Epidemiology of chronic hepatitis B and C in Victoria, Australia: insights and impacts from enhanced surveillance

Objective: To assess the impact of an enhanced viral hepatitis surveillance program on datacompleteness and on epidemiological assessment of affected populations.Methods: Notified cases of non-acute hepatitis B and C were analysed to determinedemographic characteristics and risk factors during the period prior to July 2015–June 2016,and during enhanced surveillance of the period July 2016–June 2017, during which timedoctors were contacted for information about new diagnoses.Results: During the enhanced period, completeness for country of birth and Indigenous statusdoubled for both hepatitis B and hepatitis C, from 18–37% to 48–65%. The incidence ratio ofhepatitis C among Aboriginal and Torres Strait Islander people increased from eight-fold to 11.4-fold, and the proportion of hepatitis B cases reported as born in China and Vietnam relative toother countries increased. New data fields identified that 12% of hepatitis C diagnoses occurredin a correctional facility, and 2% of hepatitis B cases were healthcare workers.Conclusions: Improved data completeness highlighted the underlying epidemiology ofchronic viral hepatitis, demonstrating the increased burden of infection among specific prioritypopulations.Implications for public health: Enhanced surveillance provides greater insight into theepidemiology of chronic viral hepatitis, identifying groups at risk and opportunities for publichealth action

Prognostic value of the ABCD2 score beyond short-term follow-up after transient ischemic attack (TIA) - a cohort study

<p>Abstract</p> <p>Background</p> <p>Transient ischemic attack (TIA) patients are at a high vascular risk. Recently the ABCD²score was validated for evaluating short-term stroke risk after TIA. We assessed the value of this score to predict the vascular outcome after TIA during medium- to long-term follow-up.</p> <p>Methods</p> <p>The ABCD²score of 176 TIA patients consecutively admitted to the Stroke Unit was retrospectively calculated and stratified into three categories. TIA was defined as an acute transient focal neurological deficit caused by vascular disease and being completely reversible within 24 hours. All patients had to undergo cerebral MRI within 5 days after onset of symptoms as well as extracranial and transcranial Doppler and duplex ultrasonography. At a median follow-up of 27 months, new vascular events were recorded. Multivariate Cox regression adjusted for EDC findings and heart failure was performed for the combined endpoint of cerebral ischemic events, cardiac ischemic events and death of vascular or unknown cause.</p> <p>Results</p> <p>Fifty-five patients (32.0%) had an ABCD²score ≤ 3, 80 patients (46.5%) had an ABCD2 score of 4-5 points and 37 patients (21.5%) had an ABCD²score of 6-7 points. Follow-up data were available in 173 (98.3%) patients. Twenty-two patients (13.8%) experienced an ischemic stroke or TIA; 5 (3.0%) a myocardial infarction or acute coronary syndrome; 10 (5.7%) died of vascular or unknown cause; and 5 (3.0%) patients underwent arterial revascularization. An ABCD²score > 3 was significantly associated with the combined endpoint of cerebral or cardiovascular ischemic events, and death of vascular or unknown cause (hazard ratio (HR) 4.01, 95% confidence interval (CI) 1.21 to 13.27). After adjustment for extracranial ultrasonographic findings and heart failure, there was still a strong trend (HR 3.13, 95% CI 0.94 to 10.49). Whereas new cardiovascular ischemic events occurred in 9 (8.3%) patients with an ABCD²score > 3, this happened in none of the 53 patients with a score ≤ 3.</p> <p>Conclusions</p> <p>An ABCD²score > 3 is associated with an increased general risk for vascular events in the medium- to long-term follow-up after TIA.</p

Identification of chemokine receptors as potential modulators of endocrine resistance in oestrogen receptor–positive breast cancers

