Search

Objectives: To investigate self‐reported out‐of‐pocket health care expenses, both overall and by cost type, for a large population‐based sample of Australians, by cancer status and socio‐demographic and medical characteristics. Study design: Cross‐sectional study. Setting, participants: New South Wales residents participating in the 45 and Up Study (recruited aged 45 years or older during 2005–2009) who completed the 2020 follow‐up questionnaire; survey responses linked with New South Wales Cancer Registry data. Main outcome measures: Proportions of respondents who reported that out‐of‐pocket health care expenses during the preceding twelve months exceeded $1000 or $10 000; adjusted odds ratios (aORs) for associations with socio‐demographic and medical characteristics. Results: Of the 267 357 recruited 45 and Up Study participants, 45 061 completed the 2020 survey (response rate, 53%); 42.7% (95% confidence interval [CI], 42.2–43.1%) reported that overall out‐of‐pocket health care expenses during the previous year exceeded $1000, including 55.4% (52.1–58.7%) of participants diagnosed in the preceding two years and 44.9% (43.7–46.1%) of participants diagnosed with cancer more than two years ago. After adjustment for socio‐demographic factors, out‐of‐pocket expenses greater than $1000 were more likely to be reported by participants with cancer than by those without cancer (diagnosis in past two years: aOR, 2.06 [95% CI, 1.77–2.40]; diagnosis more than two years ago: aOR, 1.22 [95% CI, 1.15–1.29]). The odds of out‐of‐pocket expenses exceeding $1000 increased with area‐based socio‐economic advantage and household income, and were higher for people with private health insurance (v people with Medicare coverage only: aOR, 1.64; 95% CI, 1.53–1.75). Out‐of‐pocket expenses exceeding $10 000 were also more likely for participants diagnosed with cancer during the past two years (v no cancer: aOR, 3.30; 95% CI, 2.56–4.26). Conclusions: People diagnosed with cancer during the past two years were much more likely than people without cancer to report twelve‐month out‐of‐pocket health care expenses that exceeded $1000. Out‐of‐pocket expenses for people with cancer can exacerbate financial strain at a time of vulnerability, and affect health care equity because some people cannot pay for all available treatments. [ABSTRACT FROM AUTHOR]

Objectives: To examine changes in multiple myeloma incidence and mortality rates during 1982–2018, and to estimate its incidence, mortality, and prevalence for 2019–2043. Study design: Population‐based statistical modelling study; analysis of and projections based on Australian Institute of Health and Welfare multiple myeloma incidence, mortality, and survival data. Setting: Australia, 1982–2018 (historical data) and projections to 2043. Main outcome measures: Changes in multiple myeloma incidence and mortality rates, 1982–2018, determined by joinpoint regression analysis (age‐standardised to 2021 Australian population); projection of rates to 2043 based on age–period–cohort models; estimated 5‐ and 30‐year prevalence of multiple myeloma (modified counting method). Results: The incidence of multiple myeloma increased during 1982–2018 (eg, annual percentage change [APC], 2006–2018, 1.9%; 95% confidence interval [CI], 1.7–2.2%), but the mortality rate declined during 1990–2018 (APC, –0.4%; 95% CI, –0.5% to –0.2%). The age‐standardised incidence rate was projected to increase by 14.9% during 2018–2043, from 8.7 in 2018 to 10.0 (95% CI, 9.4–10.7) new cases per 100 000 population in 2043; the mortality rate was projected to decline by 27.5%, from 4.0 to 2.9 (95% CI, 2.6–3.3) deaths per 100 000 population. The annual number of people newly diagnosed with multiple myeloma was estimated to increase by 89.2%, from 2120 in 2018 to 4012 in 2043; the number of deaths from multiple myeloma was projected to increase by 31.7%, from 979 to 1289. The number of people living with multiple myeloma up to 30 years after initial diagnosis was projected to increase by 163%, from 10 288 in 2018 to 27 093 in 2043, including 13 019 people (48.1%) diagnosed during the preceding five years. Conclusion: Although the decline in the mortality rate was projected to continue, the projected increases in the incidence and prevalence of multiple myeloma in Australia over the next 25 years indicate that investment in prevention and early detection research, and planning for prolonged treatment and care, are needed. [ABSTRACT FROM AUTHOR]

