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IntroductionHepatitis 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 analysisWe 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 disseminationExtending 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.

Background Hepatitis C Virus (HCV) is a public health threat which contributes substantially to the global burden of liver disease. There is much debate about effective approaches to scaling up diagnosis of HCV among risk groups. Tayside, a region in the East of Scotland, developed low-threshold community pathways for HCV to lay the foundations of an elimination strategy. In this retrospective study, we sought to: quantify the contribution of community pathways to increasing HCV diagnosis; understand if shifting diagnosis to community settings led to a higher proportion of individuals tested for HCV being actively infected; and describe functional characteristics of the care pathways. Methods Descriptive statistics were used to for analysis of routinely-collected HCV testing data from 1999 to 2017, and a review of the development of the care pathways was undertaken. Community-based testing was offered through general practices (GP); nurse outreach clinics; prisons; drug treatment services; needle and syringe provision (NSP) sites; community pharmacies; and mosques. Results Anti-HCV screening was undertaken on 109,430 samples, of which 5176 (4.7%) were reactive. Of all samples, 77,885 (71.2%) were taken in secondary care; 25,044 (22.9%) in GPs; 2970 (2.7%) in prisons; 2415 (2.2%) in drug services; 753 (0.7%) in NSPs; 193 (0.2%) pharmacies; and 170 (0.1%) in mosques. The highest prevalence of HCV infection among those tested was in NSP sites (26%), prisons (14%), and drug treatment centres (12%). Conclusions Decentralised care pathways, particularly in harm reduction and other drug service settings, were key to increasing diagnosis of HCV in the region, but primary and secondary care remain central to elimination efforts.

Background Community pharmacists are the most publicly accessible health professionals in high-income countries. There is increasing interest in conducting randomised controlled trials (RCT)—the benchmark of original evidence in the medical field—in community pharmacies. However, little evidence exists examining the challenges and opportunities of conducting RCTs in pharmacies, particularly with respect to project management. In this work, we aim to provide a narrative of lessons learned in conducting two RCTs in community pharmacies in two high-income countries. Methods We retrospectively reviewed multiple data sources including administrative and trial activity records. We conducted face-to-face and online sessions to create a list of lessons learned from our experiences and created a stakeholder map for the trials examined. We framed our findings using the Project Managements Institute’s model of the project life cycle, and descriptive statistics were used to estimate the outcomes reported. Results Ninety-six pharmacies were recruited. Across the project phases, seven high-level tasks within Initiation; 30 within Planning, 43 within Execution/Monitoring and Controlling, and 14 in Closure, were identified. Recruitment of pharmacies, developing documentation for trial drug supply, participant recruitment, and negotiation with pharmacy contracting bodies took longest to complete. Eight key stakeholder groups were identified, including public services/agencies; community pharmacies, communications actors; funders/sponsors; universities/research institutes; healthcare providers; suppliers; and regulators. Thirty lessons were identified, most critically across engaging and managing stakeholders; selecting and supporting trial sites; streamlining trial processes to minimise burden; optimising data collection and accuracy; and considering pharmacy constraints and costs. Conclusions Conducting RCTs in community pharmacies presents unique challenges across the project life cycle. Key lessons include the importance of early planning, streamlining processes to reduce staff burden, and addressing pharmacy constraints. The complexity of the work necessitates dedicated and well-resourced trial management staff to enhance stakeholder management and offer tailored supports where required. Trial registration. Not applicable.

People who overdose on opioids when they are alone or unmonitored are at heightened risk of death as other people do not know they should provide an emergency response. Wearable technology provides an opportunity to continuously measure respiratory function and ultimately send an alert if respiratory depression occurs. This study evaluates the feasibility and acceptability of PneumoWave DC in UK homeless hostels or supported accommodation settings (equivalent to Housing First in the USA) for individuals at high risk of opioid overdose. The PneumoWave system consists of a wearable biosensor that is affixed to the chest and records chest motion and which, in future, could potentially provide early detection of respiratory depression and trigger overdose response. RESCU-2 is a non-randomised, observational trial conducted in supported accommodation facilities across the UK. 50 participants who currently use opioids and live in homeless hostels in England and Scotland will wear the PneumoWave biosensor for varying periods to collect data over 2,000 participant-days. The biosensor will be linked via Bluetooth to a hub for continuous respiratory data collection. Self-reported drug use during the trial will be measured using drug diaries. Quantitative acceptability data will be measured using structured satisfaction surveys, while qualitative acceptability data will be obtained from interviews and focus groups with both residents and staff. Statistical analysis will include descriptive evaluation of feasibility outcomes, while qualitative data will undergo thematic analysis. The primary objectives of the study are: 1) feasibility of the study protocol within the hostel setting; 2) acceptability and usability of the device among people who use opioids and live in hostels; 3) acceptability of the device among staff who work in hostels and respond to overdose events. Primary outcomes are recruitment, total hours of usable data collected and successful recording of key outcome measures, among others. Trial registration: ISRCTN12060022. Findings will inform the feasibility of future integration of chest biosensor technology into hostel settings, assessing participant adherence, usability, and acceptability among people who use substances and staff. Insights gained will support the design of future trials and further development of remote monitoring technologies for overdose prevention and response strategies.

