Strategies for the treatment of Hepatitis C in an era of interferon-free therapies: what public health outcomes do we value most?

Objective: The expense of new therapies for HCV infection may force health systems to prioritise the treatment of certain patient groups over others. Our objective was to forecast the population impact of possible prioritisation strategies for the resource-rich setting of Scotland. Design: We created a dynamic Markov simulation model to reflect the HCV-infected population in Scotland. We determined trends in key outcomes (e.g. incident cases of chronic infection and severe liver morbidity (SLM)) until the year 2030, according to treatment strategies involving prioritising, either: (A) persons with moderate/advanced fibrosis or (B) persons who inject drugs (PWID). Results: Continuing to treat the same number of patients with the same characteristics will give rise to a fall in incident infection (from 600 cases in 2015 to 440 in 2030) and a fall in SLM (from 195 cases in 2015 to 145 in 2030). Doubling treatment-uptake and prioritising PWID will reduce incident infection to negligible levels (<50 cases per year) by 2025, while SLM will stabilise (at 70–75 cases per year) in 2028. Alternatively, doubling the number of patients treated, but, instead, prioritising persons with moderate/advanced fibrosis will reduce incident infection less favourably (only to 280 cases in 2030), but SLM will stabilise by 2023 (i.e. earlier than any competing strategy). Conclusions: Prioritising treatment uptake among PWID will substantially impact incident transmission, however, this approach foregoes the optimal impact on SLM. Conversely, targeting those with moderate/advanced fibrosis has the greatest impact on SLM but is suboptimal in terms of averting incident infection

Preformed metal crowns for decayed primary molar teeth

BackgroundPreformed metal crowns (PMCs) are recommended by the British Society of Paediatric Dentistry (BSPD) for restoring badly broken down primary molar teeth. However, few dental practitioners adopt this technique in clinical practice, citing cost and clinical difficulty as reasons for this. Whilst there is a subjective impression by clinical academics that PMCs provide a more durable restoration than filling materials, there appears to be little evidence within the literature to support this.ObjectivesThe primary aim of this systematic review was to compare clinical outcomes for primary molar teeth restored using PMCs compared to those restored with filling materials.Search methodsThe literature was searched using: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2005, Issue 3); MEDLINE (1966 to August 2005); EMBASE (1980 to August 2005); System for Information on Grey Literature in Europe (SIGLE) (1976 to August 2005). Relevant publications' reference lists were reviewed for relevant articles. The most recent search was carried out on 24 August 2005.Selection criteriaRandomised controlled trials (RCTs) that assessed the effectiveness of PMCs compared with filling materials or where there had been no treatment in children with untreated tooth decay in one or more primary molar teeth.Data collection and analysisTwo review authors independently assessed the title and abstracts for each article from the search results to decide whether it was likely to be relevant. Full papers were obtained for relevant articles and all three review authors studied these.Main resultsForty‐seven records were retrieved by the search strategies of which some were duplicates. Of these, 14 studies were scrutinised. No studies met the inclusion criteria and six studies were excluded from the review as they were either retrospective in design or reported as prospective outcomes but not randomised. No data were available for extraction and analysis and therefore, no conclusion could be made as to whether PMCs were more successful than filling materials for restoring primary molar teeth.Authors' conclusionsNo RCTs were available for appraisal. Whilst this technique is recommended by the BSPD for use in clinical practice, the evidence to support this is not strong, consisting mainly of case reports and uncontrolled studies. It is important that the absence of evidence for PMCs is not misinterpreted as evidence for their lack of efficacy.There is a strong need for prospective RCTs comparing PMCs and fillings for managing decayed primary molar teeth. The lower levels of evidence that have been produced, however, have strength in that the clinical outcomes are consistently in favour of PMCs, despite many of the studies placing PMCs on the most damaged of the pair of teeth being analysed

Evidence of continued injecting drug use after attaining sustained treatment-induced clearance of the hepatitis C virus: implications for reinfection

