A cautionary note on the use of N-acetylcysteine as a reactive oxygen species antagonist to assess copper mediated cell death.

A new form of cell death has recently been proposed involving copper-induced cell death, termed cuproptosis. This new form of cell death has been widely studied in relation to a novel class of copper ionophores, including elesclomol and disulfiram. However, the exact mechanism leading to cell death remains contentious. The oldest and most widely accepted biological mechanism is that the accumulated intracellular copper leads to excessive build-up of reactive oxygen species and that this is what ultimately leads to cell death. Most of this evidence is largely based on studies using N-acetylcysteine (NAC), an antioxidant, to relieve the oxidative stress and prevent cell death. However, here we have demonstrated using inductively coupled mass-spectrometry, that NAC pretreatment significantly reduces intracellular copper uptake triggered by the ionophores, elesclomol and disulfiram, suggesting that reduction in copper uptake, rather than the antioxidant activity of NAC, is responsible for the diminished cell death. We present further data showing that key mediators of reactive oxygen species are not upregulated in response to elesclomol treatment, and further that sensitivity of cancer cell lines to reactive oxygen species does not correlate with sensitivity to these copper ionophores. Our findings are in line with several recent studies proposing the mechanism of cuproptosis is instead via copper mediated aggregation of proteins, resulting in proteotoxic stress leading to cell death. Overall, it is vital to disseminate this key piece of information regarding NAC's activity on copper uptake since new research attributing the effect of NAC on copper ionophore activity to quenching of reactive oxygen species is being published regularly and our studies suggest their conclusions may be misleading.

Crosstalk with lung fibroblasts shapes the growth and therapeutic response of mesothelioma cells.

Mesothelioma is an aggressive cancer of the mesothelial layer associated with an extensive fibrotic response. The latter is in large part mediated by cancer-associated fibroblasts which mediate tumour progression and poor prognosis. However, understanding of the crosstalk between cancer cells and fibroblasts in this disease is mostly lacking. Here, using co-cultures of patient-derived mesothelioma cell lines and lung fibroblasts, we demonstrate that fibroblast activation is a self-propagated process producing a fibrotic extracellular matrix (ECM) and triggering drug resistance in mesothelioma cells. Following characterisation of mesothelioma cells/fibroblasts signalling crosstalk, we identify several FDA-approved targeted therapies as far more potent than standard-of-care Cisplatin/Pemetrexed in ECM-embedded co-culture spheroid models. In particular, the SRC family kinase inhibitor, Saracatinib, extends overall survival well beyond standard-of-care in a mesothelioma genetically-engineered mouse model. In short, we lay the foundation for the rational design of novel therapeutic strategies targeting mesothelioma/fibroblast communication for the treatment of mesothelioma patients.

Distinct neuroinflammatory signatures exist across genetic and sporadic amyotrophic lateral sclerosis cohorts.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of upper and lower motor neurons. ALS is on a pathogenetic disease spectrum with frontotemporal dementia, referred to as ALS-frontotemporal spectrum disorder (ALS-FTSD). For mutations associated with ALS-FTSD, such as the C9orf72 hexanucleotide repeat expansion, the molecular factors associated with heterogeneity along this spectrum require further characterization. Here, using a targeted NanoString molecular barcoding approach, we interrogate neuroinflammatory dysregulation and heterogeneity at the level of gene expression in post-mortem motor cortex tissue from a cohort of clinically heterogeneous C9-ALS-FTSD cases. We identified 20 dysregulated genes in C9-ALS-FTSD, with enrichment of microglial and inflammatory response gene sets. Two genes with significant correlations to available clinical metrics were selected for validation: FKBP5, a correlate of cognitive function, and brain-derived neurotrophic factor (BDNF), a correlate of disease duration. FKBP5 and its signalling partner, NF-κB, appeared to have a cell type-specific staining distribution, with activated (i.e. nuclear) NF-κB immunoreactivity in C9-ALS-FTSD. Expression of BDNF, a correlate of disease duration, was confirmed to be higher in individuals with long compared to short disease duration using BaseScope™ in situ hybridization. Our analyses also revealed two distinct neuroinflammatory panel signatures (NPS), NPS1 and NPS2, delineated by the direction of expression of proinflammatory, axonal transport and synaptic signalling pathways. We compared NPS between C9-ALS-FTSD cases and those from sporadic ALS and SOD1-ALS cohorts and identified NPS1 and NPS2 across all cohorts. Moreover, a subset of NPS was also able to separate publicly available RNA sequencing data from independent C9-ALS and sporadic ALS cohorts into two inflammatory subgroups. Importantly, NPS subgroups did not clearly segregate with available demographic, genetic, clinical or pathological features, highlighting the value of molecular stratification in clinical trials for inflammatory subgroup identification. Our findings thus underscore the importance of tailoring therapeutic approaches based on distinct molecular signatures that exist between and within ALS-FTSD cohorts.

