Proactive case finding of alcohol-related liver disease in high-risk populations: A systematic review.

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.

The cost-effectiveness of case-finding strategies for achieving hepatitis C elimination among men who have sex with men in the UK.

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.

Insights into circular RNAs: their biogenesis, detection, and emerging role in cardiovascular disease.

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.

Novel and Annotated Long Noncoding RNAs Associated with Ischemia in the Human Heart.

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.

The cost-effectiveness of an HCV outreach intervention for at-risk populations in London, UK.

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.

Integrating hepatitis C care for at-risk groups (HepLink): baseline data from a multicentre feasibility study in primary and community care.

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.

High response and re-infection rates among people who inject drugs treated for hepatitis C in a community needle and syringe programme.

To achieve WHO hepatitis C virus (HCV) elimination targets by 2030, mathematical models suggest there needs to be significant scale-up of treatment among people who inject drugs (PWID). We tested whether people who actively inject drugs can be recruited and treated successfully through a community needle and syringe programme (NSP), and assessed rates of re-infection. 105 HCV RNA positive participants were enrolled prospectively. Participants were recruited from the largest NSP in Dundee over 42 months. 94/105 individuals commenced treatment. Genotype 1 (G1) individuals (n = 37) were treated with peg-interferon+ribavirin+Simepravir/Telaprevir. Genotype 2/3 (G2/3) (n = 57) received peg-interferon+ribavirin. Weekly study visits took place within the NSP. Mean age of participants was 34.0 years (SD 6.9), 71.3% (61/94) were male. One in five (20/94) participants were homeless. 68.1% (64/94) were on OST (opiate substitution therapy) at enrolment; participants injected median 6.5 times/wk. In terms of clinical outcomes, >80% treatment adherence was 71.3% (67/94). There was no difference in SVR-12 rates by genotype: 81.0% (30/37) for G1 and 82.5% (47/55) for G2/3. At 18 months post-treatment, 15/77 participants were reinfected, followed up over 69.8 person-years, yielding a re-infection rate of 21.5/100 person-years (95% CI 13.00-35.65). This trial demonstrates that HCV treatment can be delivered successfully to the target population of treatment as prevention strategies. We report higher rates of re-infection than existing estimates among PWID. Scale-up of HCV treatment should be pursued alongside a comprehensive programme of harm reduction interventions to help minimize re-infection and reduce HCV transmission.

Proportionate mortality following dysvascular partial foot amputation and how this compares to transtibial amputation: a systematic review.

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.

Effect of melatonin supplementation upon parental care and nestling growth in arctic-breeding songbirds.

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.

Pilot postal birth cohort HCV Screening in UK primary care.

BACKGROUND: Birth cohort screening has been implemented in some countries to identify the potentially 'missed population' of undiagnosed chronic Hepatitis C Virus (HCV) in people who may not be found through targeted approaches. AIM: To determine uptake of HCV antibody testing using an oral swab screening method, overall yield, whether those testing positive had risk markers in their primary care record, and cost per case detected. DESIGN AND SETTING: Pilot screening study set in general practices in the Southwest, South London and Yorkshire and Humber. METHOD: Participants consenting were sent an oral swab kit in the post and saliva samples were tested for antibody to HCV. RESULTS: 16,436/98,396 (16.7%) patients consented and were sent an oral swab kit. 12,216 (12.4%) returned a kit, with 31 participants (yield 0.03%) testing positive for HCV antibody. 45% of those positive 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. Cost per case detected was £16,000 per HCV antibody and £247,997 per chronic HCV. CONCLUSIONS: Wide-scale screening could be delivered and identified people infected with HCV, however most of these individuals could have been detected through lower-cost targeted screening. Yield and cost per case found were substantially worse than model estimates and targeted screening studies. Birth cohort screening should not be rolled out in primary care in England.