Epidemiology of hepatitis C virus among people who inject drugs in Australia: Prevention coverage, incidence and treatment uptake

The Australian Needle and Syringe Program Survey (ANSPS) is a well-established sentinel surveillance tool that provides serial point antibody prevalence estimates of HIV and hepatitis C virus (HCV) antibody and associated risk behaviour among people who inject drugs (PWID). This thesis presents three studies that developed methodologies to enhance the existing ANSPS in order to investigate important epidemiological aspects of HCV infection. The extent of syringe ‘coverage’ required to prevent or reduce HCV transmission among PWID remains a key question with little high quality data informing this issue. Although Australia has achieved and maintained a low rate of HIV prevalence among PWID, the early and widespread establishment of needle and syringe programs has not been sufficient to prevent transmission of HCV among this group. The first study examined individual-level syringe coverage among a national sample of n=1,568 PWID, identifying high levels of syringe coverage by international standards. The second study used a simple deterministic linkage method to create a passive retrospective cohort of HCV antibody negative ANSPS respondents to examine HCV incidence over the period 1996 to 2010. The study demonstrated a significant decline in HCV incidence during a period of considerable change in drug markets, substantial expansion of harm reduction programs and a probable reduction in the size of the Australian PWID population. Given high prevalence of HCV among Australian PWID and an expanding burden of liver-related morbidity, the third study investigated temporal trends and predictors of HCV treatment uptake among this population. The results indicated that although lifetime treatment uptake increased significantly between 1999 and 2011, annual treatment uptake remained low. Together these studies demonstrate the additional capacity of sentinel surveillance to monitor and evaluate the effectiveness of HCV prevention and treatment interventions. Data on treatment uptake and outcomes will become increasingly valuable with the rollout of new interferon-free direct acting antiviral regimens that are likely to replace existing HCV therapy over the next 2-5 years. Future opportunities include estimation of the proportion of incident and chronic infections using recently conducted RNA serology; and investigation of the feasibility of phylogenetic analysis to examine genotype distribution and mixed infection

Rat Urinary Bladder Carcinogenesis by Dual-Acting PPARα + γ Agonists

Despite clinical promise, dual-acting activators of PPARα and γ (here termed PPARα+γ agonists) have experienced high attrition rates in preclinical and early clinical development, due to toxicity. In some cases, discontinuation was due to carcinogenic effect in the rat urothelium, the epithelial layer lining the urinary bladder, ureters, and kidney pelvis. Chronic pharmacological activation of PPARα is invariably associated with cancer in rats and mice. Chronic pharmacological activation of PPARγ can in some cases also cause cancer in rats and mice. Urothelial cells coexpress PPARα as well as PPARγ, making it plausible that the urothelial carcinogenicity of PPARα+γ agonists may be caused by receptor-mediated effects (exaggerated pharmacology). Based on previously published mode of action data for the PPARα+γ agonist ragaglitazar, and the available literature about the role of PPARα and γ in rodent carcinogenesis, we propose a mode of action hypothesis for the carcinogenic effect of PPARα+γ agonists in the rat urothelium, which combines receptor-mediated and off-target cytotoxic effects. The proposed mode of action hypothesis is being explored in our laboratories, towards understanding the human relevance of the rat cancer findings, and developing rapid in vitro or short-term in vivo screening approaches to faciliate development of new dual-acting PPAR agonist compounds

Elevated blood pressure, heart rate and body temperature in mice lacking the XL alpha s protein of the Gnas locus is due to increased sympathetic tone