IntroductionHepatitis C is a blood-borne virus (HCV) that can seriously damage the liver and is spread mainly through blood-to-blood contact with an infected person. Over 85% of individuals who have HCV in Scotland became infected following injecting drug use. Since people who inject drugs (PWID) are the main source of new infections, theoretical modelling has suggested that treatment of HCV infection in PWID may effectively reduce HCV prevalence and accomplish elimination. This protocol describes a clinical trial delivering HCV treatment within injecting equipment provision sites (IEPS) in Tayside, Scotland.Methods and analysisPWID attending IEPS are tested for HCV and, if they are chronically infected with HCV and eligible, invited to receive treatment within the IEPS. They are randomised to one of three treatment regimens; daily observed treatment, treatment dispensed every 2 weeks and treatment dispensed every 2 weeks together with an adherence psychological intervention (administered before treatment begins). The primary outcome is comparison of the rate of successful treatment (SVR12) in each treatment group. Secondary analyses include assessment of adherence, reinfection rates, viral resistance to treatment and interaction of the treatment with illicit drugs.Ethics and disseminationThe ADVANCE (A Direct obserVed therApy versus fortNightly CollEction) HCV trial was given favourable opinion by East of Scotland Research Ethics Committee (LR/17/ES/0089) prior to commencement.Trial registration numbersEuropean Clinical Trials Database (EudraCT) (2017-001039-38) and ClinicalTrials.gov (NCT03236506).

IntroductionHepatitis C virus (HCV) is a global public health threat, and novel models of care are required to treat those currently or previously at highest risk of infection, particularly persons who inject drugs (PWID; ever injected), as conventional healthcare models do not have the reach to deliver cure of HCV to disadvantaged, disproportionately affected communities. In Western Europe and Australasia, it is estimated that HCV affects between 0.4% and 1.0% of the regions’ populations, accordingly, it affects between 0.4% and 0.7% of the populations of countries in this study (Scotland, Wales and Australia). Reaching mEthadone users Attending Community pHarmacies with HCV (REACH HCV) will evaluate community pharmacy-based diagnostic outreach and HCV treatment against conventional HCV testing and treatment pathways for clients receiving opioid substitution therapy (OST) in community pharmacies.Methods and analysisREACH HCV is an international multicentre cluster randomised controlled trial with sites in Scotland, Wales and Australia. The sites are community pharmacies which are randomised equally to one of two pathways: the pharmacy intervention pathway or the education-only (control) pathway. Participants are recruited from OST clients in these pharmacies.In the pharmacy intervention pathway, participants receive a rapid point-of-care HCV PCR test in their pharmacy by a study outreach nurse. If positive, direct-acting antivirals (DAAs) are delivered to participants via their pharmacist in line with their OST schedule.In the education-only pathway, pharmacists counsel OST clients on HCV and refer them to the nearest nurse-led clinic or general practitioner offering HCV testing according to standard care protocols. If positive, DAAs are delivered as in the intervention pathway.The primary endpoint for both pathways is sustained viral response at 12 weeks post-treatment . Secondary outcomes are: cost-efficacy by pathway; participants tested by pathway; adherence to therapy by pathway and impact of blood test results on treatment decisions.A statistical analysis plan will be finalised prior to data lock. Analysis will be by intention to treat (ITT) to show superiority. Modified ITT analysis will also be undertaken to explore the steps in the pathways.Ethics and disseminationThe trial received ethical favourable opinion from the East of Scotland Research Ethics Committee 2 (19/ES/0025) for UK sites and approval from the Alfred Hospital Ethics Committee (148/19) for Australian sites and complies with principles of Good Clinical Practice. Final results will be presented in peer-reviewed journals and at relevant conferences.Trial registration numberClinicalTrials.gov Registry NCT03935906.Protocol versionV.4.0—19 March 2020.

