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We describe a new semi-analytical program, KKhhFoam, which provides a simplified framework for testing the amplitude-level exponentiation scheme (CEEX) of the full KKMChh program in the semi-soft limit. The structure of the KKhhFoam integrand is also helpful for elucidating the structure of CEEX. We also discuss the representation of ISR in KKMChh and compare the ISR added by KKMChh to the effect of switching to a QED-corrected PDF, at the individual quark level, and suggest a new approach to running KKMChh with QED-corrected PDFs.

Uremia, also known as uremic syndrome, refers to the clinical symptoms in the final stage of renal failure. The definition of the term has changed over time due to an improved comprehension of the kidney’s function and the advancement of dialysis technology. Here, we aim to present an overview of the various concepts that have developed regarding uremia throughout the years. We provide a comprehensive review of the historical progression starting from the early days of Kolff and his predecessors, continuing with the initial research conducted by Niwa et al., and culminating in the remote sensing hypothesis of Nigam. Additionally, we explore the subsequent investigation into the function of these toxins as signaling molecules in various somatic cells.

Cardiometabolic disease is the leading cause of death in zoo apes; yet its etiology remains unknown. Here, we investigated compositional and functional microbial markers in fecal samples from 57 gorillas across U.S. zoos, 20 of which are diagnosed with cardiovascular disease, in contrast with 17 individuals from European zoos and 19 wild gorillas from Central Africa. Results show that zoo-housed gorillas in the U.S. exhibit the most diverse gut microbiomes and markers of increased protein and carbohydrate fermentation, at the expense of microbial metabolic traits associated with plant cell-wall degradation. Machine learning models identified unique microbial traits in U.S. gorillas with cardiometabolic distress; including reduced metabolism of sulfur-containing amino acids and hexoses, increased abundance of potential enteric pathogens, and low fecal butyrate and propionate production. These findings show that cardiometabolic disease in gorillas is potentially associated with altered gut microbial function, influenced by zoo-specific diets and environments., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Liquid exfoliation is a scalable and effective method for synthesizing 2D nanosheets (NSs) but often induces contamination and defects. Here, liquid metal gallium (Ga) is used to exfoliate bulk layered materials into 2D NSs at near room temperature, utilizing the liquid surface tension and Ga intercalation to disrupt Van der Waals (vdW) forces. In addition, the process can transform the 2H-phase of transition metal dichalcogenides into the 1T'-phase under ambient conditions. This method produces high aspect ratio, surfactant-free 2D-NSs for more than 10 types of 2D materials that include h-BN, graphene, MoTe 2 , MoSe 2 , layered minerals, etc. The subsequent Ga separation via ethanol dispersion avoids the formation of additional defects and surfactant contamination. By adjusting initial defect levels of the layered materials, customize the metallicity and/or defectiveness of 2D NSs can be customized for applications such as birefringence-tunable modulators with exfoliated h-BN, and enhanced hydrogen evolution with defective MoS 2 . This approach offers a strategy to optimize liquid metal/2D interfaces, preserving intrinsic properties and enabling practical applications, potentially transforming optics, energy conversion, and beyond., (© 2024 Wiley‐VCH GmbH.)

Purpose: A large proportion of people die in the years following dysvascular partial foot amputation (PFA) or transtibial amputation (TTA) given the long-term consequences of peripheral vascular disease and/or diabetes. A critical appraisal of recent research is needed to understand the underlying cause of variation and synthesise data for use in consultations about amputation surgery and patient-facing resources. This systematic review aimed to describe proportionate mortality following dysvascular PFA and to compare this between PFA and TTA., Materials and Methods: The review protocol was registered in PROSPERO (CRD42023399161). Peer-reviewed studies of original research were included if they: were published in English between 1 January 2016, and 12 April 2024, included discrete cohorts with PFA, or PFA and TTA, and measured proportionate mortality following dysvascular amputation., Results: Seventeen studies were included in the review. Following dysvascular PFA, proportionate mortality increased from 30 days (2.1%) to 1-year (13.9%), 3-years (30.1%), and 5-years (42.2%). One study compared proportionate mortality 1-year after dysvascular PFA and TTA, showing a higher relative risk of dying after TTA (RR 1.51)., Conclusions: Proportionate mortality has not changed in recent years. These results are comparable to a previous systematic review that included studies published before 31 December 2015.Implications for rehabilitationIt is important to ensure data describing mortality in the years following dysvascular partial foot or transtibial amputation is up to date and accurate.Evidence about proportionate mortality has not changed in recent years and the results are comparable to previous systematic reviews.Data describing mortality outcomes can be used in decision aids that support conversations about the choice of amputation level.

Background: Birth cohort screening has been implemented in some countries to identify the potentially 'missed population' of people with undiagnosed chronic hepatitis C virus (HCV) who may not be found through targeted approaches., Aim: To determine uptake of HCV antibody testing using an oral swab screening method, the overall yield, whether those testing positive had risk markers in their primary care record, and the cost per case detected., Design and Setting: This was a pilot screening study set in general practices in the Southwest of England, Yorkshire and Humber, and South London., Method: Participants consenting were sent an oral swab kit in the post and saliva samples were tested for antibodies to HCV., Results: In total, 16 436/98 396 (16.7%) patients consented and were sent an oral swab kit. Of these, 12 216 (12.4%) returned a kit, with 31 participants (yield 0.03%) testing positive for HCV antibodies. Of those positive, 14/35 (45%) had a risk marker for HCV on their primary care record. Two (yield 0.002%) were confirmed RNA positive and referred for treatment, both had HCV risk markers. The cost per case was £16 000 per HCV antibody detected and £247 997 per chronic HCV detected., Conclusion: Wide-scale screening could be delivered and identify people infected with HCV, however, most of these individuals could have been detected through lower-cost targeted screening. The yield and cost per case found in patients were substantially worse than model estimates and targeted screening studies. Birth cohort screening should not be rolled out in primary care in England., (© The Authors.)

