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Considerable progress continues to be made with regards to the value and use of disease associated polygenic scores (PGS). PGS aim to capture a person’s genetic liability to a condition, disease, or a trait, combining information across many risk variants and incorporating their effect sizes. They are already available for clinicians and consumers to order in Australasia. However, debate is ongoing over the readiness of this information for integration into clinical practice and population health. This position statement provides the viewpoint of the Human Genetics Society of Australasia (HGSA) regarding the clinical application of disease-associated PGS in both individual patients and population health. The statement details how PGS are calculated, highlights their breadth of possible application, and examines their current challenges and limitations. We consider fundamental lessons from Mendelian genetics and their continuing relevance to PGS, while also acknowledging the distinct elements of PGS. Use of PGS in practice should be evidence based, and the evidence for the associated benefit, while rapidly emerging, remains limited. Given that clinicians and consumers can already order PGS, their current limitations and key issues warrant consideration. PGS can be developed for most complex conditions and traits and can be used across multiple clinical settings and for population health. The HGSA’s view is that further evaluation, including regulatory, implementation and health system evaluation are required before PGS can be routinely implemented in the Australasian healthcare system.

Genetic referral for Lynch syndrome (LS) exemplifies complex clinical pathways. Identifying target behaviours (TBs) for change and associated barriers requires structured group consultation activities with busy clinicians – consolidating implementation activities whilst retaining rigour is crucial. This study aimed to: i) use process mapping to gain in-depth understandings of site-specific LS testing and referral practices in Australian hospitals and support identification of TBs for change, ii) explore if barriers to identified TBs could be identified through process mapping focus-group data, and iii) demonstrate pandemic-induced transition from in-person to virtual group interactive process mapping methods. LS clinical stakeholders attended interactive in-person or virtual focus groups to develop site-specific “process maps” visually representing referral pathways. Content analysis of transcriptions informed site-specific process maps, then clinical audit data was compared to highlight TBs for change. TBs were reviewed in follow-up focus groups. Secondary thematic analysis explored barriers to identified TBs, coded against the Theoretical Domains Framework (TDF). The transition from in-person to pandemic-induced virtual group interactive process mapping methods was documented. Process mapping highlighted six key areas of clinical practice variation across sites and site-specific TBs for change were identified. Key barriers to identified TBs emerged, categorised to seven TDF domains. Process mapping revealed variations in clinical practices surrounding LS referral between sites. Incorporating qualitative perspectives enhances process mapping by facilitating identification of TBs for change and barriers, providing a pathway to developing targeted interventions. Virtual process mapping activities produced detailed data and enabled comprehensive map development.

BackgroundWhile many high-income countries including Australia have successfully implemented a range of tobacco control policies, smoking remains the leading preventable cause of cancer death in Australia. We have projected Australian mortality rates for cancer types, which have been shown to have an established relationship with cigarette smoking and estimated numbers of cancer deaths attributable to smoking to 2044.MethodsCancer types were grouped according to the proportion of cases currently caused by smoking: 8%–30% and >30%. For each group, an age–period– cohort model or generalised linear model with cigarette smoking exposure as a covariate was selected based on the model fit statistics and validation using observed data. The smoking-attributable fraction (SAF) was calculated for each smoking-related cancer using Australian smoking prevalence data and published relative risks.ResultsDespite the decreasing mortality rates projected for the period 2015–2019 to 2040–2044 for both men and women, the overall number of smoking-related cancer deaths is estimated to increase by 28.7% for men and 35.8% for women: from 138 707 (77 839 men and 60 868 women) in 2015–2019 to 182 819 (100 153 men and 82 666 women) in 2040–2044. Over the period 2020–2044, there will be 254 583 cancer deaths (173 943 men and 80 640 women) directly attributable to smoking, with lung, larynx, oesophagus and oral (comprising lip, oral cavity and pharynx) cancers having the largest SAFs.InterpretationCigarette smoking will cause over 250 000 cancer deaths in Australia from 2020 to 2044. Continued efforts in tobacco control remain a public health priority, even in countries where smoking prevalence has substantially declined.