Background: Symptoms of mental distress increased sharply during the COVID-19 pandemic, especially among older adolescents and young adults. Mental health distress may make it more challenging for young people to seek other needed health care, including contraception. This study explored the association of symptoms of depression, anxiety, and stress with delays in getting a contraceptive method or prescription. Materials and Methods: Data from a supplementary study (May 15, 2020–March 20, 2023) to a cluster randomized trial in 29 sites in Texas and California were used. The diverse study sample included community college students assigned female at birth of ages 18–29 years (n = 1,665 with 7,023 observations over time). We measured the association of depression (CES-D [Center for Epidemiologic Studies Depression Scale]) or anxiety and stress (DASS-21 [Depression Anxiety Stress Scales]) symptoms with delayed contraceptive care-seeking with mixed-effects multivariable regression with random effects for individual and site. We controlled for age and sociodemographic factors important for access to care. Results: Over one-third of participants (35%) reported they delayed getting the contraceptive method they needed. Multivariable regression results showed increased odds of delayed contraceptive care among participants with symptoms of depression (adjusted odds ratio [aOR] 1.58, 95% confidence interval [CI] 1.27–1.96). Likewise, delays were associated with anxiety and stress symptoms (aOR 1.46, 95% CI 1.17–1.82). Adolescents were more likely to delay seeking contraception than young adults (aOR 1.32, 95% CI 1.07–1.63). Conclusions: Results showed a strong association between mental distress and delayed contraception. Interventions are needed to increase contraceptive access for young people delaying care, along with supportive mental health care services, including for adolescents who face elevated odds of delay. ClinicalTrials.gov Identifier:NCT03519685. [ABSTRACT FROM AUTHOR]

This is a protocol for a systematic review and meta‐analysis of research on mental health outcomes of abortion. Does abortion increase the risk of adverse mental health outcomes? That is the central question for this review. Our review aims to inform policy and practice by locating, critically appraising, and synthesizing empirical evidence on associations between abortion and subsequent mental health outcomes. Given the controversies surrounding this topic and the complex social, political, legal, and ideological contexts in which research and reviews on abortion are conducted, it is especially important to conduct this systematic review and meta‐analysis with comprehensive, rigorous, unbiased, and transparent methods. We will include a variety of study designs to enhance understanding of studies' methodological strengths and weaknesses and to identify potential explanations for conflicting results. We will follow open science principles, providing access to our methods, measures, and results, and making data available for re‐analysis. [ABSTRACT FROM AUTHOR]

While previous reviews found a positive association between pre‐existing cancer diagnosis and COVID‐19‐related death, most early studies did not distinguish long‐term cancer survivors from those recently diagnosed/treated, nor adjust for important confounders including age. We aimed to consolidate higher‐quality evidence on risk of COVID‐19‐related death for people with recent/active cancer (compared to people without) in the pre‐COVID‐19‐vaccination period. We searched the WHO COVID‐19 Global Research Database (20 December 2021), and Medline and Embase (10 May 2023). We included studies adjusting for age and sex, and providing details of cancer status. Risk‐of‐bias assessment was based on the Newcastle‐Ottawa Scale. Pooled adjusted odds or risk ratios (aORs, aRRs) or hazard ratios (aHRs) and 95% confidence intervals (95% CIs) were calculated using generic inverse‐variance random‐effects models. Random‐effects meta‐regressions were used to assess associations between effect estimates and time since cancer diagnosis/treatment. Of 23 773 unique title/abstract records, 39 studies were eligible for inclusion (2 low, 17 moderate, 20 high risk of bias). Risk of COVID‐19‐related death was higher for people with active or recently diagnosed/treated cancer (general population: aOR = 1.48, 95% CI: 1.36‐1.61, I2 = 0; people with COVID‐19: aOR = 1.58, 95% CI: 1.41‐1.77, I2 = 0.58; inpatients with COVID‐19: aOR = 1.66, 95% CI: 1.34‐2.06, I2 = 0.98). Risks were more elevated for lung (general population: aOR = 3.4, 95% CI: 2.4‐4.7) and hematological cancers (general population: aOR = 2.13, 95% CI: 1.68‐2.68, I2 = 0.43), and for metastatic cancers. Meta‐regression suggested risk of COVID‐19‐related death decreased with time since diagnosis/treatment, for example, for any/solid cancers, fitted aOR = 1.55 (95% CI: 1.37‐1.75) at 1 year and aOR = 0.98 (95% CI: 0.80‐1.20) at 5 years post‐cancer diagnosis/treatment. In conclusion, before COVID‐19‐vaccination, risk of COVID‐19‐related death was higher for people with recent cancer, with risk depending on cancer type and time since diagnosis/treatment. [ABSTRACT FROM AUTHOR]