NEW FINDINGS: What is the central question of this study? Previously, we showed that Gnasxl knock-out mice are lean and hypermetabolic, with increased sympathetic stimulation of adipose tissue. Do these mice also display elevated sympathetic cardiovascular tone? Is the brain glucagon-like peptide-1 system involved? What is the main finding and its importance? Gnasxl knock-outs have increased blood pressure, heart rate and body temperature. Heart rate variability analysis suggests an elevated sympathetic tone. The sympatholytic reserpine had stronger effects on blood pressure, heart rate and heart rate variability in knock-out compared with wild-type mice. Stimulation of the glucagon-like peptide-1 system inhibited parasympathetic tone to a similar extent in both genotypes, with a stronger associated increase in heart rate in knock-outs. Deficiency of Gnasxl increases sympathetic cardiovascular tone. Imbalances of energy homeostasis are often associated with cardiovascular complications. Previous work has shown that Gnasxl-deficient mice have a lean and hypermetabolic phenotype, with increased sympathetic stimulation of adipose tissue. The Gnasxl transcript from the imprinted Gnas locus encodes the trimeric G-protein subunit XLαs, which is expressed in brain regions that regulate energy homeostasis and sympathetic nervous system (SNS) activity. To determine whether Gnasxl knock-out (KO) mice display additional SNS-related phenotypes, we have now investigated the cardiovascular system. The Gnasxl KO mice were ∼20 mmHg hypertensive in comparison to wild-type (WT) littermates (P≤ 0.05) and hypersensitive to the sympatholytic drug reserpine. Using telemetry, we detected an increased waking heart rate in conscious KOs (630 ± 10 versus 584 ± 12 beats min(−1), KO versus WT, P≤ 0.05). Body temperature was also elevated (38.1 ± 0.3 versus 36.9 ± 0.4°C, KO versus WT, P≤ 0.05). To investigate autonomic nervous system influences, we used heart rate variability analyses. We empirically defined frequency power bands using atropine and reserpine and verified high-frequency (HF) power and low-frequency (LF) LF/HF power ratio to be indicators of parasympathetic and sympathetic activity, respectively. The LF/HF power ratio was greater in KOs and more sensitive to reserpine than in WTs, consistent with elevated SNS activity. In contrast, atropine and exendin-4, a centrally acting agonist of the glucagon-like peptide-1 receptor, which influences cardiovascular physiology and metabolism, reduced HF power equally in both genotypes. This was associated with a greater increase in heart rate in KOs. Mild stress had a blunted effect on the LF/HF ratio in KOs consistent with elevated basal sympathetic activity. We conclude that XLαs is required for the inhibition of sympathetic outflow towards cardiovascular and metabolically relevant tissues

Environmental Drivers of Free-Living vs. Particle-Attached Bacterial Community Composition in the Mauritania Upwelling System

Saharan dust input and seasonal upwelling along North-West Africa provide a model system for studying microbial processes related to the export and recycling of nutrients. This study offers the first molecular characterization of prokaryotic particle-attached (PA; >3.0 μm) and free-living (FL; 0.2-3.0 μm) players in this important ecosystem during August 2016. Environmental drivers for alpha-diversity, bacterial community composition, and differences between FL and PA fractions were identified. The ultra-oligotrophic waters off Senegal were dominated by Cyanobacteria while higher relative abundances of Alphaproteobacteria, Bacteroidetes, Verrucomicrobia, and Planctomycetes (known particle-degraders) occurred in the upwelling area. Temperature, proxy for different water masses, was the best predictor for changes in FL communities. PA community variation was best explained by temperature and ammonium. Bray Curtis dissimilarities between FL and PA were generally very high and correlated with temperature and salinity in surface waters. Greatest similarities between FL and PA occurred at the deep chlorophyll maximum, where bacterial substrate availability was likely highest. This indicates that environmental drivers do not only influence changes among FL and PA communities but also differences between them. This could provide an explanation for contradicting results obtained by different studies regarding the dissimilarity/similarity between FL and PA communities and their biogeochemical functions.Fil: Bachmann, Jennifer. Universitat Bremen; Alemania. Leibniz Centre for Tropical Marine Research; AlemaniaFil: Heimbach, Tabea. Leibniz Centre for Tropical Marine Research; Alemania. Universitat Bremen; Alemania. Max Plank Institute for Marine Microbiology; AlemaniaFil: Hassenrück, Christiane. Leibniz Centre for Tropical Marine Research; AlemaniaFil: Kopprio, Germán Adolfo. Leibniz Centre for Tropical Marine Research; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto Argentino de Oceanografía. Universidad Nacional del Sur. Instituto Argentino de Oceanografía; ArgentinaFil: Iversen, Morten Hvitfeldt. Universitat Bremen; Alemania. Alfred Wegener Institute for Polar and Marine Research; AlemaniaFil: Grossart, Hans Peter. Leibniz-Institute of Freshwater Ecology and Inland Fisheries; Alemania. University of Potsdam; AlemaniaFil: Gärdes, Astrid. Leibniz Centre for Tropical Marine Research; Alemani

Environmental Drivers of Free-Living vs. Particle-Attached Bacterial Community Composition in the Mauritania Upwelling System

Saharan dust input and seasonal upwelling along North–West Africa provide a model system for studying microbial processes related to the export and recycling of nutrients. This study offers the first molecular characterization of prokaryotic particle-attached (PA; >3.0 μm) and free-living (FL; 0.2–3.0 μm) players in this important ecosystem during August 2016. Environmental drivers for alpha-diversity, bacterial community composition, and differences between FL and PA fractions were identified. The ultra-oligotrophic waters off Senegal were dominated by Cyanobacteria while higher relative abundances of Alphaproteobacteria, Bacteroidetes, Verrucomicrobia, and Planctomycetes (known particle-degraders) occurred in the upwelling area. Temperature, proxy for different water masses, was the best predictor for changes in FL communities. PA community variation was best explained by temperature and ammonium. Bray Curtis dissimilarities between FL and PA were generally very high and correlated with temperature and salinity in surface waters. Greatest similarities between FL and PA occurred at the deep chlorophyll maximum, where bacterial substrate availability was likely highest. This indicates that environmental drivers do not only influence changes among FL and PA communities but also differences between them. This could provide an explanation for contradicting results obtained by different studies regarding the dissimilarity/similarity between FL and PA communities and their biogeochemical functions

