based on genetic factors, was associated with a higher risk of colorectal cancer risk (odds ratio 1.08; 95% CI 1.03-1.12; P = 3.3 x 10-4). Level of IGFBP3, predicted based on genetic factors, was associated with colorectal cancer risk (odds ratio per 1 standard deviation increment, 1.12; 95% CI 1.06-1.18; P = 4.2 x 10-5). Colorectal cancer risk was associated with only 1 variant in the IGFBP3 gene re

Background: The relations between diet, chronic inflammation, and musculoskeletal health are unclear, especially among older men. Objective(s): 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. Method(s): The cross-sectional analysis included 794 community-dwelling men, mean age 81.1 +/- 4.5 y, who participated in the 5-y follow-up of the Concord Health and Aging in Men Project. Of these, 616 were seen again 3 y later for the longitudinal analysis. Energy-adjusted DII (E-DII) was calculated from a validated diet history questionnaire. Bone mineral density (BMD) was measured using DXA. Twenty-four inflammatory biomarkers were analyzed. Incident falls over 3 y were determined through telephone interviews every 4 mo. Multiple regression, linear mixed effects models, negative binomial regression, and mediation analysis were utilized in this study. Result(s): A higher E-DII score (indicating a more proinflammatory diet) was associated with higher concentrations of IL-6 (beta: 0.028 pg/mL; 95% CI: 0.003, 0.053), IL-7 (beta: 0.020 pg/mL; 95% CI: 0.002, 0.037), and TNF-alpha (beta: 0.027 pg/mL; 95% CI: 0.003, 0.051). A higher E-DII score was also associated with lower appendicular lean mass adjusted for BMI (ALMBMI) (beta: -0.006 kg/m2; 95% CI: -0.010, -0.001). For every unit increase in E-DII (range: -4.91 to +3.66 units), incident falls rates increased by 13% (incidence rate ratio: 1.13; 95% CI: 1.05, 1.21) over 3 y. Mediation analysis showed that the association between E-DII and 3-y incident falls was influenced by the concentrations of IL-7 by 24%. There was no association between E-DII and BMD. Conclusion(s): Consumption of a proinflammatory diet was associated with increased concentrations of IL-6, IL-7, and TNF-alpha; increased falls risk; and lower ALMBMI in community-dwelling older men. The association between incident falls and E

Background: Adalimumab is administered via a pre-filled syringe or spring-loaded pen. In a previous study in Crohn's disease, higher drug levels were observed in syringe users. The aim of this study was to evaluate the impact of delivery device on adalimumab drug levels in patients with Crohn's disease. Method(s): Consecutive Crohn's disease patients treated with maintenance adalimumab [40 mg fortnightly] were recruited from five centres. The first recorded drug level with matched clinical and biochemical markers of disease activity was compared between pen and syringe users. Result(s): Of 218 patients, 64% used pen, with a median faecal calprotectin 110 mug/g and serum C-reactive protein 4 mg/L. In comparison to pen, syringe users had higher albumin [39 vs 42 g/L; p = 0.016], lower Harvey-Bradshaw Index [2 vs 1; p = 0.017], and higher rates of concomitant immunomodulation [54% vs 71%; p = 0.014]. Drug levels were equivalent between pen and syringe users [median 5.3 vs 5.2 mug/ml; p = 0.584], even after controlling for disease activity and immunomodulation. Syringe users at Alfred Health had higher drug levels than pen [6.1 vs 4.5 mug/ml; p = 0.039]; a greater proportion achieved therapeutic levels [75% vs 44%; p = 0.045]. A higher proportion of pen users from Saint-Etienne had therapeutic levels [79% vs 42%; p = 0.027], yet no significant difference in drug levels [7.9 vs 4.5 mug/ml; p = 0.119]. Conclusion(s): Delivery device does not appear to significantly affect adalimumab drug levels. Given differences between study sites, studies evaluating administration education and technique are warranted.Copyright © 2019 European Crohn's and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved.

Chronic kidney disease is emerging as a novel risk factor for cerebrovascular disease, but this association remains largely unexplored in older adults. Cystatin C is a more accurate measure than creatinine of kidney function in the elderly. We evaluated cystatin C, cognitive function, and brain imaging in 193 participants from The 90+ Study neuroimaging component. The mean age was 93.9 years; 61% were women. Mean cystatin C was 1.62 mg/L with estimated glomerular filtration rate 39.2 mL/min/1.73 m2. Performance on measures of global cognition, executive function, and visual-spatial ability declined at higher tertiles of cystatin C (lower kidney function). Higher cystatin C was significantly associated with infratentorial microbleeds and lower gray matter volume. Adjusted risk of incident dementia was increased in the middle and high cystatin C tertile groups compared with the low group (hazard ratio in highest tertile 3.81 [95% confidence interval 1.14-12.7]), which appeared to be explained in part by the presence of cerebral microbleeds. Overall, cystatin C was associated with cognitive performance, brain imaging pathology, and decline to dementia in this oldest-old cohort.