Background: England aims to reach the World Health Organization (WHO) elimination target of decreasing HCV incidence among people who inject drugs (PWID) to <2 per 100 person-years (/100pyrs) by 2030. We assessed what testing and treatment strategies will achieve this target and whether they are cost-effective., Methods: A dynamic deterministic HCV transmission model among PWID was developed for four England regions, utilising data on the scale-up of HCV treatment among PWID in prisons, drug treatment centres (DTC, where opioid agonist therapy is provided), and any other setting (e.g., primary care). The model projected whether the elimination target will be reached with existing testing and treatment initiatives ('status quo' model, SQ), or whether improvements are needed from 2024. Cost data was collated through practitioners' interviews and published literature. The mean incremental cost-effectiveness ratio (ICER per quality adjusted life year (QALY) saved, 50-year time horizon; 3.5% discount rate) of SQ (assumes counterfactual of no treatment scale-up post-2015) and improved model (counterfactual: SQ model) was compared to a willingness-to-pay threshold of £20,000/QALY saved., Findings: The SQ model projects HCV incidence will decrease by 79.7-98.6% (range of medians) over 2015-2030 to 0.2-2.2/100pyrs, with an ICER of £308-1609/QALY saved across the regions. There is >80% probability of achieving the incidence target in three regions, and 40% probability in the other region. If annual testing in DTC increases to 80% (from 27%) or 75% of people get tested during their prison stay (from 55%) from 2024 in the lower impact region, then their probability increases to >65%, with both strategies being highly cost-effective., Interpretation: Many England regions could reach the WHO HCV elimination target by 2030 under existing testing and treatment pathways. Scaling up of testing in DTC or prisons will help achieve this target and is highly cost-effective., Funding: NIHR., Competing Interests: PV has received unrestricted research grants from Gilead not related to the submitted work. JV has received payments for chairing a Gilead sponsored meeting and sponsorship off ViiV to attend a European HIV conference. MD is a medical secretary of the UK Advisory Panel for Healthcare Workers Living with Bloodborne Viruses. GRF has received consulting fees off GSK, Gilead, BioMarin and CSL Behring; honoraria off Gilead, BioMarin and CSL Behring; and has Participated on Data Safety Monitoring Boards or Advisory Boards for GSK, Gilead, BioMarin and CSL Behring. MH is an unpaid trustee of the Society for Study of Addiction, and received support from the Viral Hepatitis Prevention Board to attend a meeting in Antwerp in 2024. This research was funded in whole, or in part, by a National Institute for Health Research Health Technology Health Assessment grant (NIHR128513) and the NIHR funded Health Protection Research Unit for Behavioural Science and Evaluation., (© 2024 The Authors.)

Arctic-breeding birds exhibit around-the-clock activity, and these activity cycles are postulated to maximize reproductive success during the short breeding season characteristic of high-latitude regions. Two closely related species of arctic-breeding songbirds, Lapland longspurs (Calcarius lapponicus; ground-nesting) and snow buntings (Plectrophenax nivalis; cavity-nesting) exhibit extended activity cycles throughout the polar day (71° N) except for 4-5 h of daily quiescence. Ground-nesting Lapland longspurs experience higher levels of nest predation than cavity-nesting snow buntings, and this difference is reflected in elevated nest vigilance in male longspurs compared with snow buntings. In this study, we examined the effect of melatonin supplementation upon male parental care, corresponding measures of nestling growth, and ability to reduce activity (and increase sleep). A pharmacological dose of melatonin in captive snow buntings dampened the amplitude of activity rhythms over the polar day with no detectable phase-shifting compared with control-implanted birds. Melatonin treatment reduced nest visits and overall time spent on the nest by male snow buntings compared with controls. There was no significant increase in time spent by female snow buntings on the nest to compensate for this, and there was no significant effect on offspring growth rates. There were no effects of melatonin supplementation on longspur adults or offspring, suggesting behavioral insensitivity to exogenous melatonin treatment. These differences in sensitivity underscore the importance of nest defense in ground-nesting longspurs compared with cavity-nesting snow buntings, which participate minimally in nest defense., (© 2024 Wiley Periodicals LLC.)

Background: Alcohol-related liver disease (ARLD) is often diagnosed at a late stage when mortality is unacceptably high. Earlier identification of ARLD may lead to reduced alcohol intake, participation in hepatocellular carcinoma surveillance and reduction in liver-related morbidity and mortality. People with alcohol use disorder (AUD) are at highest risk of ARLD. The aim of this systematic review was to understand the yield of proactive screening for ARLD amongst high-risk groups., Methods: Embase, Medline, Scopus and grey literature were searched for studies describing proactive assessment for alcohol-related liver disease in people with a history of alcohol excess or diagnosed AUD. Outcomes of interest were fibrosis and cirrhosis detection rates, clinical outcomes, portal hypertension evaluation, attendance at follow-up and cost-effectiveness., Results: Fifteen studies were identified for inclusion from 1115 returned by the search. Four key settings for patient engagement were identified as inpatient addiction services, outpatient addiction services, general acute hospital admissions and community outreach. Of these, acute hospital admissions were the highest yield for cirrhosis at 10.8%-29.6% and community outreach the lowest was 1.2%-2.3%., Conclusions: Targeted fibrosis assessment of high-risk populations for ARLD is feasible to conduct and identifies a proportion of patients at risk of advanced liver disease. The highest yield is amongst inpatients admitted with AUD. Prospective work is needed to establish which are the most effective and acceptable screening methods and the impact on long-term outcomes., (© 2024 The Authors. Liver International published by John Wiley & Sons Ltd.)

