Automated AI labeling of optic nerve head enables insights into cross-ancestry glaucoma risk and genetic discovery in >280,000 images from UKB and CLSA.

Cupping of the optic nerve head, a highly heritable trait, is a hallmark of glaucomatous optic neuropathy. Two key parameters are vertical cup-to-disc ratio (VCDR) and vertical disc diameter (VDD). However, manual assessment often suffers from poor accuracy and is time intensive. Here, we show convolutional neural network models can accurately estimate VCDR and VDD for 282,100 images from both UK Biobank and an independent study (Canadian Longitudinal Study on Aging), enabling cross-ancestry epidemiological studies and new genetic discovery for these optic nerve head parameters. Using the AI approach, we perform a systematic comparison of the distribution of VCDR and VDD and compare these with intraocular pressure and glaucoma diagnoses across various genetically determined ancestries, which provides an explanation for the high rates of normal tension glaucoma in East Asia. We then used the large number of AI gradings to conduct a more powerful genome-wide association study (GWAS) of optic nerve head parameters. Using the AI-based gradings increased estimates of heritability by ∼50% for VCDR and VDD. Our GWAS identified more than 200 loci associated with both VCDR and VDD (double the number of loci from previous studies) and uncovered dozens of biological pathways; many of the loci we discovered also confer risk for glaucoma.

Validation of the psychosocial consequences of screening in lung cancer questionnaire in the international lung screen trial Australian cohort.

BACKGROUND: Evaluation of psychosocial consequences of lung cancer screening with LDCT in high-risk populations has generally been performed using generic psychometric instruments. Such generic instruments have low coverage and low power to detect screening impacts. This study aims to validate an established lung cancer screening-specific questionnaire, Consequences Of Screening Lung Cancer (COS-LC), in Australian-English and describe early results from the baseline LDCT round of the International Lung Screen Trial (ILST). METHODS: The Danish-version COS-LC was translated to Australian-English using the double panel method and field tested in Australian-ILST participants to examine content validity. A random sample of 200 participants were used to assess construct validity using Rasch item response theory models. Reliability was assessed using classical test theory. The COS-LC was administered to ILST participants at prespecified timepoints including at enrolment, dependent of screening results. RESULTS: Minor linguistic alterations were made after initial translation of COS-LC to English. The COS-LC demonstrated good content validity and adequate construct validity using psychometric analysis. The four core scales fit the Rasch model, with only minor issues in five non-core scales which resolved with modification. 1129 Australian-ILST participants were included in the analysis, with minimal psychosocial impact observed shortly after baseline LDCT results. CONCLUSION: COS-LC is the first lung cancer screening-specific questionnaire to be validated in Australia and has demonstrated excellent psychometric properties. Early results did not demonstrate significant psychosocial impacts of screening. Longer-term follow-up is awaited and will be particularly pertinent given the announcement of an Australian National Lung Cancer Screening Program. TRIAL REGISTRATION: NCT02871856.

Exploring associations of population characteristics and tobacco and vape retailer density and proximity in Australia: a scoping review.

OBJECTIVE: This scoping review synthesises Australian evidence on associations between tobacco and vape retailer density/proximity and various population measures and smoking behaviour to identify research gaps and inform future policy and strategies. DATA SOURCES: Following Joanna Briggs Institute methodology, relevant studies published in English since 2003 were identified via searches of eight databases in March and August 2023. STUDY SELECTION: Two reviewers independently completed screening procedures. Eligible studies were from Australia and described associations between tobacco or vape retailer density/proximity and adult or youth smoking/vaping prevalence or behaviours, neighbourhood socioeconomic status, geographic location, school locations and/or Indigenous status. DATA EXTRACTION: Results are reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews checklist. DATA SYNTHESIS: Of 794 publications screened, 12 studies from 6 Australian states were included. Six studies from five states reported statistically significant associations between neighbourhood-level socioeconomic disadvantage and tobacco retailer density, yet only two studies from two states found a significant relationship between retailer density and adult smoking prevalence. Increasing retailer density was consistently significantly associated with increasing geographical remoteness in three states. No studies explored associations with tobacco retailer proximity or vape retailer density/proximity. CONCLUSIONS: Despite a moderate number of studies overall, state-level evidence is limited, and unknown for Australian territories. Evidence from five Australian states reflects the international evidence that increasing retailer density is significantly associated with increasing socioeconomic disadvantage and remoteness, supporting the need for tobacco supply-based policies. Further research is required to understand the impact of retailer density and adult and youth smoking prevalence in Australia.

The TSANZ and Lung Foundation Australia 2023 landscape survey of lung cancer care across Australia and Aotearoa New Zealand.