Previous studies suggest that polygenic risk scores (PRSs) may improve melanoma risk stratification. However, there has been limited independent validation of PRS-based risk prediction, particularly assessment of calibration (comparing predicted to observed risks).To evaluate PRS-based melanoma risk prediction in prospective UK and Australian cohorts with European ancestry.We analysed invasive melanoma incidence in the UK Biobank (UKB; n = 395 647, 1651 cases) and a case-cohort nested within the Melbourne Collaborative Cohort Study (MCCS, Australia; n = 4765, 303 cases). Three PRSs were evaluated: 68 single-nucleotide polymorphisms (SNPs) at 54 loci from a 2020 meta-analysis (PRS68), 50 SNPs significant in the 2020 meta-analysis excluding UKB (PRS50) and 45 SNPs at 21 loci known in 2018 (PRS45). Ten-year melanoma risks were calculated from population-level cancer registry data by age group and sex, with and without PRS adjustment.Predicted absolute melanoma risks based on age and sex alone underestimated melanoma incidence in the UKB [ratio of expected/observed cases: E/O = 0·65, 95% confidence interval (CI) 0·62-0·68] and MCCS (E/O = 0·63, 95% CI 0·56-0·72). For UKB, calibration was improved by PRS adjustment, with PRS50-adjusted risks E/O = 0·91, 95% CI 0·87-0·95. The discriminative ability for PRS68- and PRS50-adjusted absolute risks was higher than for risks based on age and sex alone (Δ area under the curve 0·07-0·10, P 0·0001), and higher than for PRS45-adjusted risks (Δ area under the curve 0·02-0·04, P 0·001).A PRS derived from a larger, more diverse meta-analysis improves risk prediction compared with an earlier PRS, and might help tailor melanoma prevention and early detection strategies to different risk levels. Recalibration of absolute risks may be necessary for application to specific populations.

BACKGROUND: The early COVID-19 literature suggested that people with cancer may be more likely to be infected with SARS-CoV-2 or develop COVID-19 than people without cancer, due to increased health services contact and/or immunocompromise. While some studies were criticised due to small patient numbers and methodological limitations, they created or reinforced concerns of clinicians and people with cancer. These risks are also important in COVID-19 vaccine prioritisation decisions. We performed a systematic review to critically assess and summarise the early literature. METHODS AND FINDINGS: We conducted a systematic search of Medline/Embase/BioRxiv/MedRxiv/SSRN databases including peer-reviewed journal articles, letters/commentaries, and non-peer-reviewed pre-print articles for 1 January-1 July 2020. The primary endpoints were diagnosis of COVID-19 and positive SARS-CoV-2 test. We assessed risk of bias using a tool adapted from the Newcastle-Ottawa Scale. Twelve studies were included in the quantitative synthesis. All four studies of COVID-19 incidence (including 24,181,727 individuals, 125,649 with pre-existing cancer) reported that people with cancer had higher COVID-19 incidence rates. Eight studies reported SARS-CoV-2 test positivity for > 472,000 individuals, 48,370 with pre-existing cancer. Seven of these studies comparing people with any and without cancer, were pooled using random effects [pooled odds ratio 0.91, 95 %CI: 0.57-1.47; unadjusted for age, sex, or comorbidities]. Two studies suggested people with active or haematological cancer had lower risk of a positive test. All 12 studies had high risk of bias; none included universal or random COVID-19/SARS-CoV-2 testing. CONCLUSIONS: The early literature on susceptibility to SARS-CoV-2/COVID-19 for people with cancer is characterised by pervasive biases and limited data. To provide high-quality evidence to inform decision-making, studies of risk of SARS-CoV-2/COVID-19 for people with cancer should control for other potential modifiers of infection risk, including age, sex, comorbidities, exposure to the virus, protective measures taken, and vaccination, in addition to stratifying analyses by cancer type, stage at diagnosis, and treatment received.

Objective: Afghanistan is one of the countries with the highest prevalence of spousal violence (56%) and a low prevalence of contraceptive use (23%), yet there is no study assessing how spousal violence is related to contraceptive use, and what methods are most used by women. Therefore, this study examined the association between the number of types of spousal violence and contraceptive use. Method: Using data from 18,985 Afghan married women, aged 15 to 49, who responded to the 2015 Afghanistan Demographic and Health Survey, the current contraceptive method was grouped into five categories: male-involved methods, pills, injectables, long-acting reversible contraception, female sterilization, and Lactation Amenorrhea Method. The number of types of spousal violence in the past 12 months was categorized as none, one type, or two or more types, based on women’s experiences with verbal, physical, and sexual violence. For analysis, binary and multinomial logistic regression were used. Results: After adjusting for the covariates, the experience of any spousal violence was associated with contraception use (adjusted odds ratio (aOR) = 1.93, 95% CI: 1.64–2.27, p = 0.0001). Among those using contraception, experiencing two or three types of spousal violence was associated with using pills (adjusted risk ratio (aRRR) = 2.12, 95% CI: 1.63–2.77, p = 0.0001), injections (aRRR = 1.75, 95% CI: 1.26–2.41, p = 0.001), and LAM (aRRR = 3.27, 95% CI: 2.05–5.20, p = 0.0001), compared to male-involved methods. Conclusions: The findings of this study may inform policymakers and program implementers in designing interventions to address the pervasive problem of violence against women, and make pills and injectables more accessible to Afghan women, since these methods are under women’s control and more often used in Afghanistan.

ObjectivesTo determine how gene expression profiles in osteoarthritis joint tissues relate to patient phenotypes and whether molecular subtypes can be reproducibly captured by a molecular classification algorithm.MethodsWe analysed RNA sequencing data from cartilage and synovium in 113 osteoarthritis patients, applying unsupervised clustering and Multi-Omics Factor Analysis to characterise transcriptional profiles. We tested the association of the molecularly defined patient subgroups with clinical characteristics from electronic health records.ResultsWe detected two patient subgroups in low-grade cartilage (showing no/minimal degeneration, cartilage normal/softening only), with differences associated with inflammation, extracellular matrix-related and cell adhesion pathways. The high-inflammation subgroup was associated with female sex (OR 4.12, p=0.0024) and prescription of proton pump inhibitors (OR 4.21, p=0.0040). We identified two independent patient subgroupings in osteoarthritis synovium: one related to inflammation and the other to extracellular matrix and cell adhesion processes. A seven-gene classifier including MMP13, APOD, MMP2, MMP1, CYTL1, IL6 and C15orf48 recapitulated the main axis of molecular heterogeneity in low-grade knee osteoarthritis cartilage (correlation ρ=−0.88, p−10) and was reproducible in an independent patient cohort (ρ=−0.85, p−10).ConclusionsThese data support the reproducible stratification of osteoarthritis patients by molecular subtype and the exploration of new avenues for tailored treatments.

Background While many past studies have constructed projections of future lung cancer rates, little is known about their consistency with the corresponding observed data for the time period covered by the projections. The aim of this study was to assess the agreement between previously published lung cancer incidence and/or mortality rate projections and observed rates. Methods Published studies were included in the current study if they projected future lung cancer rates for at least 10 years beyond the period for which rates were used to obtain the projections, and if more recent observed rates for comparison covered a minimum of 10 years from the beginning of the projection period. Projected lung cancer incidence and/or mortality rates from these included studies were extracted from the publications. Observed rates were obtained from cancer registries or the World Health Organization's Mortality Database. Agreement between projected and observed rates was assessed and the relative difference (RD) for each projected rate was calculated as the percentage difference between the projected and observed rates. Results A total of 59 projections reported in 14 studies were included. Nine studies provided projections for 20 years or more. RDs were higher for those projections in which the lung cancer rates peaked during the projection period, and RDs increased substantially with the length of the projection period. When lung cancer rates peaked during the projection period, methods incorporating smoking data were generally more successful at predicting the trend reversal than those which did not incorporate smoking data. Mean RDs for 15-year projections comparing methods with or without smoking data were 12.7% versus 48.0% for males and 8.2% versus 42.3% for females. Conclusions The agreement between projected and observed lung cancer rates is dependent on the trends in the observed rates and characteristics of the population, particularly trends in smoking.