Background: Active surveillance (AS) enrolment criteria and follow-up schedules for low-risk prostate cancer vary between institutions. However, uncertainty remains about adherence to these protocols. Objective(s): To determine adherence to institution-specific AS inclusion criteria and follow-up schedules within the Movember Foundation's Global Action Plan Prostate Cancer Active Surveillance (GAP3) initiative. Design, setting, and participants: We retrospectively assessed the data of 15 101 patients from 25 established AS cohorts worldwide between 2014 and 2016. Outcome measurements and statistical analysis: Adherence to individual AS inclusion criteria was rated on a five-point Likert scale ranging from poor to excellent. Nonadherence to follow-up schedules was defined as absence of repeat biopsy 1 yr after the scheduled date. Cohorts were pooled into annual and Prostate Cancer Research International: Active Surveillance (PRIAS)-based biopsy schedules, and a generalised linear mixed model was constructed to test for nonadherence. Results and limitations: Serum prostate-specific antigen (PSA) inclusion criteria were followed in 92%, Gleason score (GS) criteria were followed in 97%, and the number of positive biopsy cores was followed in 94% of men. Both age and tumour stage (T stage) criteria had 99% adherence overall. Pooled nonadherence rates increased over time-8%, 16%, and 34% for annual schedules and 11%, 30%, and 29% for PRIAS-based schedules at 1, 4, and 7 yr, respectively-and did not differ between biopsy schedules. A limitation is that our results do not consider the use of multiparametric magnetic resonance imaging. Conclusion(s): In on-going development of evidence-based AS protocols, variable adherence to PSA and GS inclusion criteria should be considered. Repeat biopsy adherence reduces with increased duration of surveillance, independent of biopsy frequency. This emphasises the importance of risk stratification at the commencement of AS. Patient Summa

AATD is a common inherited disorder associated with an increased risk of developing pulmonary emphysema and liver disease. Many people with AATD-associated pulmonary emphysema remain undiagnosed and therefore without access to care and counselling specific to the disease. AAT augmentation therapy is available and consists of i.v. infusions of exogenous AAT protein harvested from pooled blood products. Its clinical efficacy has been the subject of some debate and the use of AAT augmentation therapy was recently permitted by regulators in Australia and New Zealand, although treatment is not presently subsidized by the government in either country. The purpose of this position statement is to review the evidence for diagnosis and treatment of AATD-related lung disease with reference to the Australian and New Zealand population. The clinical efficacy and adverse events of AAT augmentation therapy were evaluated by a systematic review, and the GRADE process was employed to move from evidence to recommendation. Other sections address the wide range of issues to be considered in the care of the individual with AATD-related lung disease: when and how to test for AATD, changing diagnostic techniques, monitoring of progression, disease in heterozygous AATD and pharmacological and non-pharmacological therapy including surgical options for severe disease. Consideration is also given to broader issues in AATD that respiratory healthcare staff may encounter: genetic counselling, patient support groups, monitoring for liver disease and the need to establish national registries for people with AATD in Australia and New Zealand.Copyright © 2020 The Authors. Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.

High occurence of liver diseases (toxic, viral hepatitis, liver failure, cirrhosis) requires urgent search of new methods for management of the hepatobiliary diseases. At the present time, the role of immune mechanisms in pathogenesis of diffuse toxic liver damage is not finally clarified. The model of toxic hepatitis induced by carbon tetrachloride (CCl4) is widely known, but this approach allows us to perform complex evaluation and develop the methods for adequate correction of liver disorders in experimental model, which is not always feasible in clinical setting. To design a model of diffuse toxic liver damage, the CCl4 oil solution was used, having been administered intraperitoneally to experimental animals, at a single dose of 50 mg per 100 g body mass. Aiming for correction of toxic liver damage, the injections of aminophthalhydrazide (APH) to experimental animals were carried out intramuscularly at the dose of 2 mg/kg over the terms of experiment. An evaluation of the role of sinusoidal cells (SC) and cytokine production at the local and systemic level were carried out in the model of toxic liver damage caused by CCl4 and its correction by APH treatment. In the course of developing diffuse toxic liver damage induced by CCl4, the production of proinflammatory cytokines TNFα, IL-1α and IL-18 was enhanced at the local level, whereas an increase in TNFα concentration was observed in blood plasma. Following aminophthalhydrazide (APH) administration, the concentrations of proinflammatory cytokines (TNFα and IL-18) decreased at system level, along with locally decreased levels of IL-6 and IFNγ. Changes in the functional state of immunocompetent cells, which include sinusoidal cells (SC), have a significant impact on the development of pathological processes in the liver. The results of our study presume that, over the early periods of toxic impact upon liver tissue, the number of SCs increases both due to influx of blood monocytes and mature macrophages from the pe