BACKGROUND AND OBJECTIVE: Unwarranted variations in lung cancer care have been well described in both Australia and Aotearoa New Zealand, with shortfalls in hospital-based workforce and infrastructure previously demonstrated. A survey of lung cancer clinicians was performed to gain an updated understanding of current workforce and infrastructure. METHODS: An online Qualtrics survey included questions on institutional demographics, estimated lung cancer case load, multidisciplinary team (MDT) characteristics including workforce and local infrastructure. We sought to obtain one response from every institution treating lung cancer in Australia and Aotearoa New Zealand. RESULTS: Responses were received from 89 institutions, estimated to include 85% centres treating lung cancer in Australia and 100% of public hospitals in Aotearoa New Zealand. Lung cancer nurse specialist and Nuclear Medicine are poorly represented in multidisciplinary teams (MDTs) with just 34/88 (38%) institutions fulfilling recommended core workforce for MDT meetings. Case presentation is low with 32/88 (36%) regularly discussing all lung cancer patients at MDT. Metropolitan institutions appear to have a more comprehensive range of services on site, compared to non-metropolitan institutions. Few (4/88) institutions have embedded smoking cessation services. Compared to the previous 2021 Landscape Survey, thoracic surgery representation and core MDT workforce have improved, with modest change in specialist nurse numbers. CONCLUSION: This wide-reaching survey has identified persistent deficiencies and variations in lung cancer workforce and gaps in infrastructure. Multidisciplinary collaboration and care coordination are needed to ensure all patients can access timely and equitable lung cancer care.

Updated cost-effectiveness analysis of lung cancer screening for Australia, capturing differences in the health economic impact of NELSON and NLST outcomes.

BACKGROUND: A national, lung cancer screening programme is under consideration in Australia, and we assessed cost-effectiveness using updated data and assumptions. METHODS: We estimated the cost-effectiveness of lung screening by applying screening parameters and outcomes from either the National Lung Screening Trial (NLST) or the NEderlands-Leuvens Longkanker Screenings ONderzoek (NELSON) to Australian data on lung cancer risk, mortality, health-system costs, and smoking trends using a deterministic, multi-cohort model. Incremental cost-effectiveness ratios (ICERs) were calculated for a lifetime horizon. RESULTS: The ICER for lung screening compared to usual care in the NELSON-based scenario was AU$39,250 (95% CI $18,150-108,300) per quality-adjusted life year (QALY); lower than the NLST-based estimate (ICER = $76,300, 95% CI $41,750-236,500). In probabilistic sensitivity analyses, lung screening was cost-effective in 15%/60% of NELSON-like simulations, assuming a willingness-to-pay threshold of $30,000/$50,000 per QALY, respectively, compared to 0.5%/6.7% for the NLST. ICERs were most sensitive to assumptions regarding the screening-related lung cancer mortality benefit and duration of benefit over time. The cost of screening had a larger impact on ICERs than the cost of treatment, even after quadrupling the 2006-2016 healthcare costs of stage IV lung cancer. DISCUSSION: Lung screening could be cost-effective in Australia, contingent on translating trial-like lung cancer mortality benefits to the clinic.

High Polygenic Risk Is Associated with Earlier Initiation and Escalation of Treatment in Early Primary Open-Angle Glaucoma.

PURPOSE: To assess the association between a glaucoma polygenic risk score (PRS) and treatment outcomes in primary open-angle glaucoma. DESIGN: Prospective, observational cohort study. PARTICIPANTS: Participants from the Progression Risk of Glaucoma: Relevant SNPs with Significant Association Study were divided into a cohort with suspect glaucoma who were treatment naive at enrollment and one with early manifest and suspect glaucoma receiving treatment at enrollment. METHODS: A per-allele weighted glaucoma PRS was calculated for 1107 participants. Multivariable mixed-effects Cox proportional regression analysis assessed the association between PRS and time to commencement of intraocular pressure (IOP)-lowering therapy in 416 patients with suspect glaucoma who were treatment naive at study enrollment. Secondary analysis evaluated the association between PRS and escalation of IOP-lowering therapy among 691 patients with suspect and early manifest glaucoma who were receiving IOP-lowering therapy at enrollment. MAIN OUTCOME MEASURES: Commencement or escalation of IOP-lowering therapy. RESULTS: A higher PRS was associated with a greater risk of commencing IOP-lowering therapy within 5 years (hazard ratio [HR], 1.45 per 1 standard deviation [/SD]; 95% confidence interval [CI], 1.27-1.62; P < 0.001). Participants in the upper population-based quintile showed a 3.3 times greater risk of commencing therapy by 5 years than those in the lowest quintile (HR, 3.30; 95% CI, 1.63-6,70; P < 0.001) and a 5.4 times greater risk of commencing IOP-lowering therapy by 2 years than the those in the lowest quintile (HR, 5.45; 95% CI, 2.08-14.25; P < 0.001). A higher PRS was associated with a greater risk of treatment escalation among patients receiving treatment at enrollment (HR, 1.19/SD; 95% CI, 1.09-1.31; P < 0.001). In combined analysis of all participants, participants in the top population-based quintile were at 2.3 times greater risk of requiring initiation or escalation of IOP-lowering therapy than those in the lowest quintile (HR, 2.33; 95% CI, 1.75-3.01; P < 0.001). CONCLUSIONS: This study demonstrated novel associations between glaucoma polygenic risk and risk of commencement or escalation of IOP-lowering therapy, building on previous work highlighting the potential clinical usefulness of genetic risk stratification in glaucoma. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Prevalence of subclinical lung cancer detected at autopsy: a systematic review.