Rationale: Household air pollution and secondhand tobacco smoke are known carcinogens for lung cancer, but large-scale estimates of the relationship with lung cancer mortality are lacking. Objectives: Using the large-scale cohort China Kadoorie Biobank, we prospectively investigated associations between these two risk factors and lung cancer death among never-smokers. Methods: The Biobank recruited 512,715 adults aged 30–79 years from 10 regions in China during 2004–2008. Self-reported never-smoking participants were followed up to December 31, 2016, with linkage to mortality data. Total duration of exposure to household air pollution was calculated from self-reported domestic solid fuel use. Exposure to secondhand tobacco smoke was ascertained using exposure at home and/or other places. Hazard ratios and 95% confidence intervals for associations between these two exposures and lung cancer death were estimated using Cox regression, adjusting for key confounders. Measurements and Main Results: There were 979 lung cancer deaths among 323,794 never-smoking participants without a previous cancer diagnosis during 10.2 years of follow-up. There was a log-linear positive association between exposure to household air pollution and lung cancer death, with a 4% increased risk per 5-year increment of exposure (hazard ratio = 1.04; 95% confidence interval = 1.01–1.06; P trend = 0.0034), and participants with 40.1–50.0 years of exposure had the highest risk compared with the never-exposed (hazard ratio = 1.53; 95% confidence interval = 1.13–2.07). The association was largely consistent across various subgroups. No significant association was found between secondhand smoke and lung cancer death. Conclusions: This cohort study provides new prospective evidence suggesting that domestic solid fuel use is associated with lung cancer death among never-smokers.

Purpose To determine pathways to endometrial or ovarian cancer diagnosis by comparing health service utilization between cancer cases and matched cancer-free controls, using linked health records. Methods From cancer registry records, we identified 238 incident endometrial and 167 ovarian cancer cases diagnosed during 2006–2013 in the Australian 45 and Up Study cohort (142,973 female participants). Each case was matched to four cancer-free controls on birthdate, sex, place of residence, smoking status, and body mass index. The use of relevant health services during the 13–18-, 7–12-, 0–6-, and 0–1-months pre-diagnosis for cases and the corresponding dates for their matched controls was determined through linkage with subsidized medical services and hospital records. Results Healthcare utilization diverged between women with cancer and controls in the 0–6-months, particularly 0–1 months, pre-diagnosis. In the 0–1 months, 74.8% of endometrial and 50.3% of ovarian cases visited a gynecologist/gynecological oncologist, 11.3% and 59.3% had a CA125 test, 5.5% and 48.5% an abdominal pelvic CT scan, and 34.5% and 30.5% a transvaginal pelvic ultrasound, respectively (versus ≤ 1% of matched controls). Moreover, 25.1% of ovarian cancer cases visited an emergency department in the 0–1-months pre-diagnosis (versus 1.3% of matched controls), and GP visits were significantly more common for cases than controls in this period. Conclusion Most women with endometrial or ovarian cancer accessed recommended specialists and tests in the 0–1-months pre-diagnosis, but a high proportion of women with ovarian cancer visited an emergency department. This reinforces the importance of timely specialist referral.

Objective A previous Australian study compared the observed numbers of cancer cases and deaths in 2007 with the expected numbers based on 1987 rates. This study examines the impact of cancer rate changes over the 20-year period 1996–2015, for people aged under 75 years. Results The overall age-standardised cancer incidence rate increased from 350.7 in 1995 to 364.4 per 100,000 in 2015. Over the period 1996–2015, there were 29,226 (2.0%) more cases (males: 5940, 0.7%; females: 23,286, 3.7%) than expected numbers based on 1995 rates. Smaller numbers of cases were observed compared to those expected for cancers of the lung for males and colorectum, and cancers with unknown primary. Larger numbers of cases were observed compared to those expected for cancers of the prostate, thyroid and female breast. The overall age-standardised cancer mortality rate decreased from 125.6 in 1995 to 84.3 per 100,000 in 2015. During 1996 to 2015 there were 106,903 (− 20.6%) fewer cancer deaths (males: − 69,007, − 22.6%; females: − 37,896, − 17.9%) than expected based on the 1995 mortality rates. Smaller numbers of deaths were observed compared to those expected for cancers of the lung, colorectum and female breast, and more cancer deaths were observed for liver cancer.

Understanding whether postpartum depressive (PPD) symptoms vary by pregnancy intention and use of fertility treatments has implications for reproductive health policies and practices.The first aim of this study was to determine whether PPD symptoms differ between women who had unintended pregnancies, women who conceived spontaneously and were unsure about their pregnancy intention, women who used fertility treatments to conceive, and women who conceived spontaneously and intentionally. The second aim was to determine whether PPD symptoms differed based on the fertility treatment used to conceive (fertility drugs only, medicated insemination, or assisted reproductive technology [ART]).Data from the Pregnancy Risk Assessment Monitoring System (2012-2019), a cross-sectional survey administered to women throughout the U.S. who have recently given birth, was used to carry out our aims.For the first aim (unweighted N = 243,677), compared to women who had spontaneous, intended pregnancies, women who had unintended pregnancies (OR: 1.32, 95% CI: 1.26-1.39, p 0.01) and those with spontaneous pregnancies who were unsure about their intention (OR: 1.30, 95% CI: 1.23-1.38, p 0.01) had higher odds of elevated PPD symptoms, adjusting for a range of covariates. Women who conceived with fertility treatments did not have higher odds of elevated PPD symptoms (OR: 0.97, 95% CI: 0.84-1.10, p = 0.61). For the second aim (unweighted N = 2,210), compared to those in the ART group, those who conceived using only fertility enhancing drugs had greater odds of developing elevated PPD symptoms (OR: 2.00, 95% CI: 1.24-3.24, p 0.01).These findings suggest that giving birth to an unintended pregnancy in the U.S. increases risk of elevated PPD symptoms. While overall women who conceive with the use of fertility treatments are not at increased risk of experiencing elevated PPD symptoms, there may be variability in risk based on the specific fertility treatments used.

Background: The benefits and harms of breast screening may be better balanced through a risk-stratified approach. We conducted a systematic review assessing the accuracy of questionnaire-based risk assessment tools for this purpose. Methods: Population: asymptomatic women aged ≥40 years; Intervention: questionnaire-based risk assessment tool (incorporating breast density and polygenic risk where available); Comparison: different tool applied to the same population; Primary outcome: breast cancer incidence; Scope: external validation studies identified from databases including Medline and Embase (period 1 January 2008–20 July 2021). We assessed calibration (goodness-of-fit) between expected and observed cancers and compared observed cancer rates by risk group. Risk of bias was assessed with PROBAST. Results: Of 5124 records, 13 were included examining 11 tools across 15 cohorts. The Gail tool was most represented (n = 11), followed by Tyrer-Cuzick (n = 5), BRCAPRO and iCARE-Lit (n = 3). No tool was consistently well-calibrated across multiple studies and breast density or polygenic risk scores did not improve calibration. Most tools identified a risk group with higher rates of observed cancers, but few tools identified lower-risk groups across different settings. All tools demonstrated a high risk of bias. Conclusion: Some risk tools can identify groups of women at higher or lower breast cancer risk, but this is highly dependent on the setting and population.

BACKGROUND: Long-term projections of cancer incidence and mortality estimate the future burden of cancer in a population, and can be of great use in informing the planning of health services and the management of resources. We aimed to estimate incidence and mortality rates and numbers of new cases and deaths up until 2044 for all cancers combined and for 21 individual cancer types in Australia. We also illustrate the potential effect of treatment delays due to the COVID-19 pandemic on future colorectal cancer mortality rates. METHODS: In this statistical modelling study, cancer incidence and mortality rates in Australia from 2020 to 2044 were projected based on data up to 2017 and 2019, respectively. Cigarette smoking exposure (1945-2019), participation rates in the breast cancer screening programme (1996-2019), and prostate-specific antigen testing rates (1994-2020) were included where relevant. The baseline projection model using an age-period-cohort model or generalised linear model for each cancer type was selected based on model fit statistics and validation with pre-COVID-19 observed data. To assess the impact of treatment delays during the COVID-19 pandemic on colorectal cancer mortality, we obtained data on incidence, survival, prevalence, and cancer treatment for colorectal cancer from different authorities. The relative risks of death due to system-caused treatment delays were derived from a published systematic review. Numbers of excess colorectal cancer deaths were estimated using the relative risk of death per week of treatment delay and different durations of delay under a number of hypothetical scenarios. FINDINGS: Projections indicate that in the absence of the COVID-19 pandemic effects, the age-standardised incidence rate for all cancers combined for males would decline over 2020-44, and for females the incidence rate would be relatively stable in Australia. The mortality rates for all cancers combined for both males and females are expected to continuously decline during 2020-44. The total number of new cases are projected to increase by 47·4% (95% uncertainty interval [UI] 35·2-61·3) for males, from 380 306 in 2015-19 to 560 744 (95% UI 514 244-613 356) in 2040-44, and by 54·4% (95% UI 40·2-70·5) for females, from 313 263 in 2015-19 to 483 527 (95% UI 439 069-534 090) in 2040-44. The number of cancer deaths are projected to increase by 36·4% (95% UI 15·3-63·9) for males, from 132 440 in 2015-19 to 180 663 (95% UI 152 719-217 126) in 2040-44, and by 36·6% (95% UI 15·8-64·1) for females, from 102 103 in 2015-19 to 139 482 (95% UI 118 186-167 527) in 2040-44, due to population ageing and growth. The example COVID-19 pandemic scenario of a 6-month health-care system disruption with 16-week treatment delays for colorectal cancer patients could result in 460 (95% UI 338-595) additional deaths and 437 (95% UI 314-570) deaths occurring earlier than expected in 2020-44. INTERPRETATION: These projections can inform health service planning for cancer care and treatment in Australia. Despite the continuous decline in cancer mortality rates, and the decline or plateau in incidence rates, our projections suggest an overall 51% increase in the number of new cancer cases and a 36% increase in the number of cancer deaths over the 25-year projection period. This means that continued efforts to increase screening uptake and to control risk factors, including smoking exposure, obesity, physical inactivity, alcohol use, and infections, must remain public health priorities. FUNDING: Partly funded by Cancer Council Australia.

Background Prostate cancer (PC) aetiology is unclear. PC risk was examined in relation to several factors in a large population-based prospective study. Methods Male participants were from Sax Institute’s 45 and Up Study (Australia) recruited between 2006 and 2009. Questionnaire and linked administrative health data from the Centre for Health Record Linkage and Services Australia were used to identify incident PC, healthcare utilisations, Prostate Specific Antigen (PSA) testing reimbursements and dispensing of metformin and benign prostatic hyperplasia (BPH) prescriptions. Multivariable Cox and Joint Cox regression analyses were used to examine associations by cancer spread, adjusting for various confounders. Results Of 107,706 eligible men, 4257 developed incident PC up to end 2013. Risk of PC diagnosis increased with: PC family history (versus no family history of cancer; HRadjusted = 1.36; 95% CI:1.21–1.52); father and brother(s) diagnosed with PC (versus cancer-free family history; HRadjusted = 2.20; 95% CI:1.61–2.99); severe lower-urinary-tract symptoms (versus mild; HRadjusted = 1.77; 95% CI:1.53–2.04) and vasectomy (versus none; HRadjusted = 1.08; 95% CI:1.00–1.16). PC risk decreased with dispensed prescriptions (versus none) for BPH (HRadjusted = 0.76; 95% CI:0.69–0.85) and metformin (HRadjusted = 0.57; 95% CI:0.48–0.68). Advanced PC risk increased with vasectomy (HRadjusted = 1.28; 95% CI:1.06–1.55) and being obese (versus normal weight; HRadjusted = 1.31; 95% CI:1.01–1.69). Conclusion Vasectomy and obesity are associated with an increased risk of advanced PC. The reduced risk of localised and advanced PC associated with BPH, and diabetes prescriptions warrants investigation.

Background Household air pollution (HAP) has been classified as a major risk factor for lung cancer (LC) among never-smokers, however, evidence is largely from case-control studies. Using the prospective cohort China Kadoorie Biobank (CKB), we investigated the association of HAP with LC death among never-smokers. Methods The CKB, a large-scale cohort study, recruited 512,715 adults aged 30–79 years from ten regions in China during 2004-2008. Self-reported never-smoking participants were followed up to 31/12/2016 with linkage to mortality data. Total duration of HAP exposure was calculated from self-reported solid fuel use in domestic cooking and slow-burning stoves in participants’ three most recent residences, and self-reported coal-smoky home in winter during their lifetime. Hazard ratios (HR) and 95% confidence intervals (CI) of LC death associated with HAP exposure were estimated using Cox regression, adjusting for key confounders including several demographic, environmental and lifestyle factors. Results There were 979 LC deaths among 323,794 never-smokers without prior cancer during a median follow-up of 10.2 years. There was a log-linear positive association between HAP exposure and LC death (p-trend=0.0034), with 4% increased risk per 5-year longer exposure (HR = 1.04; 95% CI 1.01-1.06); and participants with 40.1-50.0 years of exposure had the highest risk compared to the never-exposed (HR = 1.53; 95% CI 1.13-2.07). Conclusions This study provides new prospective evidence that HAP exposure is associated with LC death among Chinese never-smokers, and strengthens the previous evidence largely based on case-control studies. Key messages This study supports HAP as an important risk factor for LC development among never-smokers.

Background Globally, tobacco smoking remains the largest cause of premature death. The COVID-19 pandemic has forced nations to take unprecedented measures including ‘lockdowns’ that might impact tobacco smoking behaviour. We performed a systematic review and meta-analyses to assess smoking behaviour changes during the early phases of the COVID-19 pandemic. Methods We searched Medline/Embase/PsycINFO/BioRxiv/MedRxiv/SSRN databases (January-November 2020) for published and pre-print articles that reported specific smoking behaviour changes or intentions after the onset of the COVID-19 pandemic. We used random-effects models to pool prevalence ratios comparing the prevalence of smokers during and before the pandemic, and the prevalence of smoking behaviour changes. Results 33 studies were included in meta-analyses, with smoking data for ∼230,000 participants across 24 countries. The proportions of smokers during and before the pandemic were similar, with a pooled prevalence ratio 0.85 (95%CI:0.76-0.95). In studies limited to smokers, 27% (95%CI:21-32%) smoked more, 17% (95%CI:13-21%) smoked less, 54% (95%CI:47-61%) smoked the same and 5% (95%CI:2-9%) reported quitting smoking. Among all participants, 1% (95%CI:0-2%) started smoking during the pandemic. All studies were at high risk of bias due to use of non-representative samples, likely non-response bias, and utilisation of non-validated questions. Conclusions Smoking behaviour changes during the early phases of the COVID-19 pandemic were highly mixed. Meta-analyses indicated slightly lower overall smoking prevalence during the pandemic, but higher intensity among smokers. Key messages More recent and higher quality studies of smoking behaviour changes are required to measure the longer term impact of the COVID-19 pandemic.

Background To improve melanoma early detection, tools to predict personal risk based on genetic information (polygenic risk scores, PRS) have been developed, but require external validation. Methods We analysed invasive melanoma incidence in UK Biobank (UKB; n = 395,647; 1,651 cases) and the Melbourne Collaborative Cohort Study (MCCS, Australia; n = 4,765; 303 cases). Three PRS were evaluated: 68 genetic variants (SNPs) at 54 loci from a 2020 meta-analysis (PRS68); 50 SNPs significant in the 2020 meta-analysis excluding UKB (PRS50); 45 SNPs at 21 loci known pre-2020 (PRS45). 10-year melanoma risks were calculated from population-level cancer registry data by age group and sex, with and without PRS adjustment. Results All PRS were strongly associated with melanoma incidence, including after adjustment for age, sex, ethnicity, and ease of tanning. Predicted absolute melanoma risks based on age and sex alone underestimated melanoma incidence in UKB (ratio expected/observed cases E/O=0.65, 95% confidence interval 0.62-0.68) and MCCS (E/O=0.65, 0.57-0.73). For UKB, this was reduced by PRS-adjustment, e.g. PRS50-adjusted risks E/O=0.91 (0.87-0.95). Discriminative ability for PRS68- and PRS50-adjusted absolute risks was higher than for risks based on age and sex alone (deltaAUC 0.07-0.1, p Conclusions A PRS derived from a larger, more diverse meta-analysis improves melanoma risk prediction compared to an earlier PRS. Re-calibration of absolute risks may be necessary for application to specific populations. Key messages A genetic score can improve prediction of melanoma risk and might help tailor melanoma prevention and early detection strategies to different risk levels.

Background Lung cancer in never-smokers (LCINS), if considered as a distinct type, would rank as Australia’s eighth most deadly cancer. We investigated several demographic, lifestyle and health-related risk factors for LCINS in Australia. Methods Using the longitudinal 45 and Up Study cohort with 267,153 New South Wales (NSW) residents aged ≥45 years at recruitment (2006-2009), we quantified the relationship of 20 potential risk factors with LCINS. Self-reported never-smoking participants who were cancer-free at baseline were followed for incident lung cancer (LC), and adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox regression. The NSW Cancer, Lifestyle and Evaluation of Risk (CLEAR) Study, a case-control study including 10,781 NSW residents aged ≥18 years, was also used to examine 16 potential risk factors for LCINS. Adjusted odds ratios (OR) and 95% CI for LC were estimated using logistic regression. Results In the 45 and Up Study, there were 226 LC cases among 132,354 cancer-free never-smokers with a median follow-up of 5.41 years. In the CLEAR Study, there were 58 LCINS cases and 1316 cancer-free never-smoking controls. After adjusting for potential confounders, analyses of both datasets showed that Asian-born participants had a higher risk of LCINS than those born elsewhere: cohort HR = 2.83 (95% CI: 1.64-4.89) and case-control OR = 3.78 (95% CI: 1.19-12.05). Conclusions Our findings support the growing evidence that never-smokers born in Asia are at higher risk of developing LC than those born elsewhere. Key messages Region of birth could be considered when assessing potential LC risk among never-smokers.

Purpose Lung cancer (LC) in never-smoking individuals would rank as Australia’s eighth most deadly cancer, yet risk factors remain uncertain. We investigated demographic, lifestyle and health-related exposures for LC among never-smoking Australians. Methods Using the prospective 45 and Up Study with 267,153 New South Wales (NSW) residents aged ≥ 45 years at recruitment (2006–2009), we quantified the relationship of 20 potential exposures with LC among cancer-free participants at baseline who self-reported never smoking. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) for incident LC were estimated using Cox regression. The NSW Cancer, Lifestyle and Evaluation of Risk (CLEAR) Study, a case–control study including 10,781 NSW residents aged ≥ 18 years (2006–2014), was used to examine 16 potential LC exposures among cancer-free never-smoking participants. Adjusted odds ratios (OR) and 95% CI of LC were estimated using logistic regression. Results There were 226 LC cases among 132,354 cancer-free 45 and Up Study participants who reported never smoking, with a median follow-up of 5.41 years. The CLEAR Study had 58 LC cases and 1316 cancer-free controls who had never smoked. Analyses of both datasets showed that Asian-born participants had a higher risk of LC than those born elsewhere: cohort, adjusted HR = 2.83 (95% CI 1.64–4.89) and case–control, adjusted OR = 3.78 (1.19–12.05). No significant association with LC was found for other exposures. Conclusion Our findings support the growing evidence that never-smoking, Asian-born individuals are at higher risk of developing LC than those born elsewhere. Ethnicity could be considered when assessing potential LC risk among never-smoking individuals.

Translating evidence into complex health systems is an ongoing challenge. Building the capacity of healthcare workers in behavioral and implementation science methods may facilitate the use of evidence-based implementation approaches, leading to sustainable and effective translation. The aim was to describe the development, contents and evaluation of a training workshop aimed at upskilling hospital-embedded staff to deliver an evidence-based implementation approach. The Hide and Seek Project (HaSP) is a cluster randomized controlled trial testing two implementation approaches for improving hereditary cancer referral at eight Australian hospitals. Healthcare workers were recruited as “Implementation Leads” and trained via a one-day workshop—TRAining in evideNce-baSed ImpLementATion for hEalth (TRANSLATE). The purpose of TRANSLATE was to upskill Implementation Leads in the delivery of HaSP, as well as implementation science methods more broadly. Implementation Leads participated in semi-structured evaluation interviews, which were analyzed using inductive thematic analysis. Nine Implementation Leads from various professional backgrounds completed the training. Four key themes were identified: (i) training day reactions, (ii) learning, (iii) implementation barriers and facilitators, and (iv) building health system capacity for implementation. Participants reported high levels of satisfaction, and anticipated that the knowledge and skills may be useful in the future. We describe a novel training program focused on the delivery of evidence-based implementation within health systems. Guided by insights from this study, methods to deliver the training on a larger scale and across different contexts are being explored. The prolonged impact of TRANSLATE will be further evaluated at trial completion. Trial registration: ANZCTR, ACTRN12618001072202. Registered on June 27, 2018

Recognition of RNA by receptors of the innate immune system is regulated by various posttranslational modifications. Different single 2′-O-ribose (2′-O-) methylations have been shown to convert TLR7/TLR8 ligands into specific TLR8 ligands, so we investigated whether the position of 2′-O-methylation is crucial for its function. To this end, we designed different 2′-O-methylated RNA oligoribonucleotides (ORN), investigating their immune activity in various cell systems and analyzing degradation under RNase T2 treatment. We found that the 18S rRNA-derived TLR7/8 ligand, RNA63, was differentially digested as a result of 2′-O-methylation, leading to variations in TLR8 and TLR7 inhibition. The suitability of certain 2′-O-methylated RNA63 derivatives as TLR8 agonists was further demonstrated by the fact that other RNA sequences were only weak TLR8 agonists. We were thus able to identify specific 2′-O-methylated RNA derivatives as optimal TLR8 ligands.