The impact of injecting networks on hepatitis C transmission and treatment in people who inject drugs

With the development of new highly efficacious direct acting antiviral treatments (DAAs) for hepatitis C (HCV), the concept of treatment as prevention is gaining credence. To date the majority of mathematical models assume perfect mixing with injectors having equal contact with all other injectors. This paper explores how using a networks based approach to treat people who inject drugs (PWID) with DAAs affects HCV prevalence. Method: Using observational data we parameterized an Exponential Random Graph Model containing 524 nodes. We simulated transmission of HCV through this network using a discrete time, stochastic transmission model. The effect of five treatment strategies on the prevalence of HCV was investigated; two of these strategies were 1) treat randomly selected nodes and 2) “treat your friends” where an individual is chosen at random for treatment and all their infected neighbours are treated. Results: As treatment coverage increases, HCV prevalence at 10 years reduces for both the high efficacy and low efficacy treatment. Within each set of parameters, the “treat your friends” strategy performed better than the random strategy being most marked for higher efficacy treatment. For example over 10 years of treating 25 per 1000 PWID, the prevalence drops from 50% to 40% for the random strategy, and to 33% for the “treat your friends” strategy (6.5% difference, 95% CI 5.1 – 8.1%). Discussion: “Treat your friends” is a feasible means of utilising network strategies to improve treatment efficiency. In an era of highly efficacious and highly tolerable treatment such an approach will benefit not just the individual but the community more broadly by reducing the prevalence of HCV amongst PWID

Improving estuary models by reducing uncertainties associated with river flows

© 2018 The Authors To mitigate against future changes to estuaries such as water quality, catchment and estuary models can be coupled to simulate the transport of harmful pathogenic viruses, pollutants and nutrients from their terrestrial sources, through the estuary and to the coast. To predict future changes to estuaries, daily mean river flow projections are typically used. We show that this approach cannot resolve higher frequency discharge events that have large impacts to estuarine dilution, contamination and recovery for two contrasting estuaries. We therefore characterise sub-daily scale flow variability and propagate this through an estuary model to provide robust estimates of impacts for the future. River flow data (35-year records at 15-min sampling) were used to characterise variabilities in storm hydrograph shapes and simulate the estuarine response. In particular, we modelled a fast-responding catchment-estuary system (Conwy, UK), where the natural variability in hydrograph shapes generated large variability in estuarine circulation that was not captured when using daily-averaged river forcing. In the extreme, the freshwater plume from a ‘flash’ flood (lasting < 12 h) was underestimated by up to 100% – and the response to nutrient loading was underestimated further still. A model of a slower-responding system (Humber, UK), where hydrographs typically last 2–4 days, showed less variability in estuarine circulation and good approximation with daily-averaged flow forcing. Our result has implications for entire system impact modelling; when we determine future changes to estuaries, some systems will need higher resolution future river flow estimates

Biochemical properties of mammalian TREX1 and its association with DNA replication and inherited inflammatory disease

Abstract The major DNA-specific 3 -5 exonuclease of mammalian cells is TREX1 (3 repair exonuclease 1; previously called DNase III). The human enzyme is encoded by a single exon and, like many 3 exonucleases, exists as a homodimer. TREX1 degrades ssDNA (single-stranded DNA) more efficiently than dsDNA (double-stranded DNA), and its catalytic properties are similar to those of Escherichia coli exonuclease X. However, TREX1 is only found in mammals and has an extended C-terminal domain containing a leucine-rich sequence required for its association with the endoplasmic reticulum. In normal S-phase and also in response to genotoxic stress, TREX1 at least partly redistributes to the cell nucleus. In a collaborative project, we have demonstrated TREX1 enzyme deficiency in Aicardi-Goutières syndrome. Subsequently, we have shown that AGS1 cells exhibit chronic ATM (ataxia telangiectasia mutated)-dependent checkpoint activation, and these TREX1-deficient cells accumulate ssDNA fragments of a distinct size generated during DNA replication. Other groups have shown that the syndromes of familial chilblain lupus as well as systemic lupus erythematosus, and the distinct neurovascular disorder retinal vasculopathy with cerebral leukodystrophy, can be caused by dominant mutations at different sites within the TREX1 gene