This article argues that John Gower's Confessio Amantis is a coherent poem, that its bleak conclusion is inevitable, and that the exemplary moral tales in the main body of the poem work to anticipate and prepare the ground for that conclusion. In support of this argument, I analyze a sequence of tales from book 5–the tales of Echo, Babio and Croceus, Adrian and Bardus, and Theseus and Ariadne–in order to show how they function on multiple levels. Ostensibly, they warn against sins of which the hapless Amans is not guilty (and which he accuses his lady of having committed herself); on a deeper level, and with the help of tactful hints from Genius, they warn Amans of the dangers to which his unrequited love may expose him, and of its inevitable end-point. In advancing these claims, I contest the views of scholars who have argued for the Confessio's incoherence, or for a more optimistic view of Genius's advice to Amans, and suggest that coming to terms with the poem's coherence and bleakness enhances our appreciation of its subtlety and profundity.

Hepatitis C virus (HCV) is a global public health threat, and novel models of care are required to treat those currently or previously at highest risk of infection, particularly persons who inject drugs (PWID; ever injected), as conventional healthcare models do not have the reach to deliver cure of HCV to disadvantaged, disproportionately affected communities. In Western Europe and Australasia, it is estimated that HCV affects between 0.4% and 1.0% of the regions' populations, accordingly, it affects between 0.4% and 0.7% of the populations of countries in this study (Scotland, Wales and Australia). eaching m thadone users ttending ommunity p armacies with HCV (REACH HCV) will evaluate community pharmacy-based diagnostic outreach and HCV treatment against conventional HCV testing and treatment pathways for clients receiving opioid substitution therapy (OST) in community pharmacies. REACH HCV is an international multicentre cluster randomised controlled trial with sites in Scotland, Wales and Australia. The sites are community pharmacies which are randomised equally to one of two pathways: the pharmacy intervention pathway or the education-only (control) pathway. Participants are recruited from OST clients in these pharmacies.In the pharmacy intervention pathway, participants receive a rapid point-of-care HCV PCR test in their pharmacy by a study outreach nurse. If positive, direct-acting antivirals (DAAs) are delivered to participants via their pharmacist in line with their OST schedule.In the education-only pathway, pharmacists counsel OST clients on HCV and refer them to the nearest nurse-led clinic or general practitioner offering HCV testing according to standard care protocols. If positive, DAAs are delivered as in the intervention pathway.The primary endpoint for both pathways is sustained viral response at 12 weeks post-treatment . Secondary outcomes are: cost-efficacy by pathway; participants tested by pathway; adherence to therapy by pathway and impact of blood test results on treatment decisions.A statistical analysis plan will be finalised prior to data lock. Analysis will be by intention to treat (ITT) to show superiority. Modified ITT analysis will also be undertaken to explore the steps in the pathways. The trial received ethical favourable opinion from the East of Scotland Research Ethics Committee 2 (19/ES/0025) for UK sites and approval from the Alfred Hospital Ethics Committee (148/19) for Australian sites and complies with principles of Good Clinical Practice. Final results will be presented in peer-reviewed journals and at relevant conferences. ClinicalTrials.gov Registry NCT03935906. V.4.0-19 March 2020.

There is a pervasive tendency, in Machaut scholarship, to read his poetry as having value only insofar as it speaks to our postmodern age: either it is fragmented and riven with ambiguities, or it celebrates eroticism and the things of this world for their own sake; in any case, it resists religious and moral orthodoxy. Such readings, while often valuable in themselves, fail to take sufficient account of the influence which Boethian and Neoplatonic ideas had upon Machaut, and thus misunderstand his work on a fundamental level. By paying attention to the Boethian content in the narrative dits, and by analysing Machaut's verse more thoroughly than has been done before, my thesis demonstrates not only this author's moral orthodoxy, but also his extremely sophisticated didactic methods. I begin with the Confort d'ami, Machaut's most overtly moral work. The Confort engages with the supposed 'worldly' perspective of its imprisoned addressee, adapting biblical and classical exempla in order to coax Charles of Navarre towards a deeper understanding of worldly fortune. In Chapter 2 I show how, in the Prologue and the Dit du vergier, the ambiguity so beloved of critics can serve as a moral commentary on the carnality and self-absorption of the erotic and artistic points of view. Having established, in the preceding chapters, that this author's approach to his subject is ambiguous and critical, in Chapter 3 I explore the extremes of his pessimism, and show how his love poetry can incorporate sophisticated philosophical ideas, through my analysis of the Jugement du roy de Behaigne. The thesis culminates in a detailed reading of the Remede de Fortune. Through his deliberately idealised statements about education, through his application of these views to the art of courtly love, through his composition (and setting to music) of a sequence of virtuoso lyrics, and through his explicit invocations of and borrowings from Boethius, Machaut develops an empathic but ultimately, as I argue, deeply sceptical vision of earthly love.