Sustained Dystrophin Expression Induced by Peptide-conjugated Morpholino Oligomers in the Muscles of mdx Mice

Cell-penetrating peptides (CPPs), containing arginine (R), 6-aminohexanoic acid (X), and/or β-alanine (B) conjugated to phosphorodiamidate morpholino oligomers (PMOs), enhance their delivery in cell culture. In this study, the potency, functional biodistribution, and toxicity of these conjugates were evaluated in vivo, in EGFP-654 transgenic mice that ubiquitously express the aberrantly spliced EGFP-654 pre-mRNA reporter. Correct splicing and enhanced green fluorescence protein (EGFP) upregulation serve as a positive readout for peptide-PMO (PPMO) entry into cells and access to EGFP-654 pre-mRNA in the nucleus. Intraperitoneal injections of a series of PPMOs, A-N (12 mg/kg), administered once a day for four successive days resulted in splicing correction in numerous tissues. PPMO-B was highly potent in the heart, diaphragm, and quadriceps, which are key muscles in the treatment of Duchenne muscular dystrophy. We therefore investigated PPMO M23D-B, designed to force skipping of stop-codon containing dystrophin exon 23, in an mdx mouse model of the disease. Systemic delivery of M23D-B yielded persistent exon 23 skipping, yielding high and sustained dystrophin protein expression in body-wide muscles, including cardiac muscle, without detectable toxicity. The rescued dystrophin reduced serum creatinine kinase to near-wild-type levels, indicating improvement in muscle integrity. This is the first report of oligonucleotide-mediated exon skipping and dystrophin protein induction in the heart of treated animals

Incarceration history and risk of HIV and hepatitis C virus acquisition among people who inject drugs: a systematic review and meta-analysis

Background People who inject drugs (PWID) experience a high prevalence of incarceration and might be at high risk of HIV and hepatitis C virus (HCV) infection during or after incarceration. We aimed to assess whether incarceration history elevates HIV or HCV acquisition risk among PWID. Methods In this systematic review and meta-analysis, we searched MEDLINE, Embase, and PsycINFO databases for studies in any language published from Jan 1, 2000 until June 13, 2017 assessing HIV or HCV incidence among PWID. We included studies that measured HIV or HCV incidence among community-recruited PWID. We included only studies reporting original results and excluded studies that evaluated incident infections by self-report. We contacted authors of cohort studies that met the inclusion or exclusion criteria, but that did not report on the outcomes of interest, to request data. We extracted and pooled data from the included studies using random-effects meta-analyses to quantify the associations between recent (past 3, 6, or 12 months or since last follow-up) or past incarceration and HIV or HCV acquisition (primary infection or reinfection) risk among PWID. We assessed the risk of bias of included studies using the Newcastle-Ottawa Scale. Between-study heterogeneity was evaluated using the I2 statistic and the P-value for heterogeneity. Findings We included published results from 20 studies and unpublished results from 21 studies. These studies originated from Australasia, western and eastern Europe, North and Latin America, and east and southeast Asia. Recent incarceration was associated with an 81% (relative risk [RR] 1·81, 95% CI 1·40–2·34) increase in HIV acquisition risk, with moderate heterogeneity between studies (I2=63·5%; p=0·001), and a 62% (RR 1·62, 95% CI 1·28–2·05) increase in HCV acquisition risk, also with moderate heterogeneity between studies (I2=57·3%; p=0·002). Past incarceration was associated with a 25% increase in HIV (RR 1·25, 95% CI 0·94–1·65) and a 21% increase in HCV (1·21, 1·02–1·43) acquisition risk. Interpretation Incarceration is associated with substantial short-term increases in HIV and HCV acquisition risk among PWID and could be a significant driver of HCV and HIV transmission among PWID. These findings support the need for developing novel interventions to minimise the risk of HCV and HIV acquisition, including addressing structural risks associated with drug laws and excessive incarceration of PWID