Introduction Endocrine therapies target oestrogenic stimulation of breast cancer (BC) growth, but resistance remains problematic. Our aims in this study were (1) to identify genes most strongly associated with resistance to endocrine therapy by intersecting global gene transcription data from patients treated presurgically with the aromatase inhibitor anastrazole with those from MCF7 cells adapted to long-term oestrogen deprivation (LTED) (2) to assess the clinical value of selected genes in public clinical data sets and (3) to determine the impact of targeting these genes with novel agents. Methods Gene expression and Ki67 data were available from 69 postmenopausal women with oestrogen receptor–positive (ER+) early BC, at baseline and 2 weeks after anastrazole treatment, and from cell lines adapted to LTED. The functional consequences of target genes on proliferation, ER-mediated transcription and downstream cell signalling were assessed. Results By intersecting genes predictive of a poor change in Ki67 with those upregulated in LTED cells, we identified 32 genes strongly correlated with poor antiproliferative response that were associated with inflammation and/or immunity. In a panel of LTED cell lines, C-X-C chemokine receptor type 7 (CXCR7) and CXCR4 were upregulated compared to their wild types (wt), and CXCR7, but not CXCR4, was associated with reduced relapse-free survival in patients with ER+ BC. The CXCR4 small interfering RNA variant (siCXCR4) had no specific effect on the proliferation of wt-SUM44, wt-MCF7 and their LTED derivatives. In contrast, siCXCR7, as well as CCX733, a CXCR7 antagonist, specifically suppressed the proliferation of MCF7-LTED cells. siCXCR7 suppressed proteins associated with G1/S transition and inhibited ER transactivation in MCF7-LTED, but not wt-MCF7, by impeding association between ER and proline-, glutamic acid– and leucine-rich protein 1, an ER coactivator. Conclusions These data highlight CXCR7 as a potential therapeutic target warranting clinical investigation in endocrine-resistant BC

The Effect of Anandamide on Uterine Nitric Oxide Synthase Activity Depends on the Presence of the Blastocyst

Nitric oxide production, catalyzed by nitric oxide synthase (NOS), should be strictly regulated to allow embryo implantation. Thus, our first aim was to study NOS activity during peri-implantation in the rat uterus. Day 6 inter-implantation sites showed lower NOS activity (0.19±0.01 pmoles L-citrulline mg prot−1 h−1) compared to days 4 (0.34±0.03) and 5 (0.35±0.02) of pregnancy and to day 6 implantation sites (0.33±0.01). This regulation was not observed in pseudopregnancy. Both dormant and active blastocysts maintained NOS activity at similar levels. Anandamide (AEA), an endocannabinoid, binds to cannabinoid receptors type 1 (CB1) and type 2 (CB2), and high concentrations are toxic for implantation and embryo development. Previously, we observed that AEA synthesis presents an inverted pattern compared to NOS activity described here. We adopted a pharmacological approach using AEA, URB-597 (a selective inhibitor of fatty acid amide hydrolase, the enzyme that degrades AEA) and receptor selective antagonists to investigate the effect of AEA on uterine NOS activity in vitro in rat models of implantation. While AEA (0.70±0.02 vs 0.40±0.04) and URB-597 (1.08±0.09 vs 0.83±0.06) inhibited NOS activity in the absence of a blastocyst (pseudopregnancy) through CB2 receptors, AEA did not modulate NOS on day 5 pregnant uterus. Once implantation begins, URB-597 decreased NOS activity on day 6 implantation sites via CB1 receptors (0.25±0.04 vs 0.40±0.05). While a CB1 antagonist augmented NOS activity on day 6 inter-implantation sites (0.17±0.02 vs 0.27±0.02), a CB2 antagonist decreased it (0.17±0.02 vs 0.12±0.01). Finally, we described the expression and localization of cannabinoid receptors during implantation. In conclusion, AEA levels close to and at implantation sites seems to modulate NOS activity and thus nitric oxide production, fundamental for implantation, via cannabinoid receptors. This modulation depends on the presence of the blastocyst. These data establish cannabinoid receptors as an interesting target for the treatment of implantation deficiencies