Hepatitis C transmission and treatment as prevention - The role of the injecting network

Background: The hepatitis C virus (HCV) epidemic is a major health issue; in most developed countries it is driven by people who inject drugs (PWID). Injecting networks powerfully influence HCV transmission. In this paper we provide an overview of 10 years of research into injecting networks and HCV, culminating in a network-based approach to provision of direct-acting antiviral therapy. Methods: Between 2005 and 2010 we followed a cohort of 413 PWID, measuring HCV incidence, prevalence and injecting risk, including network-related factors. We developed an individual-based HCV transmission model, using it to simulate the spread of HCV through the empirical social network of PWID. In addition, we created an empirically grounded network model of injecting relationships using exponential random graph models (ERGMs), allowing simulation of realistic networks for investigating HCV treatment and intervention strategies. Our empirical work and modelling underpins the TAP Study, which is examining the feasibility of community-based treatment of PWID with DAAs. Results: We observed incidence rates of HCV primary infection and reinfection of 12.8 per 100 person-years (PY) (95%CI: 7.7-20.0) and 28.8 per 100 PY (95%CI: 15.0-55.4), respectively, and determined that HCV transmission clusters correlated with reported injecting relationships. Transmission modelling showed that the empirical network provided some protective effect, slowing HCV transmission compared to a fully connected, homogenous PWID population. Our ERGMs revealed that treating PWID and all their contacts was the most effective strategy and targeting treatment to infected PWID with the most contacts the least effective. Conclusion: Networks-based approaches greatly increase understanding of HCV transmission and will inform the implementation of treatment as prevention using DAAs

Genomic survey of edible cockle (Cerastoderma edule) in the Northeast Atlantic: a baseline for sustainable management of its wild resources.

Knowledge on correlations between environmental factors and genome divergence between populations of marine species is crucial for sustainable management of fisheries and wild populations. The edible cockle (Cerastoderma edule) is a marine bivalve distributed along the Northeast Atlantic coast of Europe and is an important resource from both commercial and ecological perspectives. We performed a population genomics screening using 2b‐RAD genotyping on 9309 SNPs localized in the cockle's genome on a sample of 536 specimens pertaining to 14 beds in the Northeast Atlantic Ocean to analyse the genetic structure with regard to environmental variables. Larval dispersal modelling considering species behaviour and interannual/interseasonal variation in ocean conditions was carried out as an essential background to which compare genetic information. Cockle populations in the Northeast Atlantic displayed low but significant geographical differentiation between populations (F (ST) = 0.0240; p < 0.001), albeit not across generations. We identified 742 and 36 outlier SNPs related to divergent and balancing selection in all the geographical scenarios inspected, and sea temperature and salinity were the main environmental correlates suggested. Highly significant linkage disequilibrium was detected at specific genomic regions against the very low values observed across the whole genome. Two main genetic groups were identified, northwards and southwards of French Brittany. Larval dispersal modelling suggested a barrier for larval dispersal linked to the Ushant front that could explain these two genetic clusters. Further genetic subdivision was observed using outlier loci and considering larval advection. The northern group was divided into the Irish/Celtic Seas and the English Channel/North Sea, while the southern group was divided into three subgroups. This information represents the baseline for the management of cockles, designing conservation strategies, founding broodstock for depleted beds and producing suitable seed for aquaculture production

The influence of tides on the North West European shelf winter residual circulation