Background: People who inject drugs (PWID) are at the greatest risk of hepatitis C virus (HCV) infection, yet are often denied immediate treatment due to fears of on-going risk behaviour. Our principal objective was to examine evidence of continued injecting drug use among PWID following successful treatment for HCV and attainment of a sustained viral response (SVR). Methods: PWID who attained SVR between 1992 and June 2012 were selected from the National Scottish Hepatitis C Clinical Database. Hospitalisation and mortality records were sourced for these patients using record linkage techniques. Our primary outcome variable was any hospitalisation or death, which was indicative of injecting drugs post-SVR. Results: The cohort comprised 1170 PWID (mean age at SVR 39.6y; 76% male). The Kaplan Meier estimate of incurring the primary outcome after three years of SVR was 10.59% (95% CI, 8.75–12.79) After adjusting for confounding, the risk of an injection related hospital episode or death post-SVR was significantly increased with advancing year of SVR: AHR:1.07 per year (95% CI, 1.01–1.14), having a pre-SVR acute alcohol intoxication-related hospital episode: AHR:1.83 (95% CI, 1.29–2.60), and having a pre-SVR opiate or injection-related hospital episode: AHR:2.59 (95% CI, 1.84–3.64). Conclusion: Despite attaining the optimal treatment outcome, these data indicate that an increasing significant minority of PWID continue to inject post-SVR at an intensity which leads to either hospitalisation or death and increased risk of reinfection

D- and L-lactate dehydrogenases during invertebrate evolution

Background: The L-lactate and D-lactate dehydrogenases, which are involved in the reduction of pyruvate to L(-)-lactate and D(+)-lactate, belong to evolutionarily unrelated enzyme families. The genes encoding L-LDH have been used as a model for gene duplication due to the multiple paralogs found in eubacteria, archaebacteria, and eukaryotes. Phylogenetic studies have suggested that several gene duplication events led to the main isozymes of this gene family in chordates, but little is known about the evolution of L-Ldh in invertebrates. While most invertebrates preferentially oxidize L-lactic acid, several species of mollusks, a few arthropods and polychaetes were found to have exclusively D-LDH enzymatic activity. Therefore, it has been suggested that L-LDH and DLDH are mutually exclusive. However, recent characterization of putative mammalian D-LDH with significant similarity to yeast proteins showing D-LDH activity suggests that at least mammals have the two naturally occurring forms of LDH specific to L- and D-lactate. This study describes the phylogenetic relationships of invertebrate L-LDH and D-LDH with special emphasis on crustaceans, and discusses gene duplication events during the evolution of L-Ldh. Results: Our phylogenetic analyses of L-LDH in vertebrates are consistent with the general view that the main isozymes (LDH-A, LDH-B and LDH-C) evolved through a series of gene duplications after the vertebrates diverged from tunicates. We report several gene duplication events in the crustacean, Daphnia pulex, and the leech, Helobdella robusta. Several amino acid sequences with strong similarity to putative mammalian D-LDH and to yeast DLD1 with D-LDH activity were found in both vertebrates and invertebrates. Conclusion: The presence of both L-Ldh and D-Ldh genes in several chordates and invertebrates suggests that the two enzymatic forms are not necessarily mutually exclusive. Although, the evolution of L-Ldh has been punctuated by multiple events of gene duplication in both vertebrates and invertebrates, a shared evolutionary history of this gene in the two groups is apparent. Moreover, the high degree of sequence similarity among D-LDH amino acid sequences suggests that they share a common evolutionary history

Uptake of hepatitis C specialist services and treatment following diagnosis by dried blood spot in Scotland

Background: Dried blood spot (DBS) testing for hepatitis C (HCV) was introduced to Scotland in 2009. This minimally invasive specimen provides an alternative to venipuncture and can overcome barriers to testing in people who inject drugs (PWID). Objectives: The objective of this study was to determine rates and predictors of: exposure to HCV, attendance at specialist clinics and anti-viral treatment initiation among the DBS tested population in Scotland. Study design: DBS testing records were deterministically linked to the Scottish HCV Clinical database prior to logistic regression analysis. Results: In the first two years of usage in Scotland, 1322 individuals were tested by DBS of which 476 were found to have an active HCV infection. Linkage analysis showed that 32% had attended a specialist clinic within 12 months of their specimen collection date and 18% had begun anti-viral therapy within 18 months of their specimen collection date. A significantly reduced likelihood of attendance at a specialist clinic was evident amongst younger individuals (<35 years), those of unknown ethnic origin and those not reporting injecting drug use as a risk factor. Conclusion: We conclude that DBS testing in non-clinical settings has the potential to increase diagnosis and, with sufficient support, treatment of HCV infection among PWID

The Sorghum QTL Atlas: a powerful tool for trait dissection, comparative genomics and crop improvement