Precision public health holds promise to improve disease prevention and health promotion strategies, allowing the right intervention to be delivered to the right population at the right time. Growing concerns underscore the potential for precision-based approaches to exacerbate health disparities by relying on biased data inputs and recapitulating existing access inequities. To achieve its full potential, precision public health must focus on addressing social and structural drivers of health and prominently incorporate equity-related concerns, particularly with respect to race and ethnicity. In this article, we discuss how an antiracism lens could be applied to reduce health disparities and health inequities through equity-informed research, implementation, and evaluation of precision public health interventions. (Am J Public Health. 2023;113(11):1210–1218. https://doi.org/10.2105/AJPH.2023.307386) [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The article discusses the broader implications of overturning Roe v Wade in June 2022, highlighting concerns beyond abortion statistics, such as maternal and infant mortality. Topics include the potential mental health repercussions of restrictive abortion policies, a study's findings on increased anxiety and depression symptoms in trigger-ban states post-Dobbs, and the importance of clinicians' awareness in states with abortion restrictions.

There is growing, but inconsistent evidence suggesting oestrogen may play a key role in lung cancer development, especially among never‐smoking women for whom lung cancer risk factors remain largely elusive. Using the China Kadoorie Biobank, a large‐scale prospective cohort with 302 510 women aged 30 to 79 years recruited from 10 regions in China during 2004 to 2008, we assessed the risk of lung cancer death among self‐reported never‐smoking women who were cancer‐free at baseline, in relation to age at menarche, age at menopause, time since menopause, prior use of oral contraceptives (OCP), number of livebirths, breastfeeding and age at first livebirth. Women were followed up to December 31, 2016 with linkage to mortality data. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox regression, adjusting for key confounders including several socio‐demographic, environmental and lifestyle factors. Among 287 408 never‐smoking women, 814 died from lung cancer with a median follow‐up of 10.3 years. Women who had used OCP within 15 years prior to baseline had a significantly higher hazard of lung cancer death compared with never‐users: HR = 1.85 (95% CI: 1.14‐3.00) and risk increased by 6% with each additional year of use: HR = 1.06 (1.01‐1.10). Among parous women, the hazard of lung cancer death increased by 13% with each single livebirth: HR = 1.13 (1.05‐1.23); and among post‐menopausal women, the risk increased by 2% with each year since menopause: HR = 1.02 (1.01‐1.04). These results suggest that reproductive factors which were proxies for lower endogenous oestrogen level, for example, longer duration of OCP use, could play a role in lung cancer development. [ABSTRACT FROM AUTHOR]

Introduction: There have been significant advancements in risk identification and treatment for ovarian cancer over the last decade. However, their impact on health services costs is unclear. This study estimated the direct health system costs (government perspective) for women diagnosed with ovarian cancer in Australia during 2006–2013, as a benchmark prior to opportunities for precision-medicine approaches to treatment, and for health care planning. Methods: Using cancer registry data, we identified 176 incident ovarian cancers (including fallopian tube and primary peritoneal cancer) in the Australian 45 and Up Study cohort. Each case was matched with four cancer-free controls on sex, age, geography, and smoking history. Costs were derived from linked health records on hospitalisations, subsidised prescription medicines and medical services to 2016. Excess costs for cancer cases were estimated for different phases of care relative to cancer diagnosis. Overall costs for prevalent ovarian cancers in Australia in 2013 were estimated based on 5-year prevalence statistics. Results: At diagnosis, 10% of women had localised disease, 15% regional spread and 70% distant metastasis (5% unknown). The mean excess cost per ovarian cancer case was $40,556 in the initial treatment phase (≤12 months post-diagnosis), $9,514 per annum in the continuing care phase and $49,208 in the terminal phase (up to 12 months before death). Hospital admissions accounted for the greatest proportion of costs during all phases (66%, 52% and 68% respectively). Excess costs were higher for patients diagnosed with distant metastatic disease, particularly during the continuing care phase ($13,814 versus $4,884 for localised/regional disease). The estimated overall direct health services cost of ovarian cancer in 2013 was AUD$99million (4,700 women nationally). Conclusion: The excess health system costs of ovarian cancer are substantial. Continued investment in ovarian cancer research, particularly prevention, early detection and more effective personalised treatments is necessary to reduce the burden of disease. [ABSTRACT FROM AUTHOR]

