Has the HCV cascade of care changed among people who inject drugs in England since the introduction of direct-acting antivirals?

BACKGROUND: In England, over 80 % of those with hepatitis C virus (HCV) infection have injected drugs. We quantified the HCV cascade of care (CoC) among people who inject drugs (PWID) in England and determined whether this improved after direct-acting antivirals (DAAs) were introduced. METHODS: We analysed data from nine rounds of national annual cross-sectional surveys of PWID recruited from drug services (2011-2019; N = 12,320). Study rounds were grouped as: 'Pre-DAAs' (2011-2014), 'Prioritised DAAs' (2015-2016) and 'Unrestricted DAAs' (2017-2019). Participants were anonymously tested for HCV antibodies and RNA and completed a short survey. We assessed the proportion of PWID recently (current/previous year) tested for HCV. For participants ever HCV treatment eligible (past chronic infection with history of treatment or current chronic infection), we assessed the CoC as: HCV testing (ever), received a positive test result, seen a specialist nurse/doctor, and ever treated. We used logistic regression to determine if individuals progressed through the CoC differently depending on time-period, whether time-period was associated with recent testing (all participants) and lifetime HCV treatment (ever eligible participants), and predictors of HCV testing and treatment in the Unrestricted DAAs period. RESULTS: The proportion of ever HCV treatment eligible PWID reporting lifetime HCV treatment increased from 12.5 % in the Pre-DAAs period to 25.6 % in the Unrestricted DAAs period (aOR:2.40, 95 %CI:1.95-2.96). There were also increases in seeing a specialist nurse/doctor. The largest loss in the CoC was at treatment for all time periods. During the Unrestricted DAAs period, recent (past year) homelessness (vs never, aOR:0.66, 95 %CI:0.45-0.97), duration of injecting (≤3 years vs >3 years; aOR:0.26, 95 %CI:0.12-0.60), never (vs current, aOR:0.31, 95 %CI:0.13-0.75) or previously being prescribed OAT (vs current, aOR:0.67, 95 %CI:0.47-0.95), and never using a NSP (vs past year, aOR:0.27, 95 %CI:0.08-0.89) were negatively associated with lifetime HCV treatment. The proportion of PWID reporting recent HCV testing was higher during Unrestricted DAAs (56 %) compared to Pre-DAAs (48 %; aOR:1.28, 95 %CI:1.06-1.54). CONCLUSION: COC stages from seeing a specialist onwards improved after DAAs became widely available. Further improvements in HCV testing are needed to eliminate HCV in England.

Prevalence, drivers and surveillance of antibiotic resistance and antibiotic use in rural China: Interdisciplinary study.

This study aimed to characterise antibiotic prescribing and dispensing patterns in rural health facilities in China and determine the community prevalence of antibiotic resistance. We investigated patterns and drivers of antibiotic use for common respiratory and urinary tract infections (RTI/UTI) in community settings, examined relationships between presenting symptoms, clinical diagnosis and microbiological results in rural outpatient clinics, and assessed potential for using patient records to monitor antibiotic use. This interdisciplinary mixed methods study included: (i) Observations and exit interviews in eight village clinics and township health centres and 15 retail pharmacies; (ii) Urine, throat swab and sputum samples from patients to identify potential pathogens and test susceptibility; (iii) 103 semi-structured interviews with doctors, patients, pharmacy workers and antibiotic-purchasing customers; (iv) Assessment of completeness and accuracy of electronic patient records through comparison with observational data. 87.9% of 1123 recruited clinic patients were prescribed antibiotics (of which 35.5% contained antibiotic combinations and >40% were for intravenous administration), most of whom had RTIs. Antibiotic prescribing for RTIs was not associated with presence of bacterial pathogens but was correlated with longer duration of infection (OR = 3.33) and presence of sore throat (OR = 1.64). Fever strongly predicted prescription of intravenous antibiotics (OR = 2.87). Resistance rates in bacterial pathogens isolated were low compared with national data. 25.8% of patients reported antibiotics use prior to their clinic visit, but only 56.2% of clinic patients and 53% of pharmacy customers could confirm their prescription or purchase included antibiotics. Diagnostic uncertainty, financial incentives, understanding of antibiotics as anti-inflammatory and limited doctor-patient communication were identified as key drivers of antibiotic use. Completion and accuracy of electronic patient records were highly variable. Prevalence of antibiotic resistance in this rural population is relatively low despite high levels of antibiotic prescribing and self-medication. More systematic use of e-records and in-service training could improve antibiotic surveillance and stewardship in rural facilities. Combining qualitative and observational anthropological methods and concepts with microbiological and epidemiological investigation of antibiotic resistance at both research design and analytic synthesis stages substantially increases the validity of research findings and their utility in informing future intervention development.