Particle flux in the oceans: Challenging the steady state assumption

Atmospheric carbon dioxide levels are strongly controlled by the depth at which the organic matter that sinks out of the surface ocean is remineralized. This depth is generally estimated from particle flux profiles measured using sediment traps. Inherent in this analysis is a steady state assumption; that export from the surface does not significantly change in the time it takes material to reach the deepest trap. However, recent observations suggest that a significant fraction of material in the mesopelagic zone sinks slowly enough to bring this into doubt. We use data from a study in the North Atlantic during July/August 2009 to challenge the steady state assumption. An increase in biogenic silica flux with depth was observed which we interpret, based on vertical profiles of diatom taxonomy, as representing the remnants of the spring diatom bloom sinking slowly (<40 m d-1). We were able to reproduce this behaviour using a simple model using satellite-derived export rates and literature-derived remineralization rates. We further provide a simple equation to estimate ‘additional’ (or ‘excess’) POC supply to the dark ocean during non-steady state conditions, which is not captured by traditional sediment trap deployments. In seasonal systems, mesopelagic net organic carbon supply could be wrong by as much as 25% when assuming steady state. We conclude that the steady state assumption leads to misinterpretation of particle flux profiles when input fluxes from the upper ocean vary on the order of weeks, such as in temperate and polar regions with strong seasonal cycles in export

Open Science principles for accelerating trait-based science across the Tree of Life.

Synthesizing trait observations and knowledge across the Tree of Life remains a grand challenge for biodiversity science. Species traits are widely used in ecological and evolutionary science, and new data and methods have proliferated rapidly. Yet accessing and integrating disparate data sources remains a considerable challenge, slowing progress toward a global synthesis to integrate trait data across organisms. Trait science needs a vision for achieving global integration across all organisms. Here, we outline how the adoption of key Open Science principles-open data, open source and open methods-is transforming trait science, increasing transparency, democratizing access and accelerating global synthesis. To enhance widespread adoption of these principles, we introduce the Open Traits Network (OTN), a global, decentralized community welcoming all researchers and institutions pursuing the collaborative goal of standardizing and integrating trait data across organisms. We demonstrate how adherence to Open Science principles is key to the OTN community and outline five activities that can accelerate the synthesis of trait data across the Tree of Life, thereby facilitating rapid advances to address scientific inquiries and environmental issues. Lessons learned along the path to a global synthesis of trait data will provide a framework for addressing similarly complex data science and informatics challenges

Enduring science: Three decades of observing the Northeast Atlantic from the Porcupine Abyssal Plain Sustained Observatory (PAP-SO)

Until the 1980s, the deep sea was generally considered to be a particularly stable environment, free from major temporal variations (Sanders, 1968). Studies in the abyssal northeast Atlantic by Billett et al. (1983), and subsequently Lampitt (1985) discovered seasonal pulses of surface primary production-derived particulate organic matter (phytodetritus), and hence carbon, at abyssal depths. These early observations were subsequently extended to the central oceanic region of the NE Atlantic (Pfannkuche, 1993; Thiel et al., 1989), and prompted the establishment of more concerted time series studies in the Porcupine Abyssal Plain area. Today, the Porcupine Abyssal Plain Sustained Observatory (PAP–SO) is a multidisciplinary open-ocean time series site in the NE Atlantic (48°50′N 16°30′W, 4850 m water depth; Fig. 1), focused on the study of connections between the surface and deep ocean. In situ measurements of climatically and environmentally relevant variables have been made for more than 30 years. This represents an exceptionally long time series - a recent compilation of biological time series data, across terrestrial, freshwater, and marine realms, indicates an average duration of only 13-years (Dornelas et al., 2018). Long-term time series in the deep sea are rare, particularly those collecting data from surface to seabed. The PAP-SO is one of two abyssal long-term time series sites globally (Smith et al. 2015), the other being a thirty-year time series at Station M in the northeastern Pacific Ocean (34°50′N, 123°00′W, ~4000 m water depth), maintained by the Monterey Bay Aquarium Research Institute (Smith et al., 2020). This ‘sibling’ abyssal time series site also aims to understand the connections between the surface ocean and the seabed, using many similar techniques (Smith et al., 2017), facilitating comparisons between the two sites (e.g. Durden et al., 2019; Durden et al., 2020a; Laguionie-Marchais et al., 2013; Smith et al., 2009). Another source of extended comparison is the 21 year time series Long-Term Ecological Research Observatory HAUSGARTEN, Frontiers in Arctic Marine Monitoring (FRAM) in the Fram Strait between the North Atlantic and the central Arctic Ocean (78.5°N–80°N, 05°W–11°E, 250–5500 m water depth), maintained by the Alfred Wegener Institute for Polar and Marine Research (Soltwedel et al., 2016; Soltwedel et al., 2005). Much of our understanding of temporal variation in the deep sea, and connections between the surface ocean and the seabed have been derived from research conducted at these observatories