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Abstract Background There are no approved pharmacotherapies for methamphetamine use disorder. Two preliminary phase 2 randomised controlled trials have found mirtazapine, a tetracyclic antidepressant, to be effective in reducing methamphetamine use. The proposed Tina Trial is the first phase 3 placebo-controlled randomised trial to examine the effectiveness and safety of mirtazapine as an outpatient pharmacotherapy for methamphetamine use disorder. Methods This is a multi-site phase 3 randomised, double-blind, placebo-controlled parallel trial. Participants are randomly allocated (1:1) to receive either mirtazapine (30 mg/day for 12 weeks) or matched placebo, delivered as a take-home medication. The target population is 340 people aged 18–65 years who have moderate to severe methamphetamine use disorder. The trial is being conducted through outpatient alcohol and other drug treatment clinics in Australia. The primary outcome is measured as self-reported days of methamphetamine use in the past 4 weeks at week 12. Secondary outcomes are methamphetamine-negative oral fluid samples, depressive symptoms, sleep quality, HIV risk behaviour and quality of life. Other outcomes include safety (adverse events), tolerability, and health service use. Medication adherence is being monitored using MEMS® Smart Caps fitted to medication bottles. Discussion This trial will provide information on the safety and effectiveness of mirtazapine as a pharmacotherapy for methamphetamine use disorder when delivered as an outpatient medication in routine clinical practice. If found to be safe and effective, this trial will support an application for methamphetamine use disorder to be included as a therapeutic indication for the prescription of mirtazapine. Trial registration Australian and New Zealand Clinical Trials Registry ACTRN12622000235707. Registered on February 9, 2022.

Background & Aims: Direct-acting antiviral (DAA) regimens provide a cure in >95% of patients with chronic HCV infection. However, in some patients in whom therapy fails, resistance-associated substitutions (RASs) can develop, limiting retreatment options and risking onward resistant virus transmission. In this study, we evaluated RAS prevalence and distribution, including novel NS5A RASs and clinical factors associated with RAS selection, among patients who experienced DAA treatment failure. Methods: SHARED is an international consortium of clinicians and scientists studying HCV drug resistance. HCV sequence linked metadata from 3,355 patients were collected from 22 countries. NS3, NS5A, and NS5B RASs in virologic failures, including novel NS5A substitutions, were examined. Associations of clinical and demographic characteristics with RAS selection were investigated. Results: The frequency of RASs increased from its natural prevalence following DAA exposure: 37% to 60% in NS3, 29% to 80% in NS5A, 15% to 22% in NS5B for sofosbuvir, and 24% to 37% in NS5B for dasabuvir. Among 730 virologic failures, most were treated with first-generation DAAs, 94% had drug resistance in ≥1 DAA class: 31% single-class resistance, 42% dual-class resistance (predominantly against protease and NS5A inhibitors), and 21% triple-class resistance. Distinct patterns containing ≥2 highly resistant RASs were common. New potential NS5A RASs and adaptive changes were identified in genotypes 1a, 3, and 4. Following DAA failure, RAS selection was more frequent in older people with cirrhosis and those infected with genotypes 1b and 4. Conclusions: Drug resistance in HCV is frequent after DAA treatment failure. Previously unrecognized substitutions continue to emerge and remain uncharacterized. Lay summary: Although direct-acting antiviral medications effectively cure hepatitis C in most patients, sometimes treatment selects for resistant viruses, causing antiviral drugs to be either ineffective or only partially effective. Multidrug resistance is common in patients for whom DAA treatment fails. Older patients and patients with advanced liver diseases are more likely to select drug-resistant viruses. Collective efforts from international communities and governments are needed to develop an optimal approach to managing drug resistance and preventing the transmission of resistant viruses.

Introduction In Australia, the notification rate for hepatitis C is 5 times greater among Aboriginal and Torres Strait Islander peoples than non‑Indigenous populations (164 vs. 35 per 100,000). Infection with Hepatitis C virus is associated with increased morbidity, mortality and health-related costs. Recently, the use of simple, tolerable and short-duration HCV therapies with extremely high efficacy (cure rates >90%) became available through the Pharmaceutical Benefits Scheme (PBS) on 1 March 2016. Objectives and Approach Overall, this project aims to identify inequities in hepatitis C healthcare for Aboriginal and Torres Strait Islander peoples across SA and NT. By using 19 routinely collected health administration datasets, we will evaluate hepatitis C diagnoses, treatment uptake, and treatment outcomes, with focus on identifying patterns in healthcare access among Aboriginal and Torres Strait Islander people. The study links state-based and federal datasets, including Medicare, Pharmaceutical Benefits Scheme, and National Mortality Database, to hepatitis C notifications reported in SA since 1992 or in NT since 1999 using probabilistic data linkage methodology in a secured online environment. Results The study population includes all hepatitis C notifications recorded in SA and NT, totalling more than 25,000 cases. Preliminary findings will be reported including incidence of hospitalisation, mortality, and morbidity by Aboriginal and Torres Strait Islander status. Conclusion / Implications This project is of national importance to address hepatitis C related morbidity and mortality in Australia, particularly among Aboriginal and Torres Strait Islander peoples. Now that highly effective direct acting anti-viral treatments are available, it is crucial to ensure key affected populations, including Aboriginal and Torres Strait Islander people, have access to these novel biomedical approaches. Findings will underpin future policy to reduce the burden of hepatitis C across SA and NT populations.

Introduction Opioid agonist treatment is effective for opioid dependence and newer extended-release buprenorphine (BUP-XR) injections represent a significant development. The Community Long-Acting Buprenorphine (CoLAB) study aims to evaluate client outcomes among people with opioid dependence receiving 48 weeks of BUP-XR treatment, and examines the implementation of BUP-XR in diverse community healthcare settings in Australia.Methods and analysis The CoLAB study is a prospective single-arm, multicentre, open-label trial of monthly BUP-XR injections in people with opioid dependence. Participants are being recruited from a network of general practitioner and specialist drug treatment services located in the states of New South Wales, Victoria and South Australia in Australia. Following a minimum 7 days on 8–32 mg of sublingual buprenorphine (±naloxone), participants will receive monthly subcutaneous BUP-XR injections administered by a healthcare practitioner at intervals of 28 days (−2/+14 days). The primary endpoint is participant retention in treatment at 48 weeks after treatment initiation. Secondary endpoints will evaluate dosing schedule variations, craving, withdrawal, substance use, health and well-being, and client-reported treatment experience. Qualitative and costing substudies will examine implementation barriers and facilitators at the client and provider level.Ethics and dissemination The study has received ethics approval from the St Vincent’s Hospital Sydney Human Research Ethics Committee (Ref. HREC/18/SVH/221). The findings will be disseminated via publication in peer-reviewed journals, presentations at national and international scientific conferences, and in relevant community organisation publications and forums.Trial registration number NCT03809143Protocol identifier CoLAB1801, V.4.0 dated 01 August 2019

Summary: Oncogene-induced senescence (OIS) is a potent barrier for the transformation of pre-cancerous cells. The molecular pathways involved in the execution of OIS are still incompletely understood, but they include chronic DNA damage signaling and post-translational modifications of key factors. Here, we show that OIS-associated transcriptional downregulation of deubiquitinating enzyme USP1 triggers and maintains a DNA damage checkpoint response with atypical DNA lesions that is dependent on functional FANCD2-FI-ATR-CHK1-p53-CDKN1A signaling. We find that a reduced USP1 level causes aberrant aggregation of its target FANCD2 concomitant with replication stress, accumulation, and colocalization of γ-H2Ax and p53-binding protein 1 (53BP1) in large and unusual sparse DNA damage foci and an increased number of polyploid cells and cells arrested in G2/M, as well as a sensitization of senescence-bypassing cells to DNA interstrand crosslinking-mediated cell death. Our study identifies USP1 as a key senescence regulator controlling genomic integrity and a promising target for anti-cancer therapy. : Ogrunc et al. identify the deubiquitinating enzyme USP1 as an active contributor to oncogene-induced senescence. They show that USP1 controls replisome dynamics and genome stability and that USP1 dysfunction induces aberrant aggregation of mono-ubiquitinated FANCD2 concomitant with a chronic DNA damage response and senescence induction.

Hepatitis C virus (HCV) infection in prisoners represents an important public health problem. However, there is very little information about HCV-related health-related quality of life (HRQOL). We examined the effect of HCV antibody positivity, HCV viremia, and being a prisoner on prisoners'''' HRQOL. Population-based health surveys incorporating HCV screening were conducted among prisoners at New South Wales (NSW), Australia, correctional centers in 1996 and 2001. HCV antibody and HCV RNA status were determined from venous blood sampling. HRQOL and mood status were assessed using the Short Form-36 (SF-36) Health Survey and Beck Depression Inventory (BDI). Comparison of HRQOL scores between HCV antibody negative, HCV antibody positive/non-viremic, and HCV antibody positive/viremic and assessment of temporal change in HRQOL between 1996 and 2001 within groups were made using ANCOVA adjusting for confounders. Factors associated with HRQOL were determined in linear regression models. Analyses between HCV antibody negative (n = 423), HCV positive/non-viremic (n = 89), and HCV positive/viremic (n = 178) prisoners found no measurable effect of HCV on HRQOL, including that attributable to HCV viremia. Compared to uninfected Australian population norms, prisoners had lower HRQOL irrespective of HCV status. The prevalence of ‘moderate’ to ‘severe’ depressive symptoms was greater in the HCV antibody positive/viremic group than the HCV antibody positive/non-viremic group or the HCV antibody negative group. Selected demographic factors (age), co-morbidity, severity of depressive symptoms and medical care utilization influenced HRQOL. There was evidence to support the effect of knowledge of HCV status on HRQOL. In conclusion, our findings contrast with previous studies in non-prisoner groups in which HCV infection appears to decrease overall HRQOL. Non-HCV factors may override HCV-specific HRQOL impairment in this population. Targeted management strategies are required to improve HRQOL of prisoners. [ABSTRACT FROM AUTHOR]