Merkel cell carcinoma is a rare, aggressive skin tumor initiated by polyomavirus integration or UV light DNA damage. In New Zealand, there is a propensity toward the UV-driven form (31 of 107, 29% virus positive). Using archival formalin-fixed, paraffin-embedded tissues, we report targeted DNA sequencing covering 246 cancer genes on 71 tumor tissues and 38 nonmalignant tissues from 37 individuals, with 33 of 37 being negative for the virus. Somatic variants of New Zealand virus-negative Merkel cell carcinomas partially overlapped with those reported overseas, including TP53 variants in all tumors and RB1, LRP1B, NOTCH1, and EPHA3/7 variants each found in over half of the cohort. Variants in genes not analyzed or reported in previous studies were also found. Cataloging variants in TP53 and RB1 from published datasets revealed a broad distribution across these genes. Chr 1p gain and Chr 3p loss were identified in around 50% of New Zealand virus-negative Merkel cell carcinomas, and RB1 loss of heterozygosity was found in 90% of cases. Copy number variants accumulate in most metastases. Virus-negative Merkel cell carcinomas have complex combinations of somatic DNA-sequence variants and copy number variants. They likely carry the small genomic changes permissive for metastasis from early tumor development; however, chromosomal alterations may contribute to driving metastatic progression., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Measuring the incidence of HIV and hepatitis C virus (HCV) infection among people who inject drugs (PWID) is key to track progress towards elimination. We aimed to summarise global data on HIV and primary HCV incidence among PWID and associations with age and sex or gender., Methods: In this systematic review and meta-analysis, we updated an existing database of HIV and HCV incidence studies among PWID by searching MEDLINE, Embase, and PsycINFO, capturing studies published between Jan 1, 2000, and Dec 12, 2022, with no language or study design restrictions. We contacted authors of identified studies for unpublished or updated data. We included studies that estimated incidence by longitudinally re-testing people at risk of infection or by using assays for recent infection. We pooled incidence and relative risk (RR; young [generally defined as ≤25 years] vs older PWID; women vs men) estimates using random-effects meta-analysis and assessed risk of bias with a modified Newcastle-Ottawa scale. This study is registered with PROSPERO, CRD42020220884., Findings: Our updated search identified 9493 publications, of which 211 were eligible for full-text review. An additional 377 full-text records from our existing database and five records identified through cross-referencing were assessed. Including 28 unpublished records, 125 records met the inclusion criteria. We identified 64 estimates of HIV incidence (30 from high-income countries [HICs] and 34 from low-income or middle-income countries [LMICs]) and 66 estimates of HCV incidence (52 from HICs and 14 from LMICs). 41 (64%) of 64 HIV and 42 (64%) of 66 HCV estimates were from single cities rather than being multi-city or nationwide. Estimates were measured over 1987-2021 for HIV and 1992-2021 for HCV. Pooled HIV incidence was 1·7 per 100 person-years (95% CI 1·3-2·3; I 2 =98·4%) and pooled HCV incidence was 12·1 per 100 person-years (10·0-14·6; I 2 =97·2%). Young PWID had a greater risk of HIV (RR 1·5, 95% CI 1·2-1·8; I 2 =66·9%) and HCV (1·5, 1·3-1·8; I 2 =70·6%) acquisition than older PWID. Women had a greater risk of HIV (RR 1·4, 95% CI 1·1-1·6; I 2 =55·3%) and HCV (1·2, 1·1-1·3; I 2 =43·3%) acquisition than men. For both HIV and HCV, the median risk-of-bias score was 6 (IQR 6-7), indicating moderate risk., Interpretation: Although sparse, available HIV and HCV incidence estimates offer insights into global levels of HIV and HCV transmission among PWID. Intensified efforts are needed to keep track of the HIV and HCV epidemics among PWID and to expand access to age-appropriate and gender-appropriate prevention services that serve young PWID and women who inject drugs., Funding: Canadian Institutes of Health Research, Fonds de recherche du Québec-Santé, Canadian Network on Hepatitis C, UK National Institute for Health and Care Research, and WHO., Competing Interests: Declaration of interests AA acknowledges support through postdoctoral fellowships from the Canadian Institute of Health Research (CIHR), Fonds de recherche du Québec – Santé (FRQ-S), and the Canadian Network on Hepatitis C. MA reports grants paid to his institution from the Public Health Agency of Canada and grants from the Ministère de la santé et des services sociaux du Québec, during the conduct of this study, and grants from the CIHR, outside the submitted work. JA reports grants from the National Institutes of Health (NIH), during the conduct of this study. JB reports consulting fees from Gilead Sciences, AbbVie, and Cepheid; payment or honoraria from Gilead Sciences for an educational event; and receipt of equipment, materials, drugs, medical writing, gifts, or other services from Gilead Sciences, as part of an NIH R01 grant, outside of the submitted work. CSC reports grants from Gilead Sciences, Janssen Pharmaceuticals, and GSK (paid to the University of Calgary); consulting fees from Roche Pharmaceuticals, Gilead Sciences, Janssen Pharmaceuticals (paid to the University of Calgary, on behalf of the Canadian Hepatitis B Virus [HBV] Network), and Altimmune (paid to the University of Calgary, on behalf of the Canadian HBV Network); payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events through Gilead Sciences; and patents planned, issued, or pending (PCT/CA2021/050234; international patent application title: polypeptides directed against viral infection and uses thereof; compositions and methodologies for the detection and treatment of HBV infection; USA; 62/982,474; Feb 28, 2020). SC reports payments for chairing or presenting at a European HIV Testing Week webinar from the Centre of Excellence for Health, Immunity and Infections, outside the submitted work. KH reports financial support for the present manuscript paid to her institution from the US National Institute of Drug Abuse (NIDA; Vancouver Drug Users Study: the impacts of evolving drug use patterns on HIV/AIDS; U01DA038886), the Michael Smith Foundation for Health Research Scholar Award, and St Paul's Foundation, and grants or contracts from the CIHR and the William and Ada Isabelle Steel Fund through Simon Fraser University (paid to institution) and the British Columbia Centre on Substance Use (paid to KH). GM reports grants or contracts from AbbVie (clinic support, advisory board, and speaker fees), the Canadian Network on Hepatitis C (research support), Coverdale (clinic support), Gilead Sciences (clinic support and speakers fees), International Network on Health and Hepatitis in Substance Users (INHSU; speaker fees), and TD Bank (clinic support); payment or honoraria from the Canadian Association for the Study of the Liver (scientific planning committee for web-based learning, conjoint with AbbVie; payment to institution), AbbVie (speakers fees for educational podcasts and brochure; payment partly to institution and partly to GM), Gilead Sciences (speaker fees; payment partly to institution and partly to GM), and ECHO plus (honorarium for speaking); and support for attending meetings or travel, or both, from INHSU and being on the advisory board for AbbVie and Gilead. JGW reports grants and contracts from Gilead Sciences and FIND, The Global Alliance for Diagnostics. MH reports having a leadership or fiduciary role as trustee of the Society for the Study of Addiction. All other authors declare no competing interests. Declaration of interests for the members of the HIV and HCV Incidence Review Collaborative Group are provided in the appendix (p 52)., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Advances in RNA sequencing (RNA-Seq) have facilitated transcriptomic analysis of plasma for the discovery of new diagnostic and prognostic markers for disease. We aimed to develop a short-read RNA-Seq protocol to detect mRNAs, long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) in plasma for the discovery of novel markers for coronary artery disease (CAD) and heart failure (HF). Circulating cell-free RNA from 59 patients with stable CAD (half of whom developed HF within 3 years) and 30 controls was sequenced to a median depth of 108 paired reads per sample. We identified fragments from 3986 messenger RNAs (mRNAs), 164 long non-coding RNAs (lncRNAs), 405 putative novel lncRNAs and 227 circular RNAs in plasma. Circulating levels of 160 mRNAs, 10 lncRNAs and 2 putative novel lncRNAs were altered in patients compared with controls (absolute fold change >1.2, p < 0.01 adjusted for multiple comparisons). The most differentially abundant transcripts were enriched in mRNAs encoded by the mitochondrial genome. We did not detect any differences in the plasma RNA profile between patients who developed HF compared with those who did not. In summary, we show that mRNAs, lncRNAs and circular RNAs can be reliably detected in plasma by deep RNA-Seq. Multiple coding and non-coding transcripts were altered in association with CAD, including several mitochondrial mRNAs, which may indicate underlying myocardial ischaemia and oxidative stress. If validated, circulating levels of these transcripts could potentially be used to help identify asymptomatic individuals with established CAD prior to an acute coronary event.