Making community pharmacies psychologically informed environments (PIE): a feasibility study to improve engagement with people using drug services in Scotland.

AIM: This developmental study tested the feasibility of training pharmacy staff on the psychologically informed environments (PIE) approach to improve the delivery of care. BACKGROUND: Community pharmacies provide key services to people who use drugs (PWUD) through needle exchange services, medication-assisted treatment and naloxone distribution. PWUD often have trauma backgrounds, and an approach that has been demonstrated to work well in the homeless sector is PIEs. METHODS: Bespoke training was provided by clinical psychologists and assessed by questionnaire. Staff interviews explored changes made following PIE training to adapt the delivery of care. Changes in attitude of staff following training were assessed by questionnaire. Peer researchers interviewed patient/client on observed changes and experiences in participating pharmacies. Staff interviews were conducted six months after training to determine what changes, if any, staff had implemented. Normalisation process theory (NPT) provided a framework for assessing change. FINDINGS: Three pharmacies (16 staff) participated. Training evaluation was positive; all participants rated training structure and delivery as 'very good' or 'excellent'. There was no statistically significant change in attitudes. COVID-19 lockdowns restricted follow-up data collection. Staff interviews revealed training had encouraged staff to reflect on their practice and communication and consider potentially discriminatory practice. PIE informed communication skills were applied to manage COVID-19 changes. Staff across pharmacies noted mental health challenges for patients. Five patients were interviewed but COVID-19 delays in data collection meant changes in delivery of care were difficult to recall. However, they did reflect on interactions with pharmacy staff generally. Across staff and patient interviews, there was possible conflation of practice changes due to COVID-19 and the training. However, the study found that training pharmacy teams in PIE was feasible, well received, and further development is recommended. There was evidence of the four NPT domains to support change (coherence, cognitive participation, collective action and reflexive monitoring).

Multiparametric High-Content Cell Painting Identifies Copper Ionophores as Selective Modulators of Esophageal Cancer Phenotypes.

Esophageal adenocarcinoma is of increasing global concern due to increasing incidence, a lack of effective treatments, and poor prognosis. Therapeutic target discovery and clinical trials have been hindered by the heterogeneity of the disease, the lack of "druggable" driver mutations, and the dominance of large-scale genomic rearrangements. We have previously undertaken a comprehensive small-molecule phenotypic screen using the high-content Cell Painting assay to quantify the morphological response to a total of 19,555 small molecules across a panel of genetically distinct human esophageal cell lines to identify new therapeutic targets and small molecules for the treatment of esophageal adenocarcinoma. In this current study, we report for the first time the dose-response validation studies for the 72 screening hits from the target-annotated LOPAC and Prestwick FDA-approved compound libraries and the full list of 51 validated esophageal adenocarcinoma-selective small molecules (71% validation rate). We then focus on the most potent and selective hit molecules, elesclomol, disulfiram, and ammonium pyrrolidinedithiocarbamate. Using a multipronged, multitechnology approach, we uncover a unified mechanism of action and a vulnerability in esophageal adenocarcinoma toward copper-dependent cell death that could be targeted in the future.