Tides contribute to the large-scale residual circulation and mixing of shelf seas. However, tides are typically excluded from global circulation models (GCMs) so their modelled residual circulation (and mixing) in shelf seas may be systematically wrong. We focus on circulation as it is relatively unexplored, and affects shelf temperature and salinity, potentially biasing climate impact studies. Using a validated model of the North West European Shelf Seas (NWS), we show the essential role of tides in driving the residual circulation, and how this affects the NWS temperature and salinity distribution. Over most of the NWS, removing the tides increases the magnitude of residual circulation while in some regions (such as the Irish Sea) it leads to a reduction. Furthermore, we show that modelling the NWS without tides leads to a cold fresh bias in the Celtic Sea and English Channel (of >0.5°C, and >0.5 psu). This shows that NWS tidal dynamics are essential in the transport of heat and matter, and so must be included in GCMs. We explore two processes by which the tides impact the residual circulation and investigate whether these could be parameterised within non-tidal GCMs: (1) Enhancing the seabed friction to mimic the equivalent energy loss from an oscillating tidal flow; (2) Tidal Phase-driven Transport (TPT), whereby tidal asymmetry drives a net transport due to the phase between tidal-elevation and velocities (equivalent to the bolus term in oceanographic literature). To parameterise TPT, we calculate a climatology of this transport from a harmonic analysis from the tidal model and add it as an additional force in the Navier Stokes equations in the non-tidal model. We also modify the bed drag coefficient to balance the bed stress between the simulations – hypothesising that using this modified drag coefficient will simulate the effect of the tides. This tends to improve the mean and variability of the residual circulation, while the TPT improves the spatial distribution and temporal variability of the temperature and salinity. We show that our proof-of-concept parameterisation can replicate the tidally-driven impact on the residual circulation without direct simulation, thus reducing computational effort

Development and external validation of a clinical prediction model to aid coeliac disease diagnosis in primary care:an observational study

BACKGROUND: Coeliac disease (CD) affects approximately 1% of the population, although only a fraction of patients are diagnosed. Our objective was to develop diagnostic prediction models to help decide who should be offered testing for CD in primary care. METHODS: Logistic regression models were developed in Clinical Practice Research Datalink (CPRD) GOLD (between Sep 9, 1987 and Apr 4, 2021, n=107,075) and externally validated in CPRD Aurum (between Jan 1, 1995 and Jan 15, 2021, n=227,915), two UK primary care databases, using (and controlling for) 1:4 nested case-control designs. Candidate predictors included symptoms and chronic conditions identified in current guidelines and using a systematic review of the literature. We used elastic-net regression to further refine the models. FINDINGS: The prediction model included 24, 24, and 21 predictors for children, women, and men, respectively. For children, the strongest predictors were type 1 diabetes, Turner syndrome, IgA deficiency, or first-degree relatives with CD. For women and men, these were anaemia and first-degree relatives. In the development dataset, the models showed good discrimination with a c-statistic of 0·84 (95% CI 0·83–0·84) in children, 0·77 (0·77–0·78) in women, and 0·81 (0·81–0·82) in men. External validation discrimination was lower, potentially because ‘first-degree relative’ was not recorded in the dataset used for validation. Model calibration was poor, tending to overestimate CD risk in all three groups in both datasets. INTERPRETATION: These prediction models could help identify individuals with an increased risk of CD in relatively low prevalence populations such as primary care. Offering a serological test to these patients could increase case finding for CD. However, this involves offering tests to more people than is currently done. Further work is needed in prospective cohorts to refine and confirm the models and assess clinical and cost effectiveness. FUNDING: National Institute for Health Research Health Technology Assessment Programme (grant number NIHR129020

Impact of sediment concentration on the survival of wastewater-derived blaCTX-M-15-producing E. coli, and the implications for dispersal into estuarine waters

The environmental cycling of antibiotic-resistant blaCTX-M-15-producing E. coli following release from wastewater treatment plants is a major public health concern. This study aimed to (i) assess the impact of sediment concentrations on the rate of their inactivation following release from human wastewater into freshwater, and (ii) simulate their subsequent dispersal to the nearby coastline during a “worst-case” event where heavy rainfall coincided with high spring tide in the Conwy Estuary, North Wales. Freshwater microcosms of low, medium and high turbidity were inoculated with blaCTX-M-15-producing E. coli, then exposed to ultraviolet (UV) radiation. Typical regional wintertime exposure to UV was found to be insufficient to eradicate E. coli, and in highly turbid water, many bacteria survived simulated typical regional summertime UV exposure. Modelling results revealed that blaCTX-M-15-producing E. coli concentrations reduced downstream from the discharge source, with ~30% of the source concentration capable of dispersing through the estuary to the coast, taking ~36 h. Offshore, the concentration simulated at key shellfisheries and bathing water sites ranged from 1.4% to 10% of the upstream input, depending on the distance offshore and tidal regime, persisting in the water column for over a week. Our work indicates that the survival of such organisms post-release into freshwater is extended under typical wintertime conditions, which could ultimately have implications for human health