NTRK gene fusions are rare somatic mutations found across cancer types with promising targeted therapies emerging. Healthcare systems face significant challenges in integrating these treatments, with uncertainty in prevalence and optimal testing methods to identify eligible patients. We performed a systematic review of NTRK fusion prevalence to inform efficient diagnostic screening and scale of therapeutic uptake. We searched Medline, Embase and Cochrane databases on 31/03/2021. Inclusion criteria were studies reporting fusion rates in solid tumours, English language, post-2010 publication and minimum sample size. Critical appraisal was performed using a custom 11-item checklist. Rates were collated by cancer type and pooled if additional synthesis criteria were met. 160 studies were included, with estimates for 15 pan-cancer and 429 specific cancer types (63 paediatric). Adult pan-cancer estimates ranged 0.03–0.70%, with higher rates found in RNA-based assays. In common cancers, rates were consistently below 0.5%. Rare morphological subtypes, colorectal microsatellite instability, and driver mutation exclusion cancers had higher rates. Only 35.6% of extracted estimates used appropriate methods and sample size to identify NTRK fusions. NTRK fusion-positive cancers are rare and widely distributed across solid tumours. Small-scale, heterogeneous data confound prevalence prediction. Further large-scale, standardised genomic data are needed to characterise NTRK fusion epidemiology. [ABSTRACT FROM AUTHOR]

Simple Summary: Early detection of breast cancer in asymptomatic women through screening is an important strategy in reducing the burden of breast cancer. In current organized breast screening programs, age is the predominant risk factor. Breast cancer risk assessment tools are numerical models that can combine information on various risk factors to estimate the risk of being diagnosed with breast cancer within a certain time period. These tools could be used to offer risk-based screening. This systematic review assessed, using a variety of methods, how accurately breast cancer risk assessment tools can group women eligible for screening within a population, into risk groups, so that each group could potentially be offered a screening protocol with more benefits and less harms compared to current age-based screening. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer is the third most diagnosed cancer globally and the second leading cause of cancer death. We examined colon and rectal cancer treatment patterns in Australia. Methods: From cancer registry records, we identified 1,236 and 542 people with incident colon and rectal cancer, respectively, diagnosed during 2006-2013 in the 45 and Up Study cohort (267,357 participants). Cancer treatment and deaths were determined via linkage to routinely collected data, including hospital and medical services records. For colon cancer, we examined treatment categories of "surgery only", "surgery plus chemotherapy", "other treatment" (i.e. other combinations of surgery/chemotherapy/radiotherapy), "no record of cancer-related treatment, died"; and, for rectal cancer, "surgery only", "surgery plus chemotherapy and/or radiotherapy", "other treatment", and "no record of cancer-related treatment, died". We analysed survival, time to first treatment, and characteristics associated with treatment receipt using competing risks regression. Results: 86.4% and 86.5% of people with colon and rectal cancer, respectively, had a record of receiving any treatment ≤2 years post-diagnosis. Of those treated, 93.2% and 90.8% started treatment ≤2 months post-diagnosis, respectively. Characteristics significantly associated with treatment receipt were similar for colon and rectal cancer, with strongest associations for spread of disease and age at diagnosis (p<0.003). For colon cancer, the rate of "no record of cancer-related treatment, died" was higher for people with distant spread of disease (versus localised, subdistribution hazard ratio (SHR)=13.6, 95% confidence interval (CI):5.5-33.9), age ≥75 years (versus age 45-74, SHR=3.6, 95%CI:1.8-7.1), and visiting an emergency department ≤1 month pre-diagnosis (SHR=2.9, 95%CI:1.6-5.2). For rectal cancer, the rate of "surgery plus chemotherapy and/or radiotherapy" was higher for people with regional spread of disease (versus localised, SHR=5.2, 95%CI:3.6-7.7) and lower for people with poorer physical functioning (SHR=0.5, 95%CI:0.3-0.8) or no private health insurance (SHR=0.7, 95%CI:0.5-0.9). Conclusion: Before the COVID-19 pandemic, most people with colon or rectal cancer received treatment ≤2 months post-diagnosis, however, treatment patterns varied by spread of disease and age. This work can be used to inform future healthcare requirements, to estimate the impact of cancer control interventions to improve prevention and early diagnosis, and serve as a benchmark to assess treatment delays/disruptions during the pandemic. Future work should examine associations with clinical factors (e.g. performance status at diagnosis) and interdependencies between characteristics such as age, comorbidities, and emergency department visits. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A long standing challenge in biological and artificial intelligence is to understand how new knowledge can be constructed from known building blocks in a way that is amenable for computation by neuronal circuits. Here we focus on the task of storage and recall of structured knowledge in long-term memory. Specifically, we ask how recurrent neuronal networks can store and retrieve multiple knowledge structures. We model each structure as a set of binary relations between events and attributes (attributes may represent e.g., temporal order, spatial location, role in semantic structure), and map each structure to a distributed neuronal activity pattern using a vector symbolic architecture scheme.We then use associative memory plasticity rules to store the binarized patterns as fixed points in a recurrent network. By a combination of signal-to-noise analysis and numerical simulations, we demonstrate that our model allows for efficient storage of these knowledge structures, such that the memorized structures as well as their individual building blocks (e.g., events and attributes) can be subsequently retrieved from partial retrieving cues. We show that long-term memory of structured knowledge relies on a new principle of computation beyond the memory basins. Finally, we show that our model can be extended to store sequences of memories as single attractors. [ABSTRACT FROM AUTHOR]