Pathway profiling of a novel SRC inhibitor, AZD0424, in combination with MEK inhibitors for cancer treatment.

A more comprehensive understanding of how cells respond to drug intervention, the likely immediate signalling responses and how resistance may develop within different microenvironments will help inform treatment regimes. The nonreceptor tyrosine kinase SRC regulates many cellular signalling processes, and pharmacological inhibition has long been a target of cancer drug discovery projects. Here, we describe the in vitro and in vivo characterisation of the small-molecule SRC inhibitor AZD0424. We show that AZD0424 potently inhibits the phosphorylation of tyrosine-419 of SRC (IC50 ~ 100 nm) in many cancer cell lines; however, inhibition of cell viability, via a G1 cell cycle arrest, was observed only in a subset of cancer cell lines in the low (on target) micromolar range. We profiled the changes in intracellular pathway signalling in cancer cells following exposure to AZD0424 and other targeted therapies using reverse-phase protein array (RPPA) analysis. We demonstrate that SRC is activated in response to treatment of KRAS-mutant colorectal cell lines with MEK inhibitors (trametinib or AZD6244) and that AZD0424 abrogates this. Cell lines treated with trametinib or AZD6244 in combination with AZD0424 had reduced EGFR, FAK and SRC compensatory activation, and cell viability was synergistically inhibited. In vivo, trametinib treatment of mice-bearing HCT116 tumours increased phosphorylation of SRC on Tyr419, and, when combined with AZD0424, inhibition of tumour growth was greater than with trametinib alone. We also demonstrate that drug-induced resistance to trametinib is not re-sensitised by AZD0424 treatment in vitro, likely as a result of multiple compensatory signalling mechanisms; however, inhibition of SRC remains an effective way to block invasion of trametinib-resistant tumour cells. These data imply that SRC inhibition may offer a useful addition to MEK inhibitor combination strategies.

The uptake of foil from needle and syringe provision services and its role in smoking or snorting heroin among people who inject drugs in Scotland.

BACKGROUND: In the UK, legislation was implemented in 2014 allowing needle and syringe provision (NSP) services to offer foil to people who inject drugs (PWID) to encourage smoking rather than injecting. This paper aims to examine the association between foil uptake and smoking or snorting heroin among PWID. This is the first large scale national study to examine foil uptake and smoking or snorting heroin among PWID post legislative change. METHOD: Data from 1453 PWID interviewed via Scotland's Needle Exchange Surveillance Initiative in 2017-2018 were analysed using multivariate logistic regression. RESULTS: Overall, 36% of PWID had obtained foil from NSP services in the past six months. The odds of smoking or snorting heroin were higher among those who had obtained foil (Adjusted Odds Ratio (AOR) 3.79 (95% CI 2.98-4.82) p<0.001) compared to those who had not. Smoking or snorting heroin was associated with lower odds of injecting four or more times daily (AOR 0.60 (95% CI 0.40-0.90) p = 0.012) and injecting into the groin or neck (AOR 0.57 (95% CI 0.46-0.71) p<0.001) but increased odds of having had a skin and soft tissue infection (SSTI) (AOR 1.49 (95% CI 1.17-1.89) p = 0.001) and having experienced an overdose (AOR 1.58 (95% CI 1.18-2.10) p = 0.002) both in the past year. CONCLUSION: The promotion of smoking drugs via foil provision from NSP services may contribute to the package of harm reduction measures for PWID alongside the provision of injecting equipment. We found that those in receipt of foil were more likely to smoke or snort heroin, and that smoking or snorting heroin was associated with a lower likelihood of some risky injecting behaviours, namely frequent injecting and injecting into the groin or neck. But it remains uncertain if the provision of foil can lead to a reduction in health harms, such as SSTI and overdose. Future research is needed to understand PWID motivations for smoking drugs, obtaining foil from NSP services, and its uses particularly among polydrug users.

A Conformation Selective Mode of Inhibiting SRC Improves Drug Efficacy and Tolerability.

Despite the approval of several multikinase inhibitors that target SRC and the overwhelming evidence of the role of SRC in the progression and resistance mechanisms of many solid malignancies, inhibition of its kinase activity has thus far failed to improve patient outcomes. Here we report the small molecule eCF506 locks SRC in its native inactive conformation, thereby inhibiting both enzymatic and scaffolding functions that prevent phosphorylation and complex formation with its partner FAK. This mechanism of action resulted in highly potent and selective pathway inhibition in culture and in vivo. Treatment with eCF506 resulted in increased antitumor efficacy and tolerability in syngeneic murine cancer models, demonstrating significant therapeutic advantages over existing SRC/ABL inhibitors. Therefore, this mode of inhibiting SRC could lead to improved treatment of SRC-associated disorders. SIGNIFICANCE: Small molecule-mediated inhibition of SRC impairing both catalytic and scaffolding functions confers increased anticancer properties and tolerability compared with other SRC/ABL inhibitors.

Understanding the Impacts of Novel Coronavirus Outbreaks on People Who Use Drugs: A Systematic Review to Inform Practice and Drug Policy Responses to COVID-19.

People who use drugs (PWUD) experience many social and health harms and are considered at greater risk of acquiring COVID-19. Little research has examined the impact of coronaviruses either on PWUD, or on services targeted to PWUD. We report the findings of a systematic review of empirical evidence from studies which have examined the impact of coronaviruses (Severe Acute Respiratory Syndrome (SARS-CoV-1) and Middle Eastern Respiratory Syndrome (MERS-CoV) and COVID-19) on PWUD or on service responses to them. Five databases were searched (MEDLINE, PsycINFO, CINAHL, ASSIA and EMBASE) as well as COVID-19 specific databases. Inclusion criteria were studies reporting any impact of SARS, MERS or COVID-19 or any service responses to those, published between January 2000 and October 2020. Weight of Evidence judgements and quality assessment were undertaken. In total, 27 primary studies were included and grouped by seven main themes: treatment/recovery services; emergency medical settings; low-threshold services; prison setting, PWUD/substance use disorder (SUD) diagnosis; people with SUD and HIV; 'Sexual minority' men. Overall, research in the area was scant, and of average/poor quality. More robust research is required to inform on-going and future responses to coronavirus epidemics for PWUD.

The autophagy protein Ambra1 regulates gene expression by supporting novel transcriptional complexes.

Ambra1 is considered an autophagy and trafficking protein with roles in neurogenesis and cancer cell invasion. Here, we report that Ambra1 also localizes to the nucleus of cancer cells, where it has a novel nuclear scaffolding function that controls gene expression. Using biochemical fractionation and proteomics, we found that Ambra1 binds to multiple classes of proteins in the nucleus, including nuclear pore proteins, adaptor proteins such as FAK and Akap8, chromatin-modifying proteins, and transcriptional regulators like Brg1 and Atf2. We identified biologically important genes, such as Angpt1, Tgfb2, Tgfb3, Itga8, and Itgb7, whose transcription is regulated by Ambra1-scaffolded complexes, likely by altering histone modifications and Atf2 activity. Therefore, in addition to its recognized roles in autophagy and trafficking, Ambra1 scaffolds protein complexes at chromatin, regulating transcriptional signaling in the nucleus. This novel function for Ambra1, and the specific genes impacted, may help to explain the wider role of Ambra1 in cancer cell biology.

High-Content Phenotypic Profiling in Esophageal Adenocarcinoma Identifies Selectively Active Pharmacological Classes of Drugs for Repurposing and Chemical Starting Points for Novel Drug Discovery.