Severe Hindrance of Viral Infection Propagation in Spatially Extended Hosts

The production of large progeny numbers affected by high mutation rates is a ubiquitous strategy of viruses, as it promotes quick adaptation and survival to changing environments. However, this situation often ushers in an arms race between the virus and the host cells. In this paper we investigate in depth a model for the dynamics of a phenotypically heterogeneous population of viruses whose propagation is limited to two-dimensional geometries, and where host cells are able to develop defenses against infection. Our analytical and numerical analyses are developed in close connection to directed percolation models. In fact, we show that making the space explicit in the model, which in turn amounts to reducing viral mobility and hindering the infective ability of the virus, connects our work with similar dynamical models that lie in the universality class of directed percolation. In addition, we use the fact that our model is a multicomponent generalization of the Domany-Kinzel probabilistic cellular automaton to employ several techniques developed in the past in that context, such as the two-site approximation to the extinction transition line. Our aim is to better understand propagation of viral infections with mobility restrictions, e.g., in crops or in plant leaves, in order to inspire new strategies for effective viral control

Mesenchymal Stem Cell Graft Improves Recovery after Spinal Cord Injury in Adult Rats through Neurotrophic and Pro-Angiogenic Actions

Numerous strategies have been managed to improve functional recovery after spinal cord injury (SCI) but an optimal strategy doesn't exist yet. Actually, it is the complexity of the injured spinal cord pathophysiology that begets the multifactorial approaches assessed to favour tissue protection, axonal regrowth and functional recovery. In this context, it appears that mesenchymal stem cells (MSCs) could take an interesting part. The aim of this study is to graft MSCs after a spinal cord compression injury in adult rat to assess their effect on functional recovery and to highlight their mechanisms of action. We found that in intravenously grafted animals, MSCs induce, as early as 1 week after the graft, an improvement of their open field and grid navigation scores compared to control animals. At the histological analysis of their dissected spinal cord, no MSCs were found within the host despite their BrdU labelling performed before the graft, whatever the delay observed: 7, 14 or 21 days. However, a cytokine array performed on spinal cord extracts 3 days after MSC graft reveals a significant increase of NGF expression in the injured tissue. Also, a significant tissue sparing effect of MSC graft was observed. Finally, we also show that MSCs promote vascularisation, as the density of blood vessels within the lesioned area was higher in grafted rats. In conclusion, we bring here some new evidences that MSCs most likely act throughout their secretions and not via their own integration/differentiation within the host tissue

A theoretical model of inflammation- and mechanotransduction- driven asthmatic airway remodelling

Inflammation, airway hyper-responsiveness and airway remodelling are well-established hallmarks of asthma, but their inter-relationships remain elusive. In order to obtain a better understanding of their inter-dependence, we develop a mechanochemical morphoelastic model of the airway wall accounting for local volume changes in airway smooth muscle (ASM) and extracellular matrix in response to transient inflammatory or contractile agonist challenges. We use constrained mixture theory, together with a multiplicative decomposition of growth from the elastic deformation, to model the airway wall as a nonlinear fibre-reinforced elastic cylinder. Local contractile agonist drives ASM cell contraction, generating mechanical stresses in the tissue that drive further release of mitogenic mediators and contractile agonists via underlying mechanotransductive signalling pathways. Our model predictions are consistent with previously described inflammation-induced remodelling within an axisymmetric airway geometry. Additionally, our simulations reveal novel mechanotransductive feedback by which hyper-responsive airways exhibit increased remodelling, for example, via stress-induced release of pro-mitogenic and procontractile cytokines. Simulation results also reveal emergence of a persistent contractile tone observed in asthmatics, via either a pathological mechanotransductive feedback loop, a failure to clear agonists from the tissue, or a combination of both. Furthermore, we identify various parameter combinations that may contribute to the existence of different asthma phenotypes, and we illustrate a combination of factors which may predispose severe asthmatics to fatal bronchospasms