Objectives: In response to the coronavirus 2019 (COVID-19) pandemic, a research project was developed with a cohort of 45 and Up Study participants to generate timely, relevant evidence to guide policy, practice and planning. This paper describes the research model, the cohort establishment and characteristics, and some findings. Methods: A subgroup of 45 and Up Study participants was invited to enrol in 45 and Up COVID Insights -- a series of five online surveys conducted during 2020-22. The model involved a close collaborative partnership with the New South Wales Ministry of Health and a panel of scientific advisers, an agile data collection methodology and rapid dissemination of findings. Frequent, iterative engagement with stakeholders provided a framework for identifying survey themes and questions and ensured wide dissemination of findings. Themes included healthcare use, attitudes toward and uptake of COVID-19 prevention measures, and the impact of the pandemic on mental health, loneliness, and lifestyle behaviours. Results: 45 and Up COVID Insights achieved strong stakeholder engagement through extensive consultation and rapid reporting of results. The project recruited a diverse cohort of 32 115 participants: median age 68 years (range: 56-100+); 8% from outer regional/remote areas; 12% from the most socioeconomically disadvantaged communities; and 9% from culturally and linguistically diverse backgrounds. The first four surveys found that the impact of the pandemic varied across populations and stages of the pandemic. Between February--April (survey 2) 2021, 10% reported missed healthcare in the past month because of the pandemic, rising to 26% by September--November 2021 (survey 4). Quality of life remained high (>90% good--excellent across the surveys). As the pandemic progressed, the proportion reporting worsened mental health as a result increased from 29% (July--December 2020, survey 1) to 46% (survey 4). In survey 2 (February--April 2021), 89% intended to get the COVID-19 vaccine, with 8% unsure. By late 2021, vaccination uptake was high, with 98% of respondents having received at least one vaccination. Conclusion: There is great value in harnessing a large longitudinal, well-described, and diverse cohort study to generate evidence in a changing context with evolving information needs. The collaborative model enhanced the value and relevance of the data to inform decisions. [ABSTRACT FROM AUTHOR]