Key message: We describe the development and application of the Sorghum QTL Atlas, a high-resolution, open-access research platform to facilitate candidate gene identification across three cereal species, sorghum, maize and rice. Abstract: The mechanisms governing the genetic control of many quantitative traits are only poorly understood and have yet to be fully exploited. Over the last two decades, over a thousand QTL and GWAS studies have been published in the major cereal crops including sorghum, maize and rice. A large body of information has been generated on the genetic basis of quantitative traits, their genomic location, allelic effects and epistatic interactions. However, such QTL information has not been widely applied by cereal improvement programs and genetic researchers worldwide. In part this is due to the heterogeneous nature of QTL studies which leads QTL reliability variation from study to study. Using approaches to adjust the QTL confidence interval, this platform provides access to the most updated sorghum QTL information than any database available, spanning 23 years of research since 1995. The QTL database provides information on the predicted gene models underlying the QTL CI, across all sorghum genome assembly gene sets and maize and rice genome assemblies and also provides information on the diversity of the underlying genes and information on signatures of selection in sorghum. The resulting high-resolution, open-access research platform facilitates candidate gene identification across 3 cereal species, sorghum, maize and rice. Using a number of trait examples, we demonstrate the power and resolution of the resource to facilitate comparative genomics approaches to provide a bridge between genomics and applied breeding. © 2018, Springer-Verlag GmbH Germany, part of Springer Nature

An XMM-Newton Observation of the Local Bubble Using a Shadowing Filament in the Southern Galactic Hemisphere

We present an analysis of the X-ray spectrum of the Local Bubble, obtained by simultaneously analyzing spectra from two XMM-Newton pointings on and off an absorbing filament in the Southern galactic hemisphere (b ~ -45 deg). We use the difference in the Galactic column density in these two directions to deduce the contributions of the unabsorbed foreground emission due to the Local Bubble, and the absorbed emission from the Galactic halo and the extragalactic background. We find the Local Bubble emission is consistent with emission from a plasma in collisional ionization equilibrium with a temperature $\log T_{LB} = 6.06^{+0.02}_{-0.04}$ and an emission measure of 0.018 cm^{-6} pc. Our measured temperature is in good agreement with values obtained from ROSAT All-Sky Survey data, but is lower than that measured by other recent XMM-Newton observations of the Local Bubble, which find $\log T_{LB} \approx 6.2$ (although for some of these observations it is possible that the foreground emission is contaminated by non-Local Bubble emission from Loop I). The higher temperature observed towards other directions is inconsistent with our data, when combined with a FUSE measurement of the Galactic halo O VI intensity. This therefore suggests that the Local Bubble is thermally anisotropic. Our data are unable to rule out a non-equilibrium model in which the plasma is underionized. However, an overionized recombining plasma model, while observationally acceptable for certain densities and temperatures, generally gives an implausibly young age for the Local Bubble (\la 6 \times 10^5 yr).Comment: Accepted for publication in the Astrophysical Journal. 16 pages, 9 figure

Expansion of HCV treatment access to people who have injected drugs through effective translation of research into public health policy:Scotland's experience

Seven years have elapsed since the Scottish Government launched its Hepatitis C Action Plan – a Plan to improve services to prevent transmission of infection, particularly among people who inject drugs (PWID), identify those infected and ensure those infected receive optimal treatment. The Plan was underpinned by industrial scale funding (around £100 million, in addition to the general NHS funding, will have been invested by 2015), and a web of accountable national and local multi-disciplinary multi-agency networks responsible for the planning, development and delivery of services. Initiatives ranged from the introduction of testing in specialist drug services through finger-prick blood sampling by non-clinical staff, to the setting of government targets to ensure rapid scale-up of antiviral therapy. The Plan was informed by comprehensive national monitoring systems, indicating the extent of the problem not just in terms of numbers infected, diagnosed and treated but also the more penetrative data on the number advancing to end-stage liver disease and death, and also through compelling modelling work demonstrating the potential beneficial impact of scaling-up therapy and the mounting cost of not acting. Achievements include around 50% increase in the proportion of the infected population diagnosed (38% to 55%); a sustained near two-and-a-half fold increase in the annual number of people initiated onto therapy (470 to 1050) with more pronounced increases among PWID (300 to 840) and prisoners (20 to 140); and reversing of an upward trend in the overall number of people living with chronic infection. The Action Plan has demonstrated that a Government-backed, coordinated and invested approach can transform services and rapidly improve the lives of thousands. Cited as “an impressive example of a national strategy” by the Global Commission on Drug Policy, the Scottish Plan has also provided fundamental insights of international relevance into the management of HCV among PWID