BACKGROUND: Lung cancer screening in high-risk populations with low-dose computed tomography is supported by international associations and recommendations. Overdiagnosis is considered a risk of screening with associated harms. The aim of this paper is to determine the prevalence of subclinical lung cancer diagnosed post-mortem to better understand the reservoir of subclinical lung cancer. METHODS: We searched EMBASE, PubMed, and MEDLINE databases from inception until March 2022 with no language restrictions. We considered all studies with ≥100 autopsies in adults. Two reviewers independently assessed eligibility of studies, extracted data, and assessed risk of bias of included studies. We performed a meta-analysis using a random-effects model for prevalence of subclinical lung cancer diagnosed post-mortem with sensitivity and subgroup analyses. RESULTS: A total of 13 studies with 16 730 autopsies were included. Pooled prevalence was 0.4% (95% CI 0.20 to 0.82%, I2 = 84%, tau2 = 1.19, low certainty evidence,16 730 autopsies). We performed a sensitivity analysis excluding studies which did not specify exclusion of children in their cohort, with a pooled prevalence of subclinical lung cancer of 0.87% (95% CI 0.48 to 1.57%, I2 = 71%, tau2 = 0.38, 6998 autopsies, 8 studies). CONCLUSIONS: This is the first published systematic review to evaluate the prevalence of post-mortem subclinical lung cancer. Compared to autopsy systematic reviews in breast, prostate and thyroid cancers, the pooled prevalence is lower in lung cancer for subclinical cancer. This result should be interpreted with caution due to the included studies risk of bias and heterogeneity, with further high-quality studies required in target screening populations.

Education messages and strategies to inform the public, potential screening candidates and healthcare providers about lung cancer screening: A systematic review.

International lung cancer screening (LCS) trials, using low-dose computed tomography, have demonstrated clinical effectiveness in reducing mortality from lung cancer. This systematic review aims to synthesise the key messages and strategies that could be successful in increasing awareness and knowledge of LCS, and ultimately increase uptake of screening. Studies were identified via relevant database searches up to January 2022. Two authors evaluated eligible studies, extracted and crosschecked data, and assessed quality. Results were synthesised narratively. Of 3205 titles identified, 116 full text articles were reviewed and 22 studies met the inclusion criteria. Twenty studies were conducted in the United States. While the study findings were heterogenous, key messages mentioned across multiple studies were about: provision of information on LCS and the recommendations for LCS (n = 8); benefits and harms of LCS (n = 6); cost of LCS and insurance coverage for participants (n = 6) and eligibility criteria (n = 5). To increase knowledge and awareness, evidence from awareness campaigns suggests that presenting information about eligibility and the benefits and harms of screening, may increase screening intention and uptake. Evidence from behavioural studies suggests that campaigns supporting engagement with platforms such as educational videos and digital awareness campaigns might be most effective. Group based learning appears to be most suited to increasing health professionals' knowledge. This systematic review found a lack of consistent evidence to demonstrate which strategies are most effective for increasing participant healthcare professional and community awareness and education about LCS.

Introducing Quin: The design and development of a prototype chatbot to support smoking cessation.

INTRODUCTION: Chatbots emulate human-like interactions and may usefully provide on-demand access to tailored smoking cessation support. We have developed a prototype smartphone application-based smoking cessation chatbot, named Quin, grounded in real-world, evidence- and theory-based smoking cessation counselling sessions. METHOD: Conversation topics and interactions in Quitline counselling sessions (N=30; 18 hours) were characterised using thematic, content, and proponent analyses of transcripts. Quin was created by programming this content using a chatbot framework which interacts with users via speech-to-text. Reiterative changes and additions were made to the conversation structure and dialogue following regular consultation with a multidisciplinary team from relevant fields, and from evidence-based resources. RESULTS: Chatbot conversations were encoded into initial and scheduled follow-up 'appointments'. Collection of demographic information, and smoking and quit history, informed tailored discussion about pharmacotherapy preferences, behavioural strategies, and social and professional support to form a quit plan. Follow-up appointments were programmed to check in on user progress, review elements of the quit plan, answer questions and solve issues. Quin was programmed to include teachable moments and educational content to enhance health literacy and informed decision-making. Personal agency is encouraged through exploration and self-reflection of users' personal behaviours, experiences, preferences and ideas. CONCLUSION: Quin's successful development represents a movement towards improving access to personalised smoking cessation support. Qualitative foundations of Quin provide greater insight into the smoking cessation counselling relationship and enhances the conversational ability of the technology. The prototype chatbot will be refined through beta-testing with end-users and stakeholders prior to evaluation in a clinical trial. IMPLICATIONS: Our novel study provides transparent description of the translation of qualitative evidence of real-world smoking cessation counselling sessions into the design and development of a prototype smoking cessation chatbot. The successful iterative development of Quin not only embodies the science and art of health promotion, but also a step-forward in expanding the reach of tailored, evidence based, in-pocket support for people who want to quit smoking.

USPSTF2013 versus PLCOm2012 lung cancer screening eligibility criteria (International Lung Screening Trial): interim analysis of a prospective cohort study.

BACKGROUND: Lung cancer is a major health problem. CT lung screening can reduce lung cancer mortality through early diagnosis by at least 20%. Screening high-risk individuals is most effective. Retrospective analyses suggest that identifying individuals for screening by accurate prediction models is more efficient than using categorical age-smoking criteria, such as the US Preventive Services Task Force (USPSTF) criteria. This study prospectively compared the effectiveness of the USPSTF2013 and PLCOm2012 model eligibility criteria. METHODS: In this prospective cohort study, participants from the International Lung Screening Trial (ILST), aged 55-80 years, who were current or former smokers (ie, had ≥30 pack-years smoking history or ≤15 quit-years since last permanently quitting), and who met USPSTF2013 criteria or a PLCOm2012 risk threshold of at least 1·51% within 6 years of screening, were recruited from nine screening sites in Canada, Australia, Hong Kong, and the UK. After enrolment, patients were assessed with the USPSTF2013 criteria and the PLCOm2012 risk model with a threshold of at least 1·70% at 6 years. Data were collected locally and centralised. Main outcomes were the comparison of lung cancer detection rates and cumulative life expectancies in patients with lung cancer between USPSTF2013 criteria and the PLCOm2012 model. In this Article, we present data from an interim analysis. To estimate the incidence of lung cancers in individuals who were USPSTF2013-negative and had PLCOm2012 of less than 1·51% at 6 years, ever-smokers in the Prostate Lung Colorectal and Ovarian Cancer Screening Trial (PLCO) who met these criteria and their lung cancer incidence were applied to the ILST sample size for the mean follow-up occurring in the ILST. This trial is registered at ClinicalTrials.gov, NCT02871856. Study enrolment is almost complete. FINDINGS: Between June 17, 2015, and Dec 29, 2020, 5819 participants from the International Lung Screening Trial (ILST) were enrolled on the basis of meeting USPSTF2013 criteria or the PLCOm2012 risk threshold of at least 1·51% at 6 years. The same number of individuals was selected for the PLCOm2012 model as for the USPSTF2013 criteria (4540 [78%] of 5819). After a mean follow-up of 2·3 years (SD 1·0), 135 lung cancers occurred in 4540 USPSTF2013-positive participants and 162 in 4540 participants included in the PLCOm2012 of at least 1·70% at 6 years group (cancer sensitivity difference 15·8%, 95% CI 10·7-22·1%; absolute odds ratio 4·00, 95% CI 1·89-9·44; p<0·0001). Compared to USPSTF2013-positive individuals, PLCOm2012-selected participants were older (mean age 65·7 years [SD 5·9] vs 63·3 years [5·7]; p<0·0001), had more comorbidities (median 2 [IQR 1-3] vs 1 [1-2]; p<0·0001), and shorter life expectancy (13·9 years [95% CI 12·8-14·9] vs 14·8 [13·6-16·0] years). Model-based difference in cumulative life expectancies for those diagnosed with lung cancer were higher in those who had PLCOm2012 risk of at least 1·70% at 6 years than individuals who were USPSTF2013-positive (2248·6 years [95% CI 2089·6-2425·9] vs 2000·7 years [1841·2-2160·3]; difference 247·9 years, p=0·015). INTERPRETATION: PLCOm2012 appears to be more efficient than the USPSTF2013 criteria for selecting individuals to enrol into lung cancer screening programmes and should be used for identifying high-risk individuals who benefit from the inclusion in these programmes. FUNDING: Terry Fox Research Institute, The UBC-VGH Hospital Foundation and the BC Cancer Foundation, the Alberta Cancer Foundation, the Australian National Health and Medical Research Council, Cancer Research UK and a consortium of funders, and the Roy Castle Lung Cancer Foundation for the UK Lung Screen Uptake Trial.

The phenotypic spectrum of ADAMTSL4-associated ectopia lentis: Additional cases, complications, and review of literature.

Purpose: ADAMTSL4-associated ectopia lentis is a rare autosomal recessive condition that is primarily associated with crystalline lens displacement. However, the prevalence of other ocular and systemic manifestations of this condition is poorly understood. In this study, we summarize the ocular and systemic phenotypic spectrum of this condition. Methods: A cross-sectional case study series of four individuals with biallelic pathogenic or likely pathogenic ADAMTSL4 variants was performed alongside a literature review of individuals with ADAMTSL4-associated ectopia lentis on September 29, 2021. Ocular and systemic findings, complications, and genetic findings of all four individuals were collected and summarized. Results: The phenotypic spectrum across 91 individuals sourced from literature and four individuals from this case study series was highly variable. The main ocular phenotypes included ectopia lentis (95/95, 100%), ectopia lentis et pupillae (18/95, 19%), iris transillumination (13/95, 14%), iridodonesis (12/95, 13%), persistent pupillary membrane (12/95, 13%), and early-onset cataract or lens opacities (12/95, 13%). Anterior segment features other than ectopia lentis appeared to be exclusively associated with biallelic loss of function variants (p<0.001). Pupillary block glaucoma had a prevalence of 1%. Post-lensectomy complications included retinal detachment (6/41, 15%), elevated intraocular pressure (4/41, 10%), and aphakic glaucoma (1/41, 2%). Most individuals were not reported to have had systemic features (69/95, 73%). Conclusions: The clinical phenotype of ADAMTSL4-associated ectopia lentis was summarized and expanded. Clinicians should be aware of the varied ocular phenotype and the risks of retinal detachment, ocular hypertension, and glaucoma in the diagnosis and management of this condition.

What Do People Want in a Smoking Cessation App? An Analysis of User Reviews and App Quality.

INTRODUCTION: Mobile smoking cessation (mCessation) apps have the potential to complement and enhance existing interventions, but many are of low quality. Exploring app reviews can provide a broader understanding of user experiences and engagement, to enhance the quality, acceptability, and effectiveness of future developments. METHODS: Publicly available user reviews and ratings of smoking cessation apps were mined from Google Play and the App Store via a targeted two-stage search strategy. English language smoking cessation apps with at least 20 consumer reviews between 2011 and 2020 were included. User reviews were thematically analyzed using Braun and Clarke's framework. Apps were independently scored using the Mobile Apps Rating Scale (MARS) and compared to average user star ratings. RESULTS: Forty-eight versions of 42 apps, encompassing 1414 associated reviews, met eligibility criteria. Inductive coding of reviews produced 1084 coding references including reviews coded across multiple nodes. Themes generated included: (1) supportive characteristics/tools; (2) useability; (3) influence on smoking behavior; (4) benefits of quitting; and (5) role as a supplementary tool for quitting. The mean MARS score of 36 free and accessible apps was 3.10 (SD 0.71) with mean scores ranging from 2.00 to 4.47. An inverse relationship between MARS scores and average user star ratings was observed. CONCLUSIONS: App personalization, relationality, functionality, and credibility were important to users, and should be considered as key design components for future apps. Differences between user star ratings and MARS scores may illustrate competing priorities of consumers and researchers, and the importance of a codesign development method. IMPLICATIONS: This is the first study to use unsolicited user reviews from a large population to understand the general mCessation user experience in relation to making a quit attempt. Our findings highlight specific features favored and disliked by users, including their influence on engagement, and supports previous findings that mCessation applications need to be highly tailorable, functional, credible, and supportive. We recommend a consumer-driven, co-design approach for future mCessation app developments to optimize user acceptability and engagement.

Impact of low-dose computed tomography (LDCT) screening on lung cancer-related mortality.

BACKGROUND: Lung cancer is the most common cause of cancer-related death in the world, however lung cancer screening has not been implemented in most countries at a population level. A previous Cochrane Review found limited evidence for the effectiveness of lung cancer screening with chest radiography (CXR) or sputum cytology in reducing lung cancer-related mortality, however there has been increasing evidence supporting screening with low-dose computed tomography (LDCT).  OBJECTIVES: To determine whether screening for lung cancer using LDCT of the chest reduces lung cancer-related mortality and to evaluate the possible harms of LDCT screening. SEARCH METHODS: We performed the search in collaboration with the Information Specialist of the Cochrane Lung Cancer Group and included the Cochrane Lung Cancer Group Trial Register, Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library, current issue), MEDLINE (accessed via PubMed) and Embase in our search. We also searched the clinical trial registries to identify unpublished and ongoing trials. We did not impose any restriction on language of publication. The search was performed up to 31 July 2021.  SELECTION CRITERIA: Randomised controlled trials (RCTs) of lung cancer screening using LDCT and reporting mortality or harm outcomes.  DATA COLLECTION AND ANALYSIS: Two review authors were involved in independently assessing trials for eligibility, extraction of trial data and characteristics, and assessing risk of bias of the included trials using the Cochrane RoB 1 tool. We assessed the certainty of evidence using GRADE. Primary outcomes were lung cancer-related mortality and harms of screening. We performed a meta-analysis, where appropriate, for all outcomes using a random-effects model. We only included trials in the analysis of mortality outcomes if they had at least 5 years of follow-up. We reported risk ratios (RRs) and hazard ratios (HRs), with 95% confidence intervals (CIs) and used the I2 statistic to investigate heterogeneity.  MAIN RESULTS: We included 11 trials in this review with a total of 94,445 participants. Trials were conducted in Europe and the USA in people aged 40 years or older, with most trials having an entry requirement of ≥ 20 pack-year smoking history (e.g. 1 pack of cigarettes/day for 20 years or 2 packs/day for 10 years etc.). One trial included male participants only. Eight trials were phase three RCTs, with two feasibility RCTs and one pilot RCT. Seven of the included trials had no screening as a comparison, and four trials had CXR screening as a comparator. Screening frequency included annual, biennial and incrementing intervals. The duration of screening ranged from 1 year to 10 years. Mortality follow-up was from 5 years to approximately 12 years.  None of the included trials were at low risk of bias across all domains. The certainty of evidence was moderate to low across different outcomes, as assessed by GRADE. In the meta-analysis of trials assessing lung cancer-related mortality, we included eight trials (91,122 participants), and there was a reduction in mortality of 21% with LDCT screening compared to control groups of no screening or CXR screening (RR 0.79, 95% CI 0.72 to 0.87; 8 trials, 91,122 participants; moderate-certainty evidence). There were probably no differences in subgroups for analyses by control type, sex, geographical region, and nodule management algorithm. Females appeared to have a larger lung cancer-related mortality benefit compared to males with LDCT screening. There was also a reduction in all-cause mortality (including lung cancer-related) of 5% (RR 0.95, 95% CI 0.91 to 0.99; 8 trials, 91,107 participants; moderate-certainty evidence).  Invasive tests occurred more frequently in the LDCT group (RR 2.60, 95% CI 2.41 to 2.80; 3 trials, 60,003 participants; moderate-certainty evidence). However, analysis of 60-day postoperative mortality was not significant between groups (RR 0.68, 95% CI 0.24 to 1.94; 2 trials, 409 participants; moderate-certainty evidence).  False-positive results and recall rates were higher with LDCT screening compared to screening with CXR, however there was low-certainty evidence in the meta-analyses due to heterogeneity and risk of bias concerns. Estimated overdiagnosis with LDCT screening was 18%, however the 95% CI was 0 to 36% (risk difference (RD) 0.18, 95% CI -0.00 to 0.36; 5 trials, 28,656 participants; low-certainty evidence). Four trials compared different aspects of health-related quality of life (HRQoL) using various measures. Anxiety was pooled from three trials, with participants in LDCT screening reporting lower anxiety scores than in the control group (standardised mean difference (SMD) -0.43, 95% CI -0.59 to -0.27; 3 trials, 8153 participants; low-certainty evidence). There were insufficient data to comment on the impact of LDCT screening on smoking behaviour.  AUTHORS' CONCLUSIONS: The current evidence supports a reduction in lung cancer-related mortality with the use of LDCT for lung cancer screening in high-risk populations (those over the age of 40 with a significant smoking exposure). However, there are limited data on harms and further trials are required to determine participant selection and optimal frequency and duration of screening, with potential for significant overdiagnosis of lung cancer. Trials are ongoing for lung cancer screening in non-smokers.

A novel GSN variant outside the G2 calcium-binding domain associated with Amyloidosis of the Finnish type.

Gelsolin (GSN) variants have been implicated in amyloidosis of the Finnish type. This case series reports a novel GSN:c.1477T>C,p.(Trp493Arg) variant in a family with ocular and systemic features consistent with Finnish Amyloidosis. Exome sequencing performed on affected individuals from two families manifesting cutis laxa and polymorphic corneal stromal opacities demonstrated the classic GSN:c.654G>A,p.Asp214Asn variant in single affected individual from one family, and a previously undocumented GSN:c.1477T>C variant in three affected first-degree relatives from a separate family. Immunohistochemical studies on corneal tissue from a proband with the c.1477T>C variant identified gelsolin protein within histologically defined corneal amyloid deposits. This study reports a novel association between the predicted pathogenic GSN:c.1477T>C variant and amyloidosis of the Finnish type, and is the first to provide functional evidence of a pathological GSN variant at a locus distant to the critical G2 calcium-binding region, resulting in the phenotype of amyloidosis of the Finnish type.

Genome-wide association analysis of 95 549 individuals identifies novel loci and genes influencing optic disc morphology.

Optic nerve head morphology is affected by several retinal diseases. We measured the vertical optic disc diameter (DD) of the UK Biobank (UKBB) cohort (N = 67 040) and performed the largest genome-wide association study (GWAS) of DD to date. We identified 81 loci (66 novel) for vertical DD. We then replicated the novel loci in International Glaucoma Genetic Consortium (IGGC, N = 22 504) and European Prospective Investigation into Cancer-Norfolk (N = 6005); in general the concordance in effect sizes was very high (correlation in effect size estimates 0.90): 44 of the 66 novel loci were significant at P < 0.05, with 19 remaining significant after Bonferroni correction. We identified another 26 novel loci in the meta-analysis of UKBB and IGGC data. Gene-based analyses identified an additional 57 genes. Human ocular tissue gene expression analysis showed that most of the identified genes are enriched in optic nerve head tissue. Some of the identified loci exhibited pleiotropic effects with vertical cup-to-disc ratio, intraocular pressure, glaucoma and myopia. These results can enhance our understanding of the genetics of optic disc morphology and shed light on the genetic findings for other ophthalmic disorders such as glaucoma and other optic nerve diseases.

Corneal Stiffness Parameters Are Predictive of Structural and Functional Progression in Glaucoma Suspect Eyes.

PURPOSE: To investigate corneal stiffness parameters (SPs) as predictors of future progression risk in glaucoma suspect eyes. DESIGN: Prospective, longitudinal study. PARTICIPANTS: Three hundred seventy-one eyes from 228 primary open-angle glaucoma suspects, based on optic disc appearance, with normal baseline Humphrey Visual Field (HVF; Carl Zeiss Meditec) results. METHODS: Baseline corneal SPs were measured using Corvis ST (Oculus Optikgeräte GmbH). Participants were followed up every 6 months with clinical examination, HVF testing, and OCT. The baseline SP at first applanation (SP-A1) and highest concavity predicted the prospective outcome measures. MAIN OUTCOME MEASURES: Structural progression was measured by the OCT rate of thinning of the retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GCIPL). Functional progression was assessed by permutation analysis of pointwise linear regression criteria on HVF testing. RESULTS: Stiffness parameters correlated positively with central corneal thickness (CCT), which was adjusted for in all analyses. A higher SP-A1, suggestive of a stiffer cornea, was associated with a faster rate of RNFL thinning (P < 0.001), synergistic with thinner CCT (P = 0.004) over a mean follow-up of 4.2 years. Eyes with higher SP-A1 and thinner CCT (thin and stiff corneas) showed accelerated RNFL thinning by 0.72 µm/year relative to eyes with lower SP-A1 and thicker CCT (95% confidence interval [CI], 0.17-1.28; P = 0.011) and were at 2.9-fold higher likelihood of fast RNFL progression of more than 1 µm/year (95% CI, 1.4-6.1; P = 0.006). Consistent results also were observed with GCIPL thinning. Furthermore, a higher SP-A1 was associated with a greater risk of visual field progression (P = 0.002), synergistic with thinner CCT (P = 0.010). Eyes with higher SP-A1 and thinner CCT were at 3.7-fold greater risk of visual field progression relative to eyes with thicker CCT and lower SP-A1 (95% CI, 1.3-10.5; P = 0.014). CONCLUSIONS: Glaucoma suspect eyes with higher corneal SPs and lower CCT, suggestive of thin and stiff corneas, are at greater risk of progression. Corneal SPs seem to act synergistically with CCT as risk factors for glaucoma progression.

Cardiovascular Disease Predicts Structural and Functional Progression in Early Glaucoma.

PURPOSE: To investigate the association between cardiovascular disease and baseline structural defects and disease progression in glaucoma. DESIGN: Prospective, longitudinal study of preperimetric and perimetric glaucoma. PARTICIPANTS: Two thousand six hundred twenty-eight eyes from 1314 participants recruited to the Progression Risk of Glaucoma: Relevant SNPs with Significant Association (PROGRESSA) study were evaluated for baseline and longitudinal structural thinning using spectral-domain OCT and for visual field progression on Humphrey visual field (HVF) assessment. METHODS: Patients were classified as either predominantly macula ganglion cell-inner plexiform layer (mGCIPL), predominantly peripapillary retinal nerve fiber layer (pRNFL), or both mGCIPL and pRNFL structural change at enrollment, and then evaluated for longitudinal OCT or HVF progression. Cardiovascular disease and medication characteristics of the participants were compared with a reference group of stable patients. MAIN OUTCOME MEASURES: OCT and HVF baseline status and longitudinal progression. RESULTS: After accounting for age and cardiovascular characteristics, patients with predominantly mGCIPL thinning at baseline showed a higher prevalence of hypertension (odds ratio [OR], 2.70; 95% confidence interval [CI], 1.66-4.41; P < 0.001), antihypertensive use (OR, 2.03; 95% CI, 1.20-3.46; P = 0.008), and statin use (OR, 1.98; 95% CI, 1.07-3.66; P = 0.029) than reference patients. Patients with predominantly pRNFL thinning exhibited a comparable prevalence of cardiovascular disease or medication with reference patients. Review of longitudinal OCT and HVF data (mean follow-up, 5.34 ± 1.29 years) showed that hypertension was associated with an increased risk of both OCT (OR, 1.79; 95% CI, 1.17-2.75; P = 0.006) and HVF progression (OR, 1.92; 95% CI, 1.18-3.15; P = 0.013). A 1-standard deviation (approximately 21 mmHg) increase in systolic blood pressure at baseline was associated with a greater risk of OCT progression (OR, 1.27; 95% CI, 1.01-1.63; P = 0.041) and HVF progression (OR, 1.32; 95% CI, 1.01-1.73; P = 0.043). The association between systolic blood pressure and structural progression was comparable to that observed between intraocular pressure and structural progression (OR, 1.30; 95% CI, 1.01-1.67; P = 0.039). CONCLUSIONS: Cardiovascular disease is an important risk factor for glaucoma progression.

Lung cancer screening implementation: Complexities and priorities.

Lung cancer is the number one cause of cancer death worldwide. The benefits of lung cancer screening to reduce mortality and detect early-stage disease are no longer in any doubt based on the results of two landmark trials using LDCT. Lung cancer screening has been implemented in the US and South Korea and is under consideration by other communities. Successful translation of demonstrated research outcomes into the routine clinical setting requires careful implementation and co-ordinated input from multiple stakeholders. Implementation aspects may be specific to different healthcare settings. Important knowledge gaps remain, which must be addressed in order to optimize screening benefits and minimize screening harms. Lung cancer screening differs from all other cancer screening programmes as lung cancer risk is driven by smoking, a highly stigmatized behaviour. Stigma, along with other factors, can impact smokers' engagement with screening, meaning that smokers are generally 'hard to reach'. This review considers critical points along the patient journey. The first steps include selecting a risk threshold at which to screen, successfully engaging the target population and maximizing screening uptake. We review barriers to smoker engagement in lung and other cancer screening programmes. Recruitment strategies used in trials and real-world (clinical) programmes and associated screening uptake are reviewed. To aid cross-study comparisons, we propose a standardized nomenclature for recording and calculating recruitment outcomes. Once participants have engaged with the screening programme, we discuss programme components that are critical to maximize net benefit. A whole-of-programme approach is required including a standardized and multidisciplinary approach to pulmonary nodule management, incorporating probabilistic nodule risk assessment and longitudinal volumetric analysis, to reduce unnecessary downstream investigations and surgery; the integration of smoking cessation; and identification and intervention for other tobacco related diseases, such as coronary artery calcification and chronic obstructive pulmonary disease. National support, integrated with tobacco control programmes, and with appropriate funding, accreditation, data collection, quality assurance and reporting mechanisms will enhance lung cancer screening programme success and reduce the risks associated with opportunistic, ad hoc screening. Finally, implementation research must play a greater role in informing policy change about targeted LDCT screening programmes.

Electronic cigarettes: A position statement from the Thoracic Society of Australia and New Zealand.

The TSANZ develops position statements where insufficient data exist to write formal clinical guidelines. In 2018, the TSANZ addressed the question of potential benefits and health impacts of electronic cigarettes (EC). The working party included groups focused on health impacts, smoking cessation, youth issues and priority populations. The 2018 report on the Public Health Consequences of E-Cigarettes from the United States NASEM was accepted as reflective of evidence to mid-2017. A search for papers subsequently published in peer-reviewed journals was conducted in August 2018. A small number of robust and important papers published until March 2019 were also identified and included. Groups identified studies that extended, modified or contradicted the NASEM report. A total of 3793 papers were identified and reviewed, with summaries and draft position statements developed and presented to TSANZ membership in April 2019. After feedback from members and external reviewers, a collection of position statements was finalized in December 2019. EC have adverse lung effects and harmful effects of long-term use are unknown. EC are unsuitable consumer products for recreational use, part-substitution for smoking or long-term exclusive use by former smokers. Smokers who require support to quit smoking should be directed towards approved medication in conjunction with behavioural support as having the strongest evidence for efficacy and safety. No specific EC product can be recommended as effective and safe for smoking cessation. Smoking cessation claims in relation to EC should be assessed by established regulators.

Macular Ganglion Cell-Inner Plexiform Layer Loss Precedes Peripapillary Retinal Nerve Fiber Layer Loss in Glaucoma with Lower Intraocular Pressure.

PURPOSE: To investigate which clinical measures influence whether an individual demonstrates earliest glaucomatous structural progression on peripapillary retinal nerve fiber layer (pRNFL) or macular ganglion cell-inner plexiform layer (mGCIPL). DESIGN: Prospective, longitudinal cohort study. PARTICIPANTS: Two hundred seventy-one eyes from 207 individuals with statistically significant evidence of glaucomatous progression on OCT Guided Progression Analysis (GPA) software were drawn from a total of 1271 eyes from 686 individuals categorized as glaucoma suspect or having early manifest glaucoma undergoing glaucoma surveillance. METHODS: Individuals demonstrating earliest evidence of longitudinal progression on mGCIPL GPA event analysis were compared with individuals demonstrating evidence of earliest longitudinal progression on pRNFL GPA event analysis. MAIN OUTCOME MEASURES: Correlation of OCT event change analysis with intraocular pressure (IOP), clinical variables, and baseline thickness of the pRNFL and mGCIPL. RESULTS: Intraocular pressure, baseline pRNFL thickness, baseline mGCIPL thickness, and systemic hypertension were associated with location of first progression. Eyes demonstrating earliest longitudinal progression on mGCIPL had significantly lower maximum-recorded pretreatment IOP (mean difference, 3.90 mmHg; 95% confidence interval [CI], 2.37-5.43 mmHg; P < 0.001). The interval between progression on pRNFL and progression on mGCIPL increased by 12.4 months for every 5-mmHg increase in IOP (95% CI, 10.32-15.72 months). Eyes demonstrating earliest longitudinal progression on mGCIPL showed significantly lower baseline average pRNFL thickness than eyes progressing on pRNFL first (mean difference, 7.07 µm; 95% CI, 4.38-9.77 µm; P < 0.001). Eyes progressing first on mGCIPL parameters were 3.03 times more likely to demonstrate a new paracentral field defect than eyes progressing first on pRNFL parameters (odds ratio, 3.03; 95% CI, 1.26-7.28; P = 0.01). CONCLUSIONS: Clinical features, particularly pretreatment IOP, influence whether structural glaucoma progression is detected earlier with mGCIPL or pRNFL imaging. These data support the usefulness of mGCIPL imaging in addition to pRNFL analysis for detection of glaucoma progression, particularly in patients with normal IOP.