Objective: Over the 15 years since the 45 and Up Study (the Study) was established, researchers have harnessed its capacity for enabling rigorous, comprehensive investigation of cancer causes, care, and outcomes. For the first time in Australia, the entire cancer-control continuum could be investigated by linking questionnaire data with cancer registry notifications, hospital records, outpatient medical services and prescription medications at scale. Here, we use lung cancer as a case study to demonstrate the Study's potential to improve cancer control. Method: Narrative description. Results: Between 2006-2013, approximately 1200 participants in the Study cohort who had no prior history of cancer were diagnosed with lung cancer, allowing the generation of novel, policy- and practice-relevant evidence for tobacco control, screening, and systems of care. The Study produced evidence on the continuing impact of smoking, including that 'light smoking' (1-5 cigarettes/day) is associated with nine times the risk of lung cancer compared to never-smoking; and that 54% of lung cancers could be avoided long-term if all Australians who smoked were to quit. The Study was used to validate a lung cancer screening risk prediction tool, correctly identifying 70% of the participants with a history of smoking who developed lung cancer within a 6-year period as 'high-risk'. Potential inequities in lung cancer care were identified using the Study cohort, including suboptimal levels of radiotherapy utilisation, below benchmark levels of systemic therapy for patients with metastatic disease, and high numbers of emergency department presentations prior to diagnosis. Participants with lung cancer reported poorer quality of life than those with almost any other cancer type, and about 50% reported severe physical functioning limitations. The Study also provided the infrastructure for the first comprehensive report on lung cancer health system costs. Lessons learnt: As a statewide, population-based cohort, the Study provides reliable estimates of cancer risk, health services utilisation, and personcentred outcomes that can inform policy and practice decision making; and has provided the backbone for localising policy-relevant insights from international experience. We have found that the direct involvement of clinicians and policy makers in research design, and engagement with community networks, can yield tractable, policy-relevant, and ultimately impactful scientific insights. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors have been approved in the USA for tumours exhibiting mismatch repair deficiency (dMMR), microsatellite instability (MSI), or high tumour mutational burden (TMB), with regulatory and reimbursement applications in multiple other countries underway. As the estimated budget impacts of future reimbursements depend on the size of the potential target population, we performed a scoping review and meta-analysis of the prevalence of these pan-tumour biomarkers in different cancers. We systematically searched Medline/Embase and included studies reporting the prevalence of dMMR/MSI/high TMB in solid tumours published 01/01/2018–31/01/2021. Meta-analyses were performed separately for the pan-cancer prevalence of each biomarker, and by cancer type and stage where possible. The searches identified 3890 papers, with 433 prevalence estimates for 32 different cancer types from 201 studies included in meta-analyses. The pooled overall prevalence of dMMR, MSI and high TMB (≥ 10 mutations/Mb) in pan-cancer studies was 2.9%, 2.7% and 14.0%, respectively. The prevalence profiles of dMMR/MSI and high TMB differed across cancer types. For example, endometrial, colorectal, small bowel and gastric cancers showed high prevalence of both dMMR and MSI (range: 8.7–26.8% and 8.5–21.9%, respectively) and high TMB (range: 8.5–43.0%), while cervical, esophageal, bladder/urothelial, lung and skin cancers showed low prevalence of dMMR and MSI (< 5%), but high prevalence of high TMB (range: 23.7–52.6%). For other cancer types, prevalence of all three biomarkers was generally low (< 5%). This structured review of dMMR/MSI/high TMB prevalence across cancers and for specific cancer types and stages provide timely evidence to inform budget impact forecasts in health technology assessments for drug approvals based on these pan-tumour biomarkers. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Health surveys are commonly somewhat non-representative of their target population, potentially limiting the generalisability of prevalence estimates for health/behaviour characteristics and disease to the population. To reduce bias, weighting methods have been developed, though few studies have validated weighted survey estimates against generally accepted high-quality independent population benchmark estimates.Methods: We applied post-stratification and raking methods to the Australian 45 and Up Study using Census data and compared the resulting prevalence of characteristics to accepted population benchmark estimates and separately, the incidence rates of lung, colorectal, breast and prostate cancer to whole-of-population estimates using Standardised Incidence Ratios (SIRs).Results: The differences between 45 and Up Study and population benchmark estimates narrowed following sufficiently-informed raking, e.g. 13.6% unweighted prevalence of self-reported fair/poor overall health, compared to 17.0% after raking and 17.9% from a population benchmark estimate. Raking also improved generalisability of cancer incidence estimates. For example, unweighted 45 and Up Study versus whole-of-population SIRs were 0.700 (95%CI:0.574-0.848) for male lung cancer and 1.098 (95%CI:1.002-1.204) for prostate cancer, while estimated SIRs after sufficiently-informed raking were 0.828 (95%CI:0.684-0.998) and 1.019 (95%CI:0.926-1.121), respectively.Conclusion: Raking may be a useful tool for improving the generalisability of exposure prevalence and disease incidence from surveys to the population. [ABSTRACT FROM AUTHOR]

Background: To inform effective genomic medicine strategies, it is important to examