Yorkshire Lung Screening Trial (YLST): protocol for a randomised controlled trial to evaluate invitation to community-based low-dose CT screening for lung cancer versus usual care in a targeted population at risk

Introduction: Lung cancer is the world’s leading cause of cancer death. Low-dose computed tomography (LDCT) screening reduced lung cancer mortality by 20% in the US National Lung Screening Trial. Here, we present the Yorkshire Lung Screening Trial (YLST), which will address key questions of relevance for screening implementation. / Methods and analysis: Using a single-consent Zelen’s design, ever-smokers aged 55–80 years registered with a general practice in Leeds will be randomised (1:1) to invitation to a telephone-based risk-assessment for a Lung Health Check or to usual care. The anticipated number randomised by household is 62 980 individuals. Responders at high risk will be invited for LDCT scanning for lung cancer on a mobile van in the community. There will be two rounds of screening at an interval of 2 years. Primary objectives are (1) measure participation rates, (2) compare the performance of PLCOM2012 (threshold ≥1.51%), Liverpool Lung Project (V.2) (threshold ≥5%) and US Preventive Services Task Force eligibility criteria for screening population selection and (3) assess lung cancer outcomes in the intervention and usual care arms. Secondary evaluations include health economics, quality of life, smoking rates according to intervention arm, screening programme performance with ancillary biomarker and smoking cessation studies. / Ethics and dissemination: The study has been approved by the Greater Manchester West research ethics committee (18-NW-0012) and the Health Research Authority following review by the Confidentiality Advisory Group. The results will be disseminated through publication in peer-reviewed scientific journals, presentation at conferences and on the YLST website. / Trial registration numbers: ISRCTN42704678 and NCT03750110

Excision Repair Cross-Complementation Group 1 (ERCC1) Status and Lung Cancer Outcomes: A Meta-Analysis of Published Studies and Recommendations

Despite discrepant results on clinical utility, several trials are already prospectively randomizing non-small cell lung cancer (NSCLC) patients by ERCC1 status. We aimed to characterize the prognostic and predictive effect of ERCC1 by systematic review and meta-analysis.Eligible studies assessed survival and/or chemotherapy response in NSCLC or SCLC by ERCC1 status. Effect measures of interest were hazard ratio (HR) for survival or relative risk (RR) for chemotherapy response. Random-effects meta-analyses were used to account for between-study heterogeneity, with unadjusted/adjusted effect estimates considered separately.23 eligible studies provided survival results in 2,726 patients. Substantial heterogeneity was observed in all meta-analyses (I(2) always >30%), partly due to variability in thresholds defining 'low' and 'high' ERCC1. Meta-analysis of unadjusted estimates showed high ERCC1 was associated with significantly worse overall survival in platinum-treated NSCLC (average unadjusted HR = 1.61, 95%CI:1.23-2.1, p = 0.014), but not in NSCLC untreated with chemotherapy (average unadjusted HR = 0.82, 95%CI:0.51-1.31). Meta-analysis of adjusted estimates was limited by variable choice of adjustment factors and potential publication bias (Egger's p<0.0001). There was evidence that high ERCC1 was associated with reduced response to platinum (average RR = 0.80; 95%CI:0.64-0.99). SCLC data were inadequate to draw firm conclusions.Current evidence suggests high ERCC1 may adversely influence survival and response in platinum-treated NSCLC patients, but not in non-platinum treated, although definitive evidence of a predictive influence is lacking. International consensus is urgently required to provide consistent, validated ERCC1 assessment methodology. ERCC1 assessment for treatment selection should currently be restricted to, and evaluated within, clinical trials

One Health drivers of antibacterial resistance: Quantifying the relative impacts of human, animal and environmental use and transmission

This is the final version. Available on open access from Elsevier via the DOI in this recordData accessibility statement: All model code is open source and available for download on GitHub https://github.com/rdbooton/OHDARTmodelObjectives Antibacterial resistance (ABR) is a major global health security threat, with a disproportionate burden on lower-and middle-income countries (LMICs). It is not understood how ‘One Health’, where human health is co-dependent on animal health and the environment, might impact the burden of ABR in LMICs. Thailand's 2017 “National Strategic Plan on Antimicrobial Resistance” (NSP-AMR) aims to reduce AMR morbidity by 50% through 20% reductions in human and 30% in animal antibacterial use (ABU). There is a need to understand the implications of such a plan within a One Health perspective. Methods A model of ABU, gut colonisation with extended-spectrum beta-lactamase (ESBL)-producing bacteria and transmission was calibrated using estimates of the prevalence of ESBL-producing bacteria in Thailand. This model was used to project the reduction in human ABR over 20 years (2020–2040) for each One Health driver, including individual transmission rates between humans, animals and the environment, and to estimate the long-term impact of the NSP-AMR intervention. Results The model predicts that human ABU was the most important factor in reducing the colonisation of humans with resistant bacteria (maximum 65.7–99.7% reduction). The NSP-AMR is projected to reduce human colonisation by 6.0–18.8%, with more ambitious targets (30% reductions in human ABU) increasing this to 8.5–24.9%. Conclusions Our model provides a simple framework to explain the mechanisms underpinning ABR, suggesting that future interventions targeting the simultaneous reduction of transmission and ABU would help to control ABR more effectively in Thailand.Antimicrobial Resistance Cross Council Initiativ

The mediation of social influences on smoking cessation and awareness of the early signs of lung cancer

Background Whilst there has been no clear consensus on the potential for earlier diagnosis of lung cancer, recent research has suggested that the time between symptom onset and consultation can be long enough to plausibly affect prognosis. In this article, we present findings from a qualitative study involving in-depth interviews with patients who had been diagnosed with lung cancer (n = 11), and people who were at heightened risk of developing the disease (n = 14). Methods A grounded theory methodology was drawn upon to conduct thematic and narrative based approaches to analysis. Results The paper focuses on three main themes which emerged from the study: i) fatalism and resignation in pathways to help-seeking and the process of diagnosis; ii) Awareness of smoking risk and response to cessation information and advice. iii) The role of social and other networks on help-seeking. Key findings included: poor awareness among participants of the symptoms of lung cancer; ambivalence about the dangers of smoking; the perception of lung cancer as part of a homogenisation of multiple illnesses; close social networks as a key trigger in help-seeking. Conclusions We suggest that future smoking cessation and lung cancer awareness campaigns could usefully capitalise on the influence of close social networks, and would benefit from taking a ‘softer’ approach

Economic evaluation of improving HIV self-testing among men who have sex with men in China using a crowdsourced intervention: a cost-effectiveness analysis

Objectives: Crowdsourcing, which taps into the wisdom of crowds, has been successful in generating strategies to enhance HIV self-testing (HIVST) uptake. We determined the cost-effectiveness of a crowdsourced intervention (one-off or annual) compared with a control scenario (no crowdsourcing) among MSM living in China. Design: Economic evaluation. Methods: We used data from our cluster randomized controlled trial of MSM (NCT02796963). We used a micro-costing approach to measure direct health costs ($USD2017) from a health provider perspective. Using outputs from a dynamic transmission model over a 20-year time horizon, we estimated the incremental cost-effectiveness ratios using cost per disability-adjusted life years (DALYs) averted with 3$8823) per DALY averted. Results: Across all cities, the crowdsourced intervention was highly cost-effective compared with the control scenario (incremental cost-effectiveness ratios ranged from $2263 to 6152 per DALY averted for annual crowdsourcing;$171 to 204 per DALY averted for one-off crowdsourcing). The one-off intervention was cost-saving in Guangzhou and Qingdao. Sensitivity analyses confirmed the robustness of the findings; specifically, changes in discounting, costs of the crowdsourced intervention, costs of HIV testing and cost of antiretroviral therapy did not alter our conclusions. Conclusion: Scaling up a one-off or annual crowdsourced HIV prevention intervention in four cities in China was very likely to be cost-effective. Further research is warranted to evaluate the feasibility of scaling up crowdsourced HIV prevention interventions in other settings and populations

Estimating the impact of disruptions due to COVID-19 on HIV transmission and control among men who have sex with men in China

Introduction The COVID-19 pandemic is impacting HIV care globally, with gaps in HIV treatment expected to increase HIV transmission and HIV-related mortality. We estimated how COVID-19-related disruptions could impact HIV transmission and mortality among men who have sex with men (MSM) in four cities in China. Methods Regional data from China indicated that the number of MSM undergoing facility-based HIV testing reduced by 59% during the COVID-19 pandemic, alongside reductions in ART initiation (34%), numbers of sexual partners (62%) and consistency of condom use (25%). A deterministic mathematical model of HIV transmission and treatment among MSM in China was used to estimate the impact of these disruptions on the number of new HIV infections and HIV-related deaths. Disruption scenarios were assessed for their individual and combined impact over 1 and 5 years for a 3-, 4- or 6-month disruption period. Results Our China model predicted that new HIV infections and HIV-related deaths would be increased most by disruptions to viral suppression, with 25% reductions for a 3-month period increasing HIV infections by 5-14% over 1 year and deaths by 7-12%. Observed reductions in condom use increased HIV infections by 5-14% but had minimal impact (<1%) on deaths. Smaller impacts on infections and deaths (<3%) were seen for disruptions to facility testing and ART initiation, but reduced partner numbers resulted in 11-23% fewer infections and 0.4-1.0% fewer deaths. Longer disruption periods of 4 and 6 months amplified the impact of combined disruption scenarios. When all realistic disruptions were modelled simultaneously, an overall decrease in new HIV infections was always predicted over one year (3-17%), but not over 5 years (1% increase - 4% decrease), while deaths mostly increased over one year (1-2%) and 5 years (1.2 increase - 0.3 decrease). Conclusions The overall impact of COVID-19 on new HIV infections and HIV-related deaths is dependent on the nature, scale and length of the various disruptions. Resources should be directed to ensuring levels of viral suppression and condom use are maintained to mitigate any adverse effects of COVID-19 related disruption on HIV transmission and control among MSM in China

The impact of disruptions due to COVID-19 on HIV transmission and control among men who have sex with men in China

INTRODUCTION: The COVID-19 pandemic is impacting HIV care globally, with gaps in HIV treatment expected to increase HIV transmission and HIV-related mortality. We estimated how COVID-19-related disruptions could impact HIV transmission and mortality among men who have sex with men (MSM) in four cities in China, over a one- and five-year time horizon. METHODS: Regional data from China indicated that the number of MSM undergoing facility-based HIV testing reduced by 59% during the COVID-19 pandemic, alongside reductions in ART initiation (34%), numbers of all sexual partners (62%) and consistency of condom use (25%), but initial data indicated no change in viral suppression. A mathematical model of HIV transmission/treatment among MSM was used to estimate the impact of disruptions on HIV infections/HIV-related deaths. Disruption scenarios were assessed for their individual and combined impact over one and five years for 3/4/6-month disruption periods, starting from 1 January 2020. RESULTS: Our model predicted new HIV infections and HIV-related deaths would be increased most by disruptions to viral suppression, with 25% reductions (25% virally suppressed MSM stop taking ART) for a three-month period increasing HIV infections by 5% to 14% over one year and deaths by 7% to 12%. Observed reductions in condom use increased HIV infections by 5% to 14% but had minimal impact (<1%) on deaths. Smaller impacts on infections and deaths (<3%) were seen for disruptions to facility HIV testing and ART initiation, but reduced partner numbers resulted in 11% to 23% fewer infections and 0.4% to 1.0% fewer deaths. Longer disruption periods (4/6 months) amplified the impact of disruption scenarios. When realistic disruptions were modelled simultaneously, an overall decrease in new HIV infections occurred over one year (3% to 17%), but not for five years (1% increase to 4% decrease), whereas deaths mostly increased over one year (1% to 2%) and five years (1.2 increase to 0.3 decrease). CONCLUSIONS: The overall impact of COVID-19 on new HIV infections and HIV-related deaths is dependent on the nature, scale and length of the various disruptions. Resources should be directed to ensuring levels of viral suppression and condom use are maintained to mitigate any adverse effects of COVID-19-related disruption on HIV transmission and control among MSM in China

Yorkshire Lung Screening Trial (YLST): protocol for a randomised controlled trial to evaluate invitation to community-based low-dose CT screening for lung cancer versus usual care in a targeted population at risk

Introduction Lung cancer is the world’s leading cause of cancer death. Low-dose computed tomography (LDCT) screening reduced lung cancer mortality by 20% in the US National Lung Screening Trial. Here, we present the Yorkshire Lung Screening Trial (YLST), which will address key questions of relevance for screening implementation. Methods and analysis Using a single-consent Zelen’s design, ever-smokers aged 55–80 years registered with a general practice in Leeds will be randomised (1:1) to invitation to a telephone-based risk-assessment for a Lung Health Check or to usual care. The anticipated number randomised by household is 62 980 individuals. Responders at high risk will be invited for LDCT scanning for lung cancer on a mobile van in the community. There will be two rounds of screening at an interval of 2 years. Primary objectives are (1) measure participation rates, (2) compare the performance of PLCOM2012 (threshold ≥1.51%), Liverpool Lung Project (V.2) (threshold ≥5%) and US Preventive Services Task Force eligibility criteria for screening population selection and (3) assess lung cancer outcomes in the intervention and usual care arms. Secondary evaluations include health economics, quality of life, smoking rates according to intervention arm, screening programme performance with ancillary biomarker and smoking cessation studies. Ethics and dissemination The study has been approved by the Greater Manchester West research ethics committee (18-NW-0012) and the Health Research Authority following review by the Confidentiality Advisory Group. The results will be disseminated through publication in peer-reviewed scientific journals, presentation at conferences and on the YLST website. Trial registration numbers ISRCTN42704678 and NCT03750110

Participation in community-based lung cancer screening: the Yorkshire Lung Screening Trial.

QUESTION: Screening with low dose computed tomography (LDCT) reduces lung-cancer mortality; however, the most effective strategy for optimising participation is unknown. Here we present data from the Yorkshire Lung Screening Trial, including response to invitation, screening eligibility and uptake of community-based LDCT screening. METHODS: Individuals aged 55 to 80, identified from primary care records as having ever smoked, were randomised prior to consent to invitation to telephone lung cancer risk assessment or usual care. The invitation strategy included General Practitioner endorsement, pre-invitation and two reminder invitations. After telephone triage, those at higher risk were invited to a Lung Health Check (LHC) with immediate access to a mobile CT scanner. RESULTS: Of 44 943 individuals invited, 50.8% (n=22 815) responded and underwent telephone-based risk assessment (16.7% and 7.3% following first and second reminders respectively). A lower response rate was associated with current smoking status (adjOR 0.44, 95%CI 0.42-0.46) and socio-economic deprivation (adjOR 0.58, 95% CI 0.54-0.62 most versus least deprived quintile). Of those responding, 34.4% (n=7853) were potentially eligible for screening and offered a LHC, of whom 86.8% (n=6819) attended. Lower uptake was associated with current smoking status (adjOR 0.73, 95%CI 0.62-0.87) and socio-economic deprivation (adjOR 0.78, 95% CI 0.62-0.98). In total 6,650 individuals had a baseline LDCT scan, representing 99.7% of eligible LHC attendees. CONCLUSION: Telephone risk assessment followed by a community-based LHC is an effective strategy for lung cancer screening implementation. However, lower participation associated with current smoking status and socio-economic deprivation underlines the importance of research to ensure equitable access to screening