Esophageal adenocarcinoma (EAC) is a highly heterogeneous disease, dominated by large-scale genomic rearrangements and copy number alterations. Such characteristics have hampered conventional target-directed drug discovery and personalized medicine strategies, contributing to poor outcomes for patients. We describe the application of a high-content Cell Painting assay to profile the phenotypic response of 19,555 compounds across a panel of six EAC cell lines and two tissue-matched control lines. We built an automated high-content image analysis pipeline to identify compounds that selectively modified the phenotype of EAC cell lines. We further trained a machine-learning model to predict the mechanism of action of EAC selective compounds using phenotypic fingerprints from a library of reference compounds. We identified a number of phenotypic clusters enriched with similar pharmacological classes, including methotrexate and three other antimetabolites that are highly selective for EAC cell lines. We further identify a small number of hits from our diverse chemical library that show potent and selective activity for EAC cell lines and that do not cluster with the reference library of compounds, indicating they may be selectively targeting novel esophageal cancer biology. Overall, our results demonstrate that our EAC phenotypic screening platform can identify existing pharmacologic classes and novel compounds with selective activity for EAC cell phenotypes.

Unlocking the transcriptomic potential of formalin-fixed paraffin embedded clinical tissues: comparison of gene expression profiling approaches.

BACKGROUND: High-throughput transcriptomics has matured into a very well established and widely utilised research tool over the last two decades. Clinical datasets generated on a range of different platforms continue to be deposited in public repositories provide an ever-growing, valuable resource for reanalysis. Cost and tissue availability normally preclude processing samples across multiple technologies, making it challenging to directly evaluate performance and whether data from different platforms can be reliably compared or integrated. METHODS: This study describes our experiences of nine new and established mRNA profiling techniques including Lexogen QuantSeq, Qiagen QiaSeq, BioSpyder TempO-Seq, Ion AmpliSeq, Nanostring, Affymetrix Clariom S or U133A, Illumina BeadChip and RNA-seq of formalin-fixed paraffin embedded (FFPE) and fresh frozen (FF) sequential patient-matched breast tumour samples. RESULTS: The number of genes represented and reliability varied between the platforms, but overall all methods provided data which were largely comparable. Crucially we found that it is possible to integrate data for combined analyses across FFPE/FF and platforms using established batch correction methods as required to increase cohort sizes. However, some platforms appear to be better suited to FFPE samples, particularly archival material. CONCLUSIONS: Overall, we illustrate that technology selection is a balance between required resolution, sample quality, availability and cost.

High content phenotypic screening identifies serotonin receptor modulators with selective activity upon breast cancer cell cycle and cytokine signaling pathways.

Heterogeneity in disease mechanisms between genetically distinct patients contributes to high attrition rates in late stage clinical drug development. New personalized medicine strategies aim to identify predictive biomarkers which stratify patients most likely to respond to a particular therapy. However, for complex multifactorial diseases not characterized by a single genetic driver, empirical approaches to identifying predictive biomarkers and the most promising therapies for personalized medicine are required. In vitro pharmacogenomics seeks to correlate in vitro drug sensitivity testing across panels of genetically distinct cell models with genomic, gene expression or proteomic data to identify predictive biomarkers of drug response. However, the vast majority of in vitro pharmacogenomic studies performed to date are limited to dose-response screening upon a single viability assay endpoint. In this article we describe the application of multiparametric high content phenotypic screening and the theta comparative cell scoring method to quantify and rank compound hits, screened at a single concentration, which induce a broad variety of divergent phenotypic responses between distinct breast cancer cell lines. High content screening followed by transcriptomic pathway analysis identified serotonin receptor modulators which display selective activity upon breast cancer cell cycle and cytokine signaling pathways correlating with inhibition of cell growth and survival. These methods describe a new evidence-led approach to rapidly identify compounds which display distinct response between different cell types. The results presented also warrant further investigation of the selective activity of serotonin receptor modulators upon breast cancer cell growth and survival as a potential drug repurposing opportunity.

Re-emergence of HIV related to injecting drug use despite a comprehensive harm reduction environment: a cross-sectional analysis.