Background: Hepatitis C virus (HCV) infection is common among people who inject drugs, yet well-described barriers mean that only a minority have accessed HCV treatment. Recent developments in HCV diagnosis and treatment facilitate innovative approaches to HCV care that improve access to, and uptake of, care by people who inject drugs., Objective: This study aims to examine feasibility, acceptability, likely clinical effectiveness, and cost-effectiveness of an integrated model of HCV care for patients receiving opioid substitution treatment in general practice., Methods: A pre- and postintervention design with an embedded economic analysis was used to establish the feasibility, acceptability, and clinical and cost-effectiveness of a complex intervention to optimize HCV identification and linkage to HCV treatment among patients prescribed methadone in primary care. The "complex intervention" comprised general practitioner (GP)/practice staff education, nurse-led clinical support, and enhanced community-based HCV assessment of patients. General practices in North Dublin were recruited from the professional networks of the research team and from GPs who attended educational sessions., Results: A total of 135 patients from 14 practices participated. Follow-up data were collected 6 months after intervention from 131 (97.0%) patients. With regard to likely clinical effectiveness, among patients with HCV antibody positivity, there was a significant increase in the proportions of patients who had a liver FibroScan (17/101, 16.8% vs 52/100, 52.0%; P<.001), had attended hepatology/infectious diseases services (51/101, 50.5% vs 61/100 61.0%; P=.002), and initiated treatment (20/101, 19.8% vs 30/100, 30.0%; P=.004). The mean incremental cost-effectiveness ratio of the intervention was €13,255 (US $13,965.14) per quality-adjusted life-year gained at current full drug list price (€39,729 [US $41,857.48] per course), which would be cost saving if these costs are reduced by 88%., Conclusions: The complex intervention involving clinical support, access to assessment, and practitioner education has the potential to enhance patient care, improving access to assessment and treatment in a cost-effective manner., (©Geoff McCombe, Davina Swan, John S Lambert, Eileen O’Connor, Zoe Ward, Peter Vickerman, Gordana Avramovic, Des Crowley, Willard Tinago, Nyashadzaishe Mafirakureva, Walter Cullen. Originally published in the Interactive Journal of Medical Research (https://www.i-jmr.org/), 23.08.2022.)

Background: In 2019-2020, record-high numbers of overdoses have been reported across the UK. We estimated perceived availability to and carriage of naloxone and explored factors associated with carriage among people who inject drugs (PWID) engaged with services in England, Wales, and Northern Ireland., Methods: Participants were PWID enrolled in the Unlinked Anonymous Monitoring Survey in 2019 who reported past-year injection drug use (n = 2,139). Recruitment occurred through specialist and community drug agencies located across the UK, excluding Scotland. Socio-demographic, behavioural and service use characteristics were self-reported. Participants were asked whether they carry naloxone (timeframe unspecified). If they answered "no", they were further asked whether it is available in their area. Perceived naloxone availability and carriage were estimated by requirement region, classified using the Nomenclature of Territorial Units for Statistics 1. We used the Gelberg-Andersen Model of healthcare access to explore predisposing, enabling and need factors associated with regionally-aggregated naloxone carriage., Results: Perceived naloxone availability was ≥95% in all 11 regions; naloxone carriage varied (mean: 61.1; range: 48%-71%; P<0.01). Among predisposing factors, female gender (adjusted odds ratio (AOR): 1.52; 95% confidence interval (CI): 1.21-1.91) was positively associated with naloxone carriage, whilst recruitment in Yorkshire and the Humber-relative to London-was negatively associated (AOR: 0.55; 95%CI: 0.37-0.82). Among enabling factors, past-year contact with needle and syringe programmes (AOR: 1.74; 95%CI: 1.39-2.18) and currently receiving treatment for drug use (AOR: 1.75; 95%CI: 1.24-2.46) were positively associated with naloxone carriage. Among need characteristics, past-month heroin injection, with or without past-month high-risk drinking or benzodiazepine use, was positively associated with carriage relative to no heroin injection (range of AORs: 1.71-2.58)., Conclusion: Perceived naloxone availability is very high among PWID attending services in England, Wales, and Northern Ireland. Naloxone carriage is moderately high and varying across regions, and appears improved through recent engagement with harm-reduction programs., (Copyright © 2022 Elsevier B.V. All rights reserved.)

One of the main goals of the 2016 Global Health Sector Strategy on viral hepatitis is the elimination of hepatitis C virus (HCV) as a public health problem by 2030, defined as an 80% reduction in incidence and 65% reduction in mortality relative to 2015. Although monitoring HCV incidence is key to validating HCV elimination, use of the gold-standard method, which involves prospective HCV retesting of people at risk, can be prohibitively resource-intensive. Additionally, few countries collected quality data in 2015 to enable an 80% decrease by 2030 to be calculated. Here, we first review different methods of monitoring HCV incidence and discuss their resource implications and applicability to various populations. Second, using mathematical models developed for various global settings, we assess whether trends in HCV chronic prevalence or HCV antibody prevalence or scale-up levels for HCV testing, treatment, and preventative interventions can be used as reliable alternative indicators to validate the HCV incidence target. Third, we discuss the advantages and disadvantages of an absolute HCV incidence target and suggest a suitable threshold. Finally, we propose three options that countries can use to validate the HCV incidence target, depending on the available surveillance infrastructure., Competing Interests: Declaration of interests PV and JGW have received unrestricted research grants from Gilead, outside the submitted work. JGW has also recieved a research grant from FIND outside the submitted work. NM has received unrestricted research grants from Gilead and Merk outside the submitted work. MH has received speaker fees honoraria in past 5 years from Gilead and Merck Shape & Dohme (MSD). HF has received an honorarium from MSD unrelated to this research. HF, ZW, and PV declare payment to their institution from WHO to prepare a background paper that formed the basis for this paper. All other authors declare no competing interests., (Copyright © 2022 World Health Organization. Published by Elsevier Ltd. All rights reserved. Published by Elsevier Ltd.. All rights reserved.)

Background: HIV incidence is increasing in eastern Europe and central Asia, primarily driven by injecting drug use. Coverage of antiretroviral therapy (ART) and opioid agonist therapy are suboptimal, with many people who inject drugs (PWID) being incarcerated. We aimed to assess whether use of monies saved as a result of decriminalisation of drug use or possession to scale up ART and opioid agonist therapy could control HIV transmission among PWID in eastern Europe and central Asia., Methods: A dynamic HIV transmission model among PWID incorporating incarceration, ART, and opioid agonist therapy was calibrated to Belarus, Kazakhstan, Kyrgyzstan, and St Petersburg (Russia). Country-specific costs for opioid agonist therapy, ART, and incarceration were collated or estimated. Compared with baseline, the model prospectively projected the life-years gained, incremental costs (2018 euros), and infections prevented over 2020-40 for three scenarios. The decriminalisation scenario removed incarceration resulting from drug use or possession for personal use, reducing incarceration among PWID by 24·8% in Belarus, Kazakhstan, and Kyrgyzstan and 46·4% in St Petersburg; the public health approach scenario used savings from decriminalisation to scale up ART and opioid agonist therapy; and the full scale-up scenario included the decriminalisation scenario plus investment of additional resources to scale up ART to the UNAIDS 90-90-90 target of 81% coverage and opioid agonist therapy to the WHO target of 40% coverage. The incremental cost-effectiveness ratios per life-year gained for each scenario were calculated and compared with country-specific gross domestic product per-capita willingness-to-pay thresholds. Costs and life-years gained were discounted 3% annually., Findings: Current levels of incarceration, opioid agonist therapy, and ART were estimated to cost from €198 million (95% credibility interval 173-224) in Kyrgyzstan to €4129 million (3897-4358) in Kazakhstan over 2020-40; 74·8-95·8% of these total costs were incarceration costs. Decriminalisation resulted in cost savings (€38-773 million due to reduced prison costs; 16·9-26·1% reduction in overall costs) but modest life-years gained (745-1694). The public health approach was cost saving, allowing each setting to reach 81% ART coverage and 29·7-41·8% coverage of opioid agonist therapy, resulting in 17 768-148 464 life-years gained and 58·9-83·7% of infections prevented. Results were similar for the full scale-up scenario., Interpretation: Cost savings from decriminalisation of drug use could greatly reduce HIV transmission through increased coverage of opioid agonist therapy and ART among PWID in eastern Europe and central Asia., Funding: Alliance for Public Health, US National Institute of Allergy and Infectious Diseases and National Institute for Drug Abuse, and Economist Intelligence Unit., Competing Interests: Declaration of interests FLA has grants from Gilead and Merck and is on advisory boards for Gilead, Merck, and AbbVie. PV has received research support from Gilead Sciences and honoraria from AbbVie and Gilead in relation to hepatitis C virus treatment. RH has received research support from Gilead Sciences unrelated to this work. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Circular RNAs (circRNAs) are an evolutionarily conserved form of noncoding RNA with covalently closed loop structures. Initial studies established a functional role for circRNAs as potent microRNA sponges and many other studies have focussed solely on this. However, the biological functions of most circRNAs are still undetermined and other functional roles are gaining traction. These include protein sponges and regulators, and coding for proteins with an alternative mechanism of translation, potentially opening up a whole new transcriptome. The first step to gaining insight into circRNA function is accurate identification and various software platforms have been developed. Specialized detection software has now evolved into whole bioinformatics pipelines that can be used for detection, de novo identification, functional prediction, and validation of circRNAs. However, few cardiovascular circRNA studies have utilized these tools. This review summarizes current knowledge of circRNA biogenesis, bioinformatic detection tools and the emerging role of circRNAs in cardiovascular disease.

Background: Long noncoding RNAs (lncRNAs) have been implicated in the pathogenesis of cardiovascular diseases. We aimed to identify novel lncRNAs associated with the early response to ischemia in the heart., Methods and Results: RNA sequencing data gathered from 81 paired left ventricle samples from patients undergoing cardiopulmonary bypass was collected before and after a period of ischemia. Novel lncRNAs were validated with Oxford Nanopore Technologies long-read sequencing. Gene modules associated with an early ischemic response were identified and the subcellular location of selected lncRNAs was determined with RNAscope. A total of 2446 mRNAs, 270 annotated lncRNAs and one novel lncRNA differed in response to ischemia (adjusted p < 0.001, absolute fold change >1.2). The novel lncRNA belonged to a gene module of highly correlated genes that also included 39 annotated lncRNAs. This module associated with ischemia (Pearson correlation coefficient = -0.69, p = 1 × 10 -23 ) and activation of cell death pathways ( p < 6 × 10 -9 ). A further nine novel cardiac lncRNAs were identified, of which, one overlapped five cis-eQTL eSNPs for the gene RWD Domain-Containing Sumoylation Enhancer (RWDD3) and was itself correlated with RWDD3 expression (Pearson correlation coefficient -0.2, p = 0.002)., Conclusion: We have identified 10 novel lncRNAs, one of which was associated with myocardial ischemia and may have potential as a novel therapeutic target or early marker for myocardial dysfunction.

Background: In Irish prisons, there is a high proportion of people who inject drugs (PWID; 26%) and a high prevalence of HCV (16%), making prison a high priority setting for HCV testing and treatment. We evaluate the cost-effectiveness of a mass HCV screening intervention in Mountjoy Prison, Dublin, compared to the standard-of-care of intermittent screening on committal., Methods: Primary cost data was collected from the intervention using an overall provider perspective. Standard-of-care (SOC) costs were estimated through interview. All costs were inflated to 2020 Euros. An HCV transmission and disease progression model among incarcerated and community PWID and ex-injectors was calibrated to the Dublin HCV epidemic, allowing inclusion of population-level health benefits. The model used intervention data, suggesting 419 individuals were screened, 50 HCV infections diagnosed and 32 individuals initiated treatment, to project the resulting costs and health benefits (quality adjusted life years or QALYs) over 50 years with 5% discounting. The incremental cost effectiveness ratio (ICER), cost per QALY gained, was estimated for the screening intervention compared to the standard-of-care. Probabilistic sensitivity analyses (PSA) determined the probability that the intervention was cost-effective compared to a willingness-to-pay threshold of €30,000/QALY as used in Ireland. The ICER for 1- or 3-yearly mass screening in all Dublin prisons was also calculated., Results: The total direct costs of the intervention (not including treatment drug costs) was €82,392, with most costs being due to staff (43%) and overhead or management costs (38%). Despite having little epidemiological impact due to the small numbers treated, over 50 years the incremental cost of the intervention was €36,592 and 3.8 QALYs were gained, giving a mean ICER of €9,552/QALY. The majority (84%) of PSA runs were below the willingness-to-pay threshold. Yearly mass screening had an ICER of €2,729/QALY compared to SOC and gave a higher net monetary benefit (€7,393,382) than screening every 3 years (€6,252,816)., Conclusion: Prison mass screening could be a cost-effective initiative for increasing testing and treatment of HCV in Ireland., Competing Interests: Declarations of Interest Peter Vickerman has received research support from Gilead Sciences and honoraria from AbbVie and Gilead unrelated to this project. John S Lambert has received non-restricted grants from Gilead, Abbvie and MSD for hepatitis C related educational and research activities. John S Lambert has received honorariums for advisory board meetings on HIV and HCV, organised by Gilead, Abbvie, Glaxo Smith Kline, Viiv, and Merck. Jack Stone has received a conference attendance sponsorship from Gilead. All other authors declare no conflicts of interest., (Copyright © 2021. Published by Elsevier B.V.)

Modelling suggests hepatitis C virus (HCV) elimination is possible among men who have sex with men (MSM), with key screening groups including HIV-diagnosed MSM and MSM using pre-exposure prophylaxis (PrEP). Mathematical modelling was used to determine the cost-effectiveness of HCV case-finding strategies among MSM from the provider perspective, and to determine which interventions could achieve a 90% reduction in HCV incidence over 2015-2030. At baseline, we assumed symptomatic screening in HIV-negative MSM (including PrEP users) and 12-monthly screening among HIV-diagnosed MSM. Improved case-finding strategies included screening alongside HIV testing in HIV-negative MSM not using PrEP (PrEP non-users); 12/6/3-monthly screening in PrEP users; and 6-monthly screening in HIV-diagnosed MSM, with the cost-effectiveness being compared incrementally. Costs (GBP) and quality-adjusted life years (QALYs) were assessed to estimate the mean incremental cost-effectiveness ratio (ICER) with a time horizon to 2050, compared to a willingness-to-pay threshold of £20,000/QALY. From the baseline, the most incrementally cost-effective strategy is to firstly undertake: (1) 12-monthly HCV screening of PrEP users (gaining 6715 QALYs with ICER £1760/QALY), followed by (2) HCV screening among PrEP non-users alongside HIV testing (gaining 7048 QALYs with ICER £4972/QALY). Compared to the baseline, this combined strategy would cost £46.9 (95%CrI £25.3-£66.9) million and achieve the HCV elimination target in 100% of model runs. Additional screening incurs ICERs >£20,000/QALY compared to this combined strategy. In conclusion, HCV elimination can be achieved cost-effectively among UK MSM. Policymakers should consider scaling-up HCV screening in HIV-negative MSM, especially PrEP users, for achieving this target., (© 2021 The Authors. Journal of Viral Hepatitis published by John Wiley & Sons Ltd.)

The dissociation process of spherical sII mixed methane-propane hydrate particles in liquid hydrocarbon was investigated via microsecond-long molecular dynamics simulations. A strong dependence of the melting temperature on the particle size was found. Analysis in the context of the Gibbs-Thomson effect provided insights into the fundamental properties of gas hydrates.

Background: People who inject drugs (PWID) are at increased risk for HIV and hepatitis C virus (HCV) infection and also have high levels of homelessness and unstable housing. We assessed whether homelessness or unstable housing is associated with an increased risk of HIV or HCV acquisition among PWID compared with PWID who are not homeless or are stably housed., Methods: In this systematic review and meta-analysis, we updated an existing database of HIV and HCV incidence studies published between Jan 1, 2000, and June 13, 2017. Using the same strategy as for this existing database, we searched MEDLINE, Embase, and PsycINFO for studies, including conference abstracts, published between June 13, 2017, and Sept 14, 2020, that estimated HIV or HCV incidence, or both, among community-recruited PWID. We only included studies reporting original results without restrictions to study design or language. We contacted authors of studies that reported HIV or HCV incidence, or both, but did not report on an association with homelessness or unstable housing, to request crude data and, where possible, adjusted effect estimates. We extracted effect estimates and pooled data using random-effects meta-analyses to quantify the associations between recent (current or within the past year) homelessness or unstable housing compared with not recent homelessness or unstable housing, and risk of HIV or HCV acquisition. We assessed risk of bias using the Newcastle-Ottawa Scale and between-study heterogeneity using the I 2 statistic and p value for heterogeneity., Findings: We identified 14 351 references in our database search, of which 392 were subjected to full-text review alongside 277 studies from our existing database. Of these studies, 55 studies met inclusion criteria. We contacted the authors of 227 studies that reported HIV or HCV incidence in PWID but did not report association with the exposure of interest and obtained 48 unpublished estimates from 21 studies. After removal of duplicate data, we included 37 studies with 70 estimates (26 for HIV; 44 for HCV). Studies originated from 16 countries including in North America, Europe, Australia, east Africa, and Asia. Pooling unadjusted estimates, recent homelessness or unstable housing was associated with an increased risk of acquiring HIV (crude relative risk [cRR] 1·55 [95% CI 1·23-1·95; p=0·0002]; I 2 = 62·7%; n=17) and HCV (1·65 [1·44-1·90; p<0·0001]; I 2 = 44·8%; n=28]) among PWID compared with those who were not homeless or were stably housed. Associations for both HIV and HCV persisted when pooling adjusted estimates (adjusted relative risk for HIV: 1·39 [95% CI 1·06-1·84; p=0·019]; I 2 = 65·5%; n=9; and for HCV: 1·64 [1·43-1·89; p<0·0001]; I 2 = 9·6%; n=14). For risk of HIV acquisition, the association for unstable housing (cRR 1·82 [1·13-2·95; p=0·014]; n=5) was higher than for homelessness (1·44 [1·13-1·83; p=0·0036]; n=12), whereas no difference was seen between these outcomes for risk of HCV acquisition (1·72 [1·48-1·99; p<0·0001] for unstable housing, 1·66 [1·37-2·00; p<0·0001] for homelessness)., Interpretation: Homelessness and unstable housing are associated with increased risk of HIV and HCV acquisition among PWID. Our findings support the development of interventions that simultaneously address homelessness and unstable housing and HIV and HCV transmission in this population., Funding: National Institute for Health Research, National Institute on Drug Abuse, National Institute of Allergy and Infectious Diseases, and Commonwealth Scholarship Commission., Competing Interests: Declaration of interests HF reports honoraria from MSD outside of the submitted work. JA reports grants from National Institutes of Health (NIH) during the conduct of the study. SSS reports grants from NIH during the conduct of the study, and grants from Gilead Sciences and Abbot Diagnostics outside of the submitted work. VS reports grants, personal fees, and non-financial support from Gilead Sciences and AbbVie and personal fees from Janssen outside of the submitted work. JGW reports grants from Gilead Sciences outside of the submitted work. All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Using both computational and experimental methods, the capacity of four different surfactant molecules to inhibit the agglomeration of sII hydrate particles was assessed. The computational simulations were carried out using both steered and non-steered molecular dynamics (MD), simulating the coalescence process of a hydrate slab and a water droplet, both covered with surfactant molecules. The surfactants were ranked according to free energy calculations (steered MD) and the number of agglomeration events (non-steered MD). The experimental work was based on rocking cell measurements, determining the minimum effective dose necessary to inhibit agglomeration. Overall, good agreement was obtained between the performance predicted by the simulations and the experimental measurements. Moreover, the simulations allowed us to gain additional insights that are not directly accessible via experiments, such as an analysis of the mass density profiles, the diffusion coefficients, or the orientations of the long tails.

Objectives: Hepatitis C Virus (HCV) is a significant cause of chronic liver disease. Among at-risk populations, access to diagnosis and treatment is challenging. We describe an integrated model of care, Hepcare Europe, developed to address this challenge., Methods: Using a case-study approach, we describe the cascade of care outcomes at all sites. Cost analyses estimated the cost per person screened and linked to care., Results: A total of 2608 participants were recruited across 218 clinical sites. HCV antibody test results were obtained for 2568(98•5%); 1074(41•8%) were antibody-positive, 687(60•5%) tested positive for HCV-RNA, 650(60•5%) were linked to care, and 319(43•5%) started treatment. 196(61•4%) of treatment initiates achieved a Sustained Viral Response (SVR) at dataset closure, 108(33•9%) were still on treatment, eight (2•7%) defaulted from treatment, and seven (2•6%) had virologic failure or died. The cost per person screened varied from €194 to €635, while the cost per person linked to care varied from €364 to €2035., Conclusions: Hepcare enhanced access to HCV treatment and cure, and costs were affordable in all settings, offering a framework for scale-up and reproducibility., (Copyright © 2020. Published by Elsevier Ltd.)

Background and Aims: People who inject drugs (PWID) are at high risk of hepatitis C virus (HCV) infection; however, ~50% are undiagnosed in England and linkage-to-care is poor. This study investigated the cost-effectiveness of an intervention (HepCATT) to improve case-finding and referral to HCV treatment compared with standard-of-care pathways in drug treatment centres in England., Design: HCV transmission and disease progression model with cost-effectiveness analysis using a health-care perspective. Primary outcome and cost data from the HepCATT study parameterized the intervention, suggesting that HepCATT increased HCV testing in drug treatment centres 2.5-fold and engagement onto the HCV treatment pathway 10-fold. A model was used to estimate the decrease in HCV infections and HCV-related deaths from 2016, with costs and health benefits (quality-adjusted life-years or QALYs) tracked over 50 years. Univariable and probabilistic sensitivity analyses (PSA) were undertaken., Setting: England-specific epidemic with 40% prevalence of chronic HCV among PWID., Participants: PWID attending drug treatment centres., Intervention: Nurse facilitator in drug treatment centres to improve the HCV care pathway from HCV case-finding to referral and linkage to specialist care. Comparator was the standard-of-care HCV care pathway., Measurements: Incremental cost-effectiveness ratio (ICER) in terms of cost per QALY gained through improved case-finding., Findings: Over 50 years per 1000 PWID, the HepCATT intervention could prevent 75 (95% central interval 37-129) deaths and 1330 (827-2040) or 51% (30-67%) of all new infections. The mean ICER was £7986 per QALY gained, with all PSA simulations being cost-effective at a £20 000 per QALY willingness-to-pay threshold. Univariable sensitivity analyses suggest the intervention would become cost-saving if the cost of HCV treatment reduces to £3900. If scaled up to all PWID in England, the intervention would cost £8.8 million and decrease incidence by 56% (33-70%) by 2030., Conclusions: Increasing hepatitis C virus infection case-finding and treatment referral in drug treatment centres could be a highly cost-effective strategy for decreasing hepatitis C virus incidence among people who inject drugs., (© 2020 Society for the Study of Addiction.)

Background and Aims: Traditional detachable syringes used by people who inject drugs (PWID) retain larger volumes of blood when the plunger is depressed than syringes with fixed needles-referred to as high (HDSS) and low dead space syringes (LDSS), respectively. Evidence suggests that using HDSS may result in greater hepatitis C virus (HCV) transmission risk than LDSS. We evaluated the cost-effectiveness of an intervention to introduce detachable LDSS in a needle and syringe programme (NSP)., Design: HCV transmission and disease progression model with cost-effectiveness analysis using a health-care perspective. Detachable LDSS are associated with increased costs (£0.008) per syringe, yearly staff training costs (£536) and an estimated decreased risk (by 47.5%) of HCV transmission compared with HDSS. The intervention was modelled for 10 years, with costs and health benefits (quality-adjusted life-years: QALYs) tracked over 50 years., Setting: Bristol, UK., Participants and Cases: PWID attending NSP., Intervention and Comparator: Gradual replacement of HDSS at NSP, with 8, 58 and 95% of HDSS being replaced by detachable LDSS in 2016, 2017 and 2018, respectively. Comparator was continuing use of HDSS., Measurements: Net monetary benefit. Benefits were measured in QALYs., Findings: Introducing detachable LDSS was associated with a small increase in intervention costs (£21 717) compared with not introducing detachable LDSS, but considerable savings in HCV-related treatment and care costs (£4 138 118). Overall cost savings were £4 116 401 over 50 years and QALY gains were 1000, with an estimated 30% reduction in new infections over the 10-year intervention period. In all sensitivity analyses, detachable LDSS resulted in cost savings and additional QALYs. Threshold analyses suggested that detachable LDSS would need to reduce HCV transmission risk of HDSS by 0.26% to be cost-saving and 0.04% to be cost-effective., Conclusions: Replacing high dead space syringes with detachable low dead space syringes in needle and syringe programmes in the United Kingdom is likely to be a cost-saving approach for reducing hepatitis C virus transmission., (© 2019 Society for the Study of Addiction.)

Background: HCV disproportionately affects marginalized communities such as homeless populations and people who inject drugs (PWID), posing a challenge to traditional health services. The HepFriend initiative in London is a model of care utilizing HCV outreach screening and peer support to link vulnerable individuals to HCV treatment in secondary care., Objectives: To assess the cost-effectiveness of the HepFriend initiative from a healthcare provider perspective, compared with standard-of-care pathways (consisting of testing in primary care and other static locations, including drug treatment centres, and linkage to secondary care)., Methods: Cost-effectiveness analysis using a dynamic HCV transmission and disease progression model among PWID and those who have ceased injecting, including housing status and drug treatment service contact. The model was parameterized using London-specific surveillance and survey data, and primary intervention cost and effectiveness data (September 2015 to June 2018). Out of 461 individuals screened, 197 were identified as HCV RNA positive, 180 attended secondary care and 89 have commenced treatment to date. The incremental cost-effectiveness ratio (ICER) was determined using a 50 year time horizon., Results: For a willingness-to-pay threshold of £20000 per QALY gained, the HepFriend initiative is cost-effective, with a mean ICER of £9408/QALY, and would become cost saving at 27% (£10525 per treatment) of the current drug list price. Results are robust to variations in intervention costs and model assumptions, and if treatment rates are doubled the intervention becomes more cost-effective (£8853/QALY)., Conclusions: New models of care that undertake active case-finding with enhanced peer support to improve testing and treatment uptake amongst marginalized and vulnerable groups could be highly cost-effective and possibly cost saving., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)

Objectives: To examine HCV prevalence and management among people who inject drugs (PWID) attending primary care and community-based health services at four European sites using baseline data from a multicentre feasibility study of a complex intervention (HepLink)., Methods: Primary care and community-based health services in Dublin, London, Bucharest and Seville were recruited from the professional networks of the HepLink consortium. Patients were eligible to participate if aged ≥18 years, on opioid substitution treatment or at risk of HCV (i.e. injecting drug use, homeless or incarcerated), and attended the service. Data on patient demographics and prior HCV management were collected on participants at baseline., Results: Twenty-nine primary care and community-based health services and 530 patients were recruited. Baseline data were collected on all participants. Participants' mean age ranged from 35 (Bucharest) to 51 years (London), with 71%-89% male. Prior lifetime HCV antibody testing ranged from 65% (Bucharest) to 95% (Dublin) and HCV antibody positivity among those who had been tested ranged from 78% (Dublin) to 95% (Bucharest). Prior lifetime HCV RNA testing among HCV antibody-positive participants ranged from 17% (Bucharest) to 84% (London). Among HCV antibody- or RNA-positive participants, prior lifetime attendance at a hepatology/infectious disease service ranged from 6% (London) to 50% (Dublin) and prior lifetime HCV treatment initiation from 3% (London) to 33% (Seville)., Conclusions: Baseline assessment of the HCV cascade of care among PWID attending primary care and community-based health services at four European sites identified key aspects of the care cascade at each site that need to be improved., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)

Introduction: Hepatitis C virus (HCV) is the second largest contributor to liver disease in the UK, with injecting drug use as the main risk factor among the estimated 200 000 people currently infected. Despite effective prevention interventions, chronic HCV prevalence remains around 40% among people who inject drugs (PWID). New direct-acting antiviral (DAA) HCV therapies combine high cure rates (>90%) and short treatment duration (8 to 12 weeks). Theoretical mathematical modelling evidence suggests HCV treatment scale-up can prevent transmission and substantially reduce HCV prevalence/incidence among PWID. Our primary aim is to generate empirical evidence on the effectiveness of HCV 'Treatment as Prevention' (TasP) in PWID., Methods and Analysis: We plan to establish a natural experiment with Tayside, Scotland, as a single intervention site where HCV care pathways are being expanded (including specialist drug treatment clinics, needle and syringe programmes (NSPs), pharmacies and prison) and HCV treatment for PWID is being rapidly scaled-up. Other sites in Scotland and England will act as potential controls. Over 2 years from 2017/2018, at least 500 PWID will be treated in Tayside, which simulation studies project will reduce chronic HCV prevalence among PWID by 62% (from 26% to 10%) and HCV incidence will fall by approximately 2/3 (from 4.2 per 100 person-years (p100py) to 1.4 p100py). Treatment response and re-infection rates will be monitored. We will conduct focus groups and interviews with service providers and patients that accept and decline treatment to identify barriers and facilitators in implementing TasP. We will conduct longitudinal interviews with up to 40 PWID to assess whether successful HCV treatment alters their perspectives on and engagement with drug treatment and recovery. Trained peer researchers will be involved in data collection and dissemination. The primary outcome - chronic HCV prevalence in PWID - is measured using information from the Needle Exchange Surveillance Initiative survey in Scotland and the Unlinked Anonymous Monitoring Programme in England, conducted at least four times before and three times during and after the intervention. We will adapt Bayesian synthetic control methods (specifically the Causal Impact Method) to generate the cumulative impact of the intervention on chronic HCV prevalence and incidence. We will use a dynamic HCV transmission and economic model to evaluate the cost-effectiveness of the HCV TasP intervention, and to estimate the contribution of the scale-up in HCV treatment to observe changes in HCV prevalence. Through the qualitative data we will systematically explore key mechanisms of TasP real world implementation from provider and patient perspectives to develop a manual for scaling up HCV treatment in other settings. We will compare qualitative accounts of drug treatment and recovery with a 'virtual cohort' of PWID linking information on HCV treatment with Scottish Drug treatment databases to test whether DAA treatment improves drug treatment outcomes., Ethics and Dissemination: Extending HCV community care pathways is covered by ethics (ERADICATE C, ISRCTN27564683, Super DOT C Trial clinicaltrials.gov: NCT02706223). Ethical approval for extra data collection from patients including health utilities and qualitative interviews has been granted (REC ref: 18/ES/0128) and ISCRCTN registration has been completed (ISRCTN72038467). Our findings will have direct National Health Service and patient relevance; informing prioritisation given to early HCV treatment for PWID. We will present findings to practitioners and policymakers, and support design of an evaluation of HCV TasP in England., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)