Cost-effectiveness of pharmacy-led versus conventionally delivered antiviral treatment for hepatitis C in patients receiving opioid substitution therapy: An economic evaluation alongside a pragmatic cluster randomised trial.

BACKGROUND: Elimination targets for hepatitis C have been set across the world. In the UK almost 90% of infections are in people who inject drugs. Evidence shows community case-finding is effective at identifying and treating undiagnosed patients. The aim of this analysis was to assess, from a healthcare provider perspective, the cost-effectiveness of a new pharmacist-led test and treat pathway for hepatitis C in opioid agonist treatment (OAT) patients attending community pharmacies compared to conventional care. METHODS: In a cluster randomised controlled trial, pharmacies were randomised to the pharmacist-led or conventional care pathway. Mean cost per OAT patient and per patient initiating treatment was identified for each pathway. A Markov model tracking disease progression was developed, with a 50-year time horizon and 3·5% time discount rate, to estimate the incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) gained and the probability of being cost-effective at a £30,000 per QALY willingness-to-pay threshold. Probabilistic sensitivity analysis was performed for a range of drug discounts, re-infection rates, and model assumptions. FINDINGS: Mean cost per OAT patient (£3,674 vs £1,965) and per patient initiating treatment (£863 vs £404) was higher in the pharmacist-led pathway, due to higher uptake of testing and pharmacist time requirements. Over a 50-year time horizon the ICER per QALY gained was £31,612 at NHS indicative price for treatment (£38,979 for 12 weeks) and 12·1/100 person-years re-infection rate, reducing to £21,027/£10,220/-£501 per QALY gained with 30%/60%/90% drug price discounts and £25,373/£21,738/£14,912 per QALY gained at re-infection rates of 8/5/2 per 100 person-years. At 30%/60%/90% drug discount rates, the pharmacist-led pathway has an 80%/98%/100% probability of being cost-effective. INTERPRETATION: The pharmacist-led pathway is effective at increasing testing and treatment uptake, with cost-effectiveness being highly dependent on drug price discounts. FUNDING: Trial funding provided by the Scottish Government, Gilead Sciences, and Bristol-Myers Squibb.

Ophthalmic Telesurgery with a Low-Cost Smartphone Video System for Surgeon Self-Reflection and Remote Synchronous Consultation: A Qualitative and Quantitative Study.

Summary: More than a third of the global burden of blindness is due to cataracts, yet cataract surgery is one of the most cost-effective surgical treatments in medicine. Poor surgical outcomes in many settings remain a major challenge, raising concerns about the quality and efficacy of surgical training. Reflective learning from video recordings of a trainees' surgical performance has a high educational impact and is available routinely for surgical training within high-resource institutions. However, the prohibitive cost and limited portability of current surgical video recording systems make its use problematic in low-resource settings and outreach environments. Objective: The study's aim was to evaluate the potential of smartphone-captured surgical videos for surgeon learning via self-recording and self-review as well as the potential to support live telesurgical consultation. Methodology: A quantitative and qualitative methodology was used to explore and describe the utility and acceptance of smartphone videos in two training facilities in Nepal. Twenty surgeries were recorded on the smartphone for surgeon self-review, to assess image quality, and its application to measure performance against the International Council of Ophthalmology (ICO) Ophthalmology Surgical Competency Assessment Rubrics (OSCAR) SICS Rubric. The same system was used to transmit 15 different surgeries live via Skype from Nepal to an ophthalmologist surgical trainer in South Africa to evaluate the feasibility of live consultation. Findings: Overall video quality was described as high in 65% and moderate in 35% for the videos recorded for self-review. In the surgeries streamed via Skype, quality was described as high in 92.9% and moderate in 7.1%. There were no instances where the video quality was described as poor. The video quality was good enough that the surgeons could measure against ICO-OSCAR rubric in all cases. Discussion: The video quality of smartphone-captured surgical videos was found to be high and gained acceptance for reflective teaching and learning purposes. The extended telesurgical potential and portability of the smartphone enables use across many settings. More studies over a longer period are needed to determine how they can support training and learning in cataract surgery.

Low uptake of COVID-19 lateral flow testing among university students: a mixed methods evaluation.

OBJECTIVE: This study aimed to evaluate COVID-19 lateral flow testing (LFT) among asymptomatic university students. STUDY DESIGN: This study was a mixed methods evaluation of LFT among University of Bristol students. METHODS: We conducted (1) an analysis of testing uptake and exploration of demographic variations in uptake using logistic regression; (2) an online student survey about views on university testing; and (3) qualitative interviews to explore participants' experiences of testing and subsequent behaviour, analysed using a thematic approach. RESULTS: A total of 12,391 LFTs were conducted on 8025 of 36,054 (22.3%) students. Only one in 10 students had the recommended two tests. There were striking demographic disparities in uptake with those from ethnic minority groups having lower uptake (e.g. 3% of Chinese students were tested vs 30.7% of White students) and variations by level and year of study (ranging from 5.3% to 33.7%), place of residence (29.0%-35.6%) and faculty (15.2%-32.8%). Differences persisted in multivariable analyses. A total of 436 students completed the online survey, and 20 in-depth interviews were conducted. Barriers to engagement with testing included a lack of awareness, knowledge and understanding, and concerns about the accuracy and safety. Students understood the limitations of LFTs but requested further information about test accuracy. Tests were used to inform behavioural decisions, often in combination with other information, such as the potential for exposure to the virus and perceptions of vulnerability. CONCLUSIONS: The low uptake of testing brings into question the role of mass LFT in university settings. Innovative strategies may be needed to increase LFT uptake among students.

Learning about COVID-19 across borders: public health information and adherence among international travellers to the UK.

OBJECTIVE: Public health control measures at borders have long been central to national strategies for the prevention and containment of infectious diseases. Travel was inevitably associated with the rapid global transmission of COVID-19. In the UK, public health authorities tried to reduce the risks of travel-associated spread by providing public health information at ports of entry. This study investigates risk assessment processes, decision-making and adherence to official advice among international travellers, to provide evidence for future policy on the provision of public health information to facilitate safer international travel. STUDY DESIGN: This study is a qualitative study evaluation. METHOD: International air passengers arriving at the London Heathrow Airport on scheduled flights from China and Singapore were approached for interview after consenting to contact in completed surveys. Semi-structured interviews were conducted by telephone, using two topic guides to explore views of official public health information and self-isolation. Interview transcripts were coded and analysed thematically. RESULTS: Participants regarded official advice from Public Health England as adequate at the time, despite observing differences with intervention measures implemented in their countries of departure. Most participants also described adopting precautionary measures, including self-isolation and the use of face coverings that went beyond official advice, but reported adherence to guidance on contacting health authorities was more variable. Adherence to the official guidance was informed by the perceived salience of specific transmission possibilities and containment measures assessed in relation to participants' local social and institutional environments. CONCLUSION: Analysis of study findings demonstrates that international air travellers' responses to public health advice constitute a proactive process of risk assessment and rationalised decision-making to guide preventive action. This process incorporates consideration of the current living situation, trust in information sources, correspondence with cultural logics and willingness to accept potential risk to self and significant others. Our findings concerning international passengers' understanding of, and compliance with, official advice and mitigation measures provide valuable evidence to inform future policy and generate recommendations on the presentation of public health information to facilitate safer international travel. Access to a central source of regularly updated official information would help minimise confusion between different national guidelines. Greater attention to the differentiated information needs of diverse groups in creating future public-facing guidance would help to minimise the uncertainties generated by the receipt of generic information.

Adverse childhood experiences and substance misuse in young people in India: results from the multisite cVEDA cohort.

BACKGROUND: Adverse childhood experiences (ACEs) increases vulnerability to externalising disorders such as substance misuse. The study aims to determine the prevalence of ACEs and its association with substance misuse. METHODS: Data from the Consortium on Vulnerability to Externalising Disorders and Addictions (cVEDA) in India was used (n = 9010). ACEs were evaluated using the World Health Organisation (WHO) Adverse Childhood Experiences International Questionnaire whilst substance misuse was assessed using the WHO Alcohol, Smoking and Substance Involvement Screening Test. A random-effects, two-stage individual patient data meta-analysis explained the associations between ACEs and substance misuse with adjustments for confounders such as sex and family structure. RESULTS: 1 in 2 participants reported child maltreatment ACEs and family level ACEs. Except for sexual abuse, males report more of every individual childhood adversity and are more likely to report misusing substances compared with females (87.3% vs. 12.7%). In adolescents, family level ACEs (adj OR 4.2, 95% CI 1.5-11.7) and collective level ACEs (adj OR 6.6, 95% CI 1.4-31.1) show associations with substance misuse whilst in young adults, child level ACEs such as maltreatment show similar strong associations (adj OR 2.0, 95% CI 1.1-3.5). CONCLUSION: ACEs such as abuse and domestic violence are strongly associated with substance misuse, most commonly tobacco, in adolescent and young adult males in India. The results suggest enhancing current ACE resilience programmes and 'trauma-informed' approaches to tackling longer-term impact of ACEs in India. FUNDING: Newton Bhabha Grant jointly funded by the Medical Research Council, UK (MR/N000390/1) and the Indian Council of Medical Research (ICMR/MRC-UK/3/M/2015-NCD-I).

Increasing drug-related mortality rates over the last decade in Scotland are not just due to an ageing cohort: A retrospective longitudinal cohort study.

BACKGROUND: In Europe, North America, and Australia, mortality due to drug-related (DR) causes amongst people who inject drugs (PWID) is a major issue. Our objective was to characterise temporal trends in DR mortality rates in a large cohort of PWID in Scotland over the past decade, all of whom had been diagnosed with hepatitis C virus (HCV) infection, and to investigate factors associated with DR mortality. METHODS: Retrospective longitudinal cohort study linking Scotland's national HCV Diagnosis Database and deaths registry. The study cohort consisted of all individuals with likely injection drug use-related route of HCV acquisition, who had been diagnosed with HCV between 1991 and 2018, and were alive and aged under 65 years on 1 January 2009. We used Lexis expansion to adjust for ageing cohort effects and calculated the mortality rate from an underlying/contributing DR cause over the period 2009-2018. We fitted Poisson regression models to estimate the temporal trend adjusting for attained age, sex, referral setting, region, and viraemic status at baseline. RESULTS: Amongst the study population (n = 35,065; 236,914 person-years), a total of 1900 DR deaths occurred; the DR mortality rate increased from 5.6/1000 [101 deaths] in 2009 to 12.4/1000 [342] person-years in 2018. Increasing trends were observed for all age-groups except 55-64 years. The overall DR mortality rate was highest for referrals for HCV testing from prison (11.0/1000) and hospital settings (10.0/1000). Mortality increased with calendar time period, with significantly raised adjusted rate ratios (RRs) from 2015 (RR=1.40, 95% CI:1.16-1.69) to 2018 (RR=2.23, 95% CI:1.88-2.64), compared with 2011-2012, for older age (35-44: RR=1.37, 95% CI:1.20-1.56; 45-54: RR=1.32, CI:1.14-1.53) compared with <35 years, for persons diagnosed with HCV since 2009 (RR=1.34, 95% CI:1.21-1.49), and for prison and hospital referrals (RRs of 1.30, 1.37) compared with GP referrals. CONCLUSION: Increasing DR mortality rates in Scotland over the past decade are not just due to an ageing cohort. Harm reduction services will likely need to expand and adapt to reverse the recent upward trends in DR mortality in PWID.

Public health information on COVID-19 for international travellers: lessons learned from a mixed-method evaluation.

OBJECTIVES: In the containment phase of the response to the COVID-19 outbreak, Public Health England (PHE) delivered advice to travellers arriving at major UK ports. We aimed to rapidly evaluate the impact and effectiveness of these communication materials for passengers in the early stages of the pandemic. STUDY DESIGN: The study design used is the mixed-methods evaluation. METHODS: A questionnaire survey and follow-up interviews with passengers arriving at London Heathrow Airport on scheduled flights from China and Singapore. The survey assessed passengers' knowledge of symptoms, actions to take, and attitudes towards PHE COVID-19 public health information; interviews explored their views of official public health information and self-isolation. RESULTS: One hundred and twenty-one passengers participated in the survey and 15 in follow-up interviews. Eighty three percentage of surveyed passengers correctly identified all three COVID-19 associated symptoms listed in PHE information at that time. Most could identify the recommended actions and found the advice understandable and trustworthy. Interviews revealed that passengers shared concerns about the lack of wider official action, and that passengers' knowledge had been acquired elsewhere as much from PHE. Respondents also noted their own agency in choosing to self-isolate, partially as a self-protective measure. CONCLUSION: PHE COVID-19 public health information was perceived as clear and acceptable, but we found that passengers acquired knowledge from various sources and they saw the provision of information alone on arrival as an insufficient official response. Our study provides fresh insights into the importance of taking greater account of diverse information sources and of the need for public assurance in creating public health information materials to address global health threats.

Monitoring liver transplant rates in persons diagnosed with hepatitis C: a data linkage study, England 2008 to 2017.

IntroductionLiver transplantation is an important measure of burden from hepatitis C virus (HCV)-associated liver disease.AimsTo describe transplant rates and survival in individuals with HCV infection from 2008 to 2017 in England through data linkage.MethodsThis is a retrospective observational cohort study. Laboratory reports of HCV infection were linked to the Liver Transplant Registry for individuals aged 15 years and over, first diagnosed between 1998 and 2017. We estimated age-sex standardised incidence rates and used Poisson regression to investigate predictors of liver transplantation and test for a change in incidence after introduction of direct-acting antivirals (DAAs) in 2014. Kaplan-Meier survival analysis was used to calculate post-transplant survival rates.ResultsOf 124,238 individuals diagnosed with HCV infection, 1,480 were registered and 1,217 received a liver transplant. Of individuals registered, 1,395 had post-HCV cirrhosis and 636 had hepatocellular carcinoma (618 also had post-HCV cirrhosis). Median time from HCV diagnosis to transplant was 3.4 years (interquartile range: 1.3-6.8 years). Liver transplant rates were lower 2014-17 compared with 2011-13 (incidence rate ratio: 0.64; 95% confidence interval: 0.55-0.76). Survival rates were 93.4%, 79.9% and 67.9% at 1, 5 and 10 years, respectively. Data linkage showed minimal under-reporting of HCV in the transplant registry.ConclusionIn the post-DAA era, liver transplant rates have fallen in individuals with HCV infection, showing early impact of HCV treatment scale-up; but the short time from HCV diagnosis to liver transplant suggests late diagnosis is a problem.

Chronic hepatitis B virus case-finding in UK populations born abroad in intermediate or high endemicity countries: an economic evaluation.

OBJECTIVES: The majority (>90%) of new or undiagnosed cases of hepatitis B virus (HBV) in the UK are among individuals born in countries with intermediate or high prevalence levels (≥2%). We evaluate the cost-effectiveness of increased HBV case-finding among UK migrant populations, based on a one-time opt out case-finding approach in a primary care setting. DESIGN: Cost-effectiveness evaluation. A decision model based on a Markov approach was built to assess the progression of HBV infection with and without treatment as a result of case-finding. The model parameters, including the cost and effects of case-finding and treatment, were estimated from the literature. All costs were expressed in 2017/2018 British Pounds (GBPs) and health outcomes as quality-adjusted life-years (QALYs). INTERVENTION: Hepatitis B virus case-finding among UK migrant populations born in countries with intermediate or high prevalence levels (≥2%) in a primary care setting compared with no intervention (background testing). RESULTS: At a 2% hepatitis B surface antigen (HBsAg) prevalence, the case-finding intervention led to a mean incremental cost-effectiveness ratio of £13 625 per QALY gained which was 87% and 98% likely of being cost-effective at willingness to pay (WTP) thresholds of £20 000 and £30 000 per additional QALY, respectively. Sensitivity analyses indicated that the intervention would remain cost-effective under a £20 000 WTP threshold as long as HBsAg prevalence among the migrant population is at least 1%. However, the results were sensitive to a number of parameters, especially the time horizon and probability of treatment uptake. CONCLUSIONS: HBV case-finding using a one-time opt out approach in primary care settings is very likely to be cost-effective among UK migrant populations with HBsAg prevalence ≥1% if the WTP for an additional QALY is around £20 000.

Mapping the hepatitis C cascade of care in people attending drug treatment services in England: A data linkage study.

INTRODUCTION: Hepatitis C (HCV) infection in England primarily affects people who inject drugs (PWID). We describe persons HCV tested, estimate incidence and establish the cascade of care (CoC) for people engaging with drug services. METHODS: Persons testing for HCV in drug services in Sentinel Surveillance of Blood Borne Virus Testing (SSBBV) between 2008 and 2016 were linked with people attending drug services in the National Drug and Treatment Monitoring System (NDTMS). We describe risk characteristics, establish the CoC, and estimate HCV incidence in PWID diagnosed in drug services. RESULTS: Of 46,721 persons tested for anti-HCV in SSBBV in drug services, 29,773 (63.7%) linked to NDTMS. Of these, 9100 (30.6%) were antiV positive and anti-HCV positivity was 45.0% in persons reporting urgent housing problems and 43.8% in persons reporting ever injecting. Among persons anti-HCV positive, half had ≥1 positive anti-HCV test. For persons' first anti-HCV positive between 2008 and 2013 (n = 3123), 74.9% were HCV RNA tested, of whom 71.2% were RNA positive, and of these, 14.0% had evidence of interferon-based treatment, with 52.8% achieving cure. Among PWID, HCV incidence was 8.7 per 100 person-years (95% CI: 8.1-9.2). CONCLUSION: Through record linkage of surveillance datasets, we estimated the HCV CoC for people attending drug services, providing a benchmark from which to monitor the impact of strategies to scale-up prevention, testing, and curative treatment with direct acting antivirals. Our study highlights wasteful repeated testing and poor linkage to care for this high risk population which need to be addressed.

Safety and Efficacy of Tigecycline to Treat Multidrug-resistant Infections in Pediatrics: An Evidence Synthesis.

BACKGROUND: The need for antimicrobial therapies effective against multidrug resistant organisms for children remains unmet. Tigecycline shows antibacterial activity across a broad spectrum of bacteria and is approved for treating complicated skin and skin-structure infections, complicated intra-abdominal infections and, in the United States, community-acquired bacterial pneumonia for adult patients. No blinded, randomized phase 3 tigecycline clinical trials on neonates or children have been completed or planned. This review aimed to provide a comprehensive synthesis of all the existing data sources, both on-label and off-label, for tigecycline use in children. METHODS: Data on tigecycline use in children were identified from published and unpublished sources including clinical trials, expanded access and compassionate use programs, databases of healthcare records and patient safety monitoring. RESULTS: Pharmacokinetic simulations predicted that tigecycline 1.2 mg/kg (maximum dose 50 mg) every 12 hours (q12h) in children 8-11 years and 50 mg q12h in children 12 to <18 years would achieve exposure similar to adults receiving 50 mg q12h. Available phase 2 pediatric clinical trial data and data from other sources demonstrated similar clinical efficacy between adult and pediatric patients treated with tigecycline. These data showed no new or unexpected safety concerns with tigecycline in children. CONCLUSIONS: Information presented here may help guide the appropriate use of tigecycline in children with multidrug resistant infections. Continued pharmacovigilance from real-world observational studies may also further refine appropriate use of tigecycline.

A multicenter, double-blind, randomized, comparison study of the efficacy and safety of tigecycline to imipenem/cilastatin to treat complicated intra-abdominal infections in hospitalized subjects in China.

PURPOSE: To assess the efficacy and safety of tigecycline in treating complicated intra-abdominal infections (cIAIs) in hospitalized patients in China. PATIENTS AND METHODS: A Phase IV, multicenter, randomized, double-blinded, active-controlled, non-inferiority study was conducted. Hospitalized cIAI patients ≥18 years of age were randomized (1:1) to receive intravenous tigecycline (initial dose 100 mg, then 50 mg q12h) or imipenem/cilastatin (500 mg/500 mg or adjusted for renal dysfunction, q6h) for 5-14 days. The primary end point was clinical response for clinically evaluable (CE) subjects at test-of-cure (TOC) assessment. RESULTS: Four hundred and seventy subjects were randomized; 232 in the tigecycline and 231 in the imipenem/cilastatin group were treated. Tigecycline was non-inferior to imipenem/cilastatin with respect to clinical response at TOC for all CE subjects, ie, the lower bound of the two-sided 95% CI (-12.0%, -1.4%) for the treatment difference in cure rate, tigecycline (89.9%) minus imipenem/cilastatin (96.6%), was >-15%. As non-inferiority was concluded in the CE population, superiority of tigecycline over imipenem/cilastatin and superiority of imipenem/cilastatin over tigecycline were tested on the CE and the modified intent-to-treat (mITT) populations according to pre-specified statistical criteria, and neither could be demonstrated (the cure rate was 82.8% vs 88.7%, difference -6.0% [-12.8%, 0.8%], for the mITT population). The subject-level microbiological response rate at TOC for the microbiologically evaluable population was 88.0% (110/125) vs 95.3% (102/107, difference -7.3% [-15.2%, 0.5%]). Nausea, drug ineffectiveness, postoperative wound infection, vomiting, and pyrexia were the most common adverse events in tigecycline-treated subjects; pyrexia, nausea, vomiting, and increased alanine aminotransferase and aspartate aminotransferase levels were most common in imipenem/cilastatin-treated subjects; none were unanticipated. CONCLUSION: Tigecycline was non-inferior to imipenem/cilastatin in treating hospitalized adult patients with cIAI. Superiority of tigecycline over imipenem/cilastatin or imipenem/cilastatin over tigecycline could not be demonstrated. Safety was consistent with the known profile for tigecycline. CLINICALTRIALSGOV IDENTIFIER: NCT01721408.

Understanding hepatitis C intervention success-Qualitative findings from the HepCATT study.

The United Kingdom has committed to eliminating viral hepatitis as a public health threat. Innovative interventions for marginalized populations are required to realize this goal. In 2016, the HepCATT study team implemented a complex hepatitis C (HCV) intervention in three English drug treatment services, with five controls. We report qualitative study findings from two intervention sites to explore intervention success and transferability potential. The intervention comprised multiple components, including a nurse facilitator, peer support and education initiatives. Qualitative data were generated at baseline (2014) and post-intervention (2016) at two sites through in-depth interviews, focus groups and observations. The 96 participants comprised drug service and intervention providers and clients with an injecting history. Data were triangulated and thematically analysed. Client engagement with a HCV treatment service rose from 16 at baseline to 147 in 2016. There was no comparable increase at the five control sites. Baseline testing and treatment barriers included the following: limited HCV knowledge; fear of diagnosis and treatment; precarious living circumstances and service-specific obstacles. Treatment engagement was aided by intervention timeliness; improved communication structures; personalized care; streamlined testing and treatment pathways; peer support. Multiple interrelated components influenced the increased levels of treatment engagement documented in HepCATT. The nurse facilitator, involved in implementation and innovation, was key to intervention success. Baseline barriers correspond with international literature-indicating transferability potential. Control data indicate that biomedical innovation alone is not sufficient to increase engagement among the most marginalized. Sustainable resourcing of community services is crucial to effect change.

DNA methylation from birth to late adolescence and development of multiple-risk behaviours.

BACKGROUND: Risk behaviours in adolescence are linked to poor educational attainment and health and other outcomes in young adulthood. We explored whether there are molecular mechanisms associated with the development, or the result, of multiple risk behaviours (MRBs). METHODS: MRBs (antisocial behaviour and delinquency, traffic-related risk behaviour, risky sexual behaviour, lack of exercise) and their sumscore were characterized based on self-reported questions at age 7 and 17 within the ARIES subsample of the ALSPAC birth cohort, and were linked to DNA methylation at over 485,000 CpG sites at ages 0,7 and 17. Associations were determined for participants with complete data (n = 227-575). RESULTS: There was weak evidence of associations between cumulative MRBs and methylation at cg01783492 and cg16720578 at age 17. DNA methylation at age 17 was associated with risky sexual behaviour (cg22883332), lack of exercise (cg03152353, cg20056908, cg20571116) and substance use (cg02188400, cg13906377). No associations between DNA methylation and individual risk behaviours at age 7 were observed. DNA methylation at age 7 might predispose for traffic-related risk behaviour (cg24683561) and substance use (cg08761410) at age 17. LIMITATIONS: Main limitations are absence of information on directly measured blood cell type proportions and tissue specificity, and a modest sample size. CONCLUSIONS: Cumulative MRB in late adolescence was associated with effects on DNA methylation. More specifically, risky sexual behaviour and sedentary behaviour are associated with changes in DNA methylation, while DNA methylation in childhood may predict later traffic-related risky behaviour. For substance use effects in both temporal directions were observed.

'DrinkThink' alcohol screening and brief intervention for young people: a qualitative evaluation of training and implementation.

Background: Alcohol Screening and Brief Intervention (ASBI) helps reduce risky drinking in adults, but less is known about its effectiveness with young people. This article explores implementation of DrinkThink, an ASBI co-produced with young people, by health, youth and social care professionals trained in its delivery. Methods: A qualitative evaluation was conducted using focus groups with 33 staff trained to deliver DrinkThink, and eight interviews with trained participants and service managers. These were recorded, transcribed and a thematic analysis undertaken. Results: DrinkThink was not delivered fully by health, youth or social care agencies. The reasons for this varied by setting but included: the training staff received, a working culture that was ill-suited to the intervention, staff attitudes towards alcohol which prioritized other health problems presented by young people, over alcohol use. Conclusions: Implementation was limited because staff had not been involved in the design and planning of DrinkThink. Staffs' perceptions of alcohol problems in young people and the diverse cultures in which they work were subsequently not accounted for in the design. Co-producing youth focused ASBIs with the professionals expected to deliver them, and the young people whom they target, may ensure greater success in integrating them into working practice.

Establishing the cascade of care for hepatitis C in England-benchmarking to monitor impact of direct acting antivirals.

Little is known about engagement and retention in care of people diagnosed with chronic hepatitis C (HCV) in England. Establishing a cascade of care informs targeted interventions for improving case finding, referral, treatment uptake and retention in care. Using data from the sentinel surveillance of blood-borne virus (SSBBV) testing between 2005 and 2014, we investigate the continuum of care of those tested for HCV in England. Persons ≥1 year old with an anti-HCV test and subsequent RNA tests between 2005 and 2014 reported to SSBBV were collated. We describe the cascade of care, as the patient pathway from a diagnostic test, referral into care, treatment and patient outcomes. Between 2005 and 2014, 2 390 507 samples were tested for anti-HCV, corresponding to 1 766 515 persons. A total of 53 038 persons (35 190 men and 17 165 women) with anti-HCV positive were newly reported to SSBBV. An RNA test was conducted on 77.0% persons who were anti-HCV positive, 72.3% of whom were viraemic (RNA positive) during this time period, 21.4% had evidence of treatment and 3130 49.5% had evidence of a sustained virological response (SVR). In multivariable models, confirmation of viraemia by RNA test varied by age and region/test setting; evidence of treatment varied by age, year of test and region/test setting; and SVR varied by age, year of test and region/setting of test. In conclusion, our findings provide HCV cascade of care estimates prior to the introduction of direct acting antivirals. These findings provide important baseline cascade estimates to benchmark progress towards elimination of HCV as a major public health threat.

Facultative Parasitism by the Bivalve Kurtiella pedroana in the Mole Crab Emerita analoga.

Evolutionary transitions to parasitism are rare. In this study, we documented a potential step toward parasitism in the commensal clam Kurtiella pedroana (Bivalvia: Galeommatoidea). Galeommatoideans are known commensals of various invertebrates, including crustaceans. Emerita analoga (Decapoda: Hippidae) is an abundant intertidal mole crab inhabiting Pacific coast beaches in North and South America. Mole crabs collected from Monterey Bay, California, were measured and examined externally and internally for associated molluscs. Out of the 520 mole crabs, 37 large female individuals harbored 49 clams (prevalence of 7.11% and mean intensity of 1.3). Forty-one ectocommensal clams were attached by their byssal threads to the inside of the gill chambers or to the lateroventral surfaces. However, our key finding was 8 clams that lacked byssal threads and were living in the hemocoel of 6 crabs. These internal clams were smaller than the ectocommensals. Because these internal clams lacked access to their normal food, we hypothesize they might have fed on hemolymph as would a parasite. Clam larvae have no obvious exit from the hemocoel, implying that endoparasitism is a dead-end for K. pedroana. Regardless, facultative parasitism in a free-living or an ectocommensal is uncommon and suggests a pathway to parasitism.