BACKGROUND: In 2015, an outbreak of HIV was identified among people who inject drugs (PWID) in the Greater Glasgow and Clyde (GGC) area of Scotland, an area which distributes more than 1 million needles and syringes per year. This is the largest such incident in the UK for 30 years. Here, we provide an epidemiological analysis of the impact of the outbreak on HIV prevalence trends in the population and the individual and environmental risk factors associated with infection. METHODS: Four cross-sectional, anonymous, bio-behavioural surveys of almost 4000 PWID attending services providing injecting equipment across GGC between 2011 and 2018 were analysed. Participants were recruited by trained independent interviewers and eligible if they had a history of injecting drug use, either current (within the past 6 months) or historical. Interviewers asked participants questions about demographics, behaviours, and service use and to give a dried blood spot sample that was tested anonymously for the presence of blood-borne viruses. Our primary outcome measure was HIV infection status, as determined by the dried blood spot sample. We removed duplicates and participants with missing data and used all remaining participants to examine trends in prevalence of HIV infection, risk behaviours, and intervention coverage. We then did multivariate analysis with adjusted and unadjusted logistic regression to determine individual and environmental factors associated with HIV infection. FINDINGS: The overall GGC sample comprised 3641 PWID; data from 2712 PWID were available for multivariate analysis after further removal of duplicate participants and missing data. Between 2011 and 2018, HIV prevalence in GGC rose from 0·1% (95% CI 0·0-0·6) to 4·8% (3·4-6·2) overall, and from 1·1% (0·2-6·2) to 10·8% (7·4-15·5) in Glasgow city centre. Over the same period, the prevalence of cocaine injecting in all individuals in GGC in our sample rose from 16% (129/805) to 50% (291/583) overall, and from 37% (26/70) to 77% (117/153) in Glasgow city centre. HIV infection was more likely among PWID who had participated in surveys after the start of the outbreak in 2014 (adjusted odds ratio 3·4, 95% CI 1·7-6·7; p=0·00052), been homeless in the past 6 months (3·0, 1·7-5·0; p<0·0001), had had more than five incarcerations since they first began injecting (2·1, 1·2-3·7; p=0·0098); and had injected cocaine within the past 6 months (6·7, 3·8-12·1; p<0·0001). Age (per 1-year increase) was also a significant factor (1·1, 1·0-1·1; p=0·0016) but sex was not (1·7, 0·9-3·2; p=0·083). INTERPRETATION: Despite high coverage of harm reduction interventions, Glasgow has experienced a rapid rise in prevalence of HIV among its PWID population, associated with homelessness, incarceration, and a major shift to injection of cocaine. Robust surveillance through regular HIV testing of high-risk populations is crucial to ensure outbreaks are detected and rapid responses are informed by the best available evidence. FUNDING: Health Protection Scotland.

Emergence of Novel Psychoactive Substance injecting associated with rapid rise in the population prevalence of hepatitis C virus.

BACKGROUND: Novel Psychoactive Substance (NPS) use has increased in recent years and generated significant concern within public health. People who inject drugs (PWID) are at increased risk of blood borne viruses, in particular Hepatitis C virus (HCV). However, little is known about the extent of NPS injecting at a national level and its association with HCV. This study provides one of the first epidemiological analyses of the association between NPS injecting and HCV among a population level sample of PWID. METHODS: Five cross sectional surveys of almost 13,000 PWID attending services providing injecting equipment across Scotland between 2008 and 2016 were analysed. Logistic regression was used to determine associations between NPS injecting and HCV. RESULTS: The proportion of PWID reporting that they had injected NPS in the previous six months increased from 0.2% in 2008-09 to 11.0% in 2015-16. Those who reported injecting NPS were considerably more likely to be resident in the Lothian NHS Board area at the time of the study (AOR 5.6 (95% CI 4.1-7.5)) and to have had recent experience of homelessness (AOR 1.4 (95% CI 1.0-1.9)). People who injected NPS were also significantly more likely to be HCV positive (AOR 1.7 (95% CI 1.2-2.4)). In Lothian, HCV prevalence rose from around 30% between 2008 and 2012 to 41% and then 48% in 2013-14 and 2015-16 respectively. Increases in prevalent HCV infection in Lothian may be partly attributed to increases in NPS injecting. CONCLUSION: In Scotland, people who had injected Novel Psychoactive Substances were at increased risk of hepatitis C virus. Novel Psychoactive Substance injecting poses a threat to HCV elimination strategies.

"Once I'd done it once it was like writing your name": Lived experience of take-home naloxone administration by people who inject drugs.

BACKGROUND: The supply of naloxone, the opioid antagonist, for peer administration ('take-home naloxone' (THN)) has been promoted as a means of preventing opioid-related deaths for over 20 years. Despite this, little is known about PWID experiences of take-home naloxone administration. The aim of this study was to advance the evidence base on THN by producing one of the first examinations of the lived-experience of THN use among PWID. METHODS: Qualitative, face to face, semi-structured interviews were undertaken at a harm reduction service with individuals known to have used take-home naloxone in an overdose situation in a large urban area in Scotland. Interpretative Phenomenological Analysis (IPA) was then applied to the data from these in-depth accounts. RESULTS: The primary analysis involved a total of 8 PWID (seven male, one female) known to have used take-home naloxone. This paper focuses on the two main themes concerning naloxone administration: psychological impacts of peer administration and role perceptions. In the former, the feelings participants encounter at different stages of their naloxone experience, including before, during and after use, are explored. In the latter, the concepts of role legitimacy, role adequacy, role responsibility and role support are considered. CONCLUSION: This study demonstrates that responding to an overdose using take-home naloxone is complex, both practically and emotionally, for those involved. Although protocols exist, a multitude of individual, social and environmental factors shape responses in the short and longer terms. Despite these challenges, participants generally conveyed a strong sense of therapeutic commitment to using take-home naloxone in their communities.

Modelling the impact of a national scale-up of interventions on hepatitis C virus transmission among people who inject drugs in Scotland.

BACKGROUND AND AIMS: To reduce hepatitis C virus (HCV) transmission among people who inject drugs (PWID), Scottish Government-funded national strategies, launched in 2008, promoted scaling-up opioid substitution therapy (OST) and needle and syringe provision (NSP), with some increases in HCV treatment. We test whether observed decreases in HCV incidence post-2008 can be attributed to this intervention scale-up. DESIGN: A dynamic HCV transmission model among PWID incorporating intervention scale-up and observed decreases in behavioural risk, calibrated to Scottish HCV prevalence and incidence data for 2008/09. SETTING: Scotland, UK. PARTICIPANTS: PWID. MEASUREMENTS: Model projections from 2008 to 2015 were compared with data to test whether they were consistent with observed decreases in HCV incidence among PWID while incorporating the observed intervention scale-up, and to determine the impact of scaling-up interventions on incidence. FINDINGS: Without fitting to epidemiological data post-2008/09, the model incorporating observed intervention scale-up agreed with observed decreases in HCV incidence among PWID between 2008 and 2015, suggesting that HCV incidence decreased by 61.3% [95% credibility interval (CrI) = 45.1-75.3%] from 14.2/100 person-years (py) (9.0-20.7) to 5.5/100 py (2.9-9.2). On average, each model fit lay within 84% (10.1/12) of the confidence bounds for the 12 incidence data points against which the model was compared. We estimate that scale-up of interventions (OST + NSP + HCV treatment) and decreases in high-risk behaviour from 2008 to 2015 resulted in a 33.9% (23.8-44.6%) decrease in incidence, with the remainder [27.4% (17.6-37.0%)] explained by historical changes in OST + NSP coverage and risk pre-2008. Projections suggest that scaling-up of all interventions post-2008 averted 1492 (657-2646) infections over 7 years, with 1016 (308-1996), 404 (150-836) and 72 (27-137) due to scale-up of OST + NSP, decreases in high-risk behaviour and HCV treatment, respectively. CONCLUSIONS: Most of the decline in hepatitis C virus (HCV) incidence in Scotland between 2008 and 2015 appears to be attributable to intervention scale-up (opioid substitution therapy and needle and syringe provision) due to government strategies on HCV and drugs.

Determinants of hepatitis C antiviral effectiveness awareness among people who inject drugs in the direct-acting antiviral era.

BACKGROUND & AIMS: Although people who inject drugs (PWID) are at greatest risk of hepatitis C (HCV), treatment uptake in this population has historically been low. Highly effective direct acting antiviral (DAA) treatments for HCV have recently become available. Our aim was to assess the awareness among PWID of these new therapies and their effectiveness. METHODS: A national survey of PWID attending injecting equipment provision sites in Scotland during 2015-2016 included questions to gauge the awareness in this population of antiviral treatment and the high cure rates associated with new therapies (defined here as >80%). RESULTS: Among 2623 PWID, 92% had ever been tested for HCV. After excluding those ever treated for HCV (n = 226), 79% were aware of HCV treatment. Awareness was more likely among those who had ever been tested and self-reported either a positive (adjusted odds ratio: 16.04, 95%CI 10.57-24.33) or negative (3.11, 2.30-4.22) test result, compared to those who were never tested. The minority of all respondents (17%) were aware of high cure rates. This awareness was more likely among those who had ever been in HCV specialist care (9.76, 5.13-18.60) and those who had not been in specialist care but had been tested and self-reported either a positive (3.91, 2.20-7.53) or negative (2.55, 1.35-4.81) test result, compared to those who had never been tested. CONCLUSION: We found poor awareness of the high cure rates associated with DAAs among PWID in Scotland, despite relatively high rates of HCV testing in this population. Increased effort is needed to ensure population groups with high risk of HCV infection are fully informed of the highly effective antiviral medications now available to treat this chronic disease.

Correction to: Psychiatric comorbidity and intimate partner violence among women who inject drugs in Europe: a cross-sectional study.

The original version of this article unfortunately missed the Acknowledgment.

Spore forming bacteria infections and people who inject drugs: Implications for harm reduction.

BACKGROUND: There is no research on public health interventions that alert people who inject drugs (PWID) to clusters/outbreaks of severe bacterial infections. In Scotland, during the botulism cluster/outbreak of Dec 2014-July 2015 harm reduction (HR) messages detailed on a postcard (Botulism Postcard) were distributed to PWID between Feb-April 2015. We examined the impact of the Botulism Postcard on cluster/outbreak awareness, healthcare seeking and HR behaviours among PWID; and their views on such clusters/outbreaks. METHODS: The Botulism Postcard questionnaire survey was undertaken with 288 PWID recruited in Greater Glasgow and Clyde between May-August 2015. Multivariate logistic regression was undertaken. Between Oct 2015-January 2016 22 in-depth interviews were conducted with PWID in Glasgow and Edinburgh, these underwent thematic analysis. RESULTS: 38% (108/284) had never seen the postcard, 14% (40/284) had only seen it, 34% (98/284) read but not discussed it and 13% (38/284) had discussed it with service staff. Cluster/outbreak awareness was higher among those who had read (adjusted odds ratio (aOR) = 5.374, CI 2.394-11.349, p < 0.001) or discussed the postcard (aOR = 25.114, CI 3.188-190.550, p < 0.001); and symptom awareness was higher among those who had read (aOR = 2.664, CI 1.322-4.890, p < 0.001) or discussed the postcard (aOR = 6.707, CI 2.744 16.252, p < 0.001) than among those who had never seen it. The odds of introducing HR was higher among those who had discussed the postcard (AOR = 3.304 CI 1.425 7.660, p < 0.01) than those who had only read it. PWID learnt about clusters/outbreaks from several sources and despite concerns they continued to inject during such events. CONCLUSION: More widespread exposure to the Botulism Postcard during the outbreak/cluster was needed. The Botulism Postcard distributed to PWID may raise awareness of such events, the symptoms, and may encourage HR particularly when used as a tool by frontline staff to initiate discussion. Acknowledging that people continue to inject during clusters/outbreaks of such infections necessitates a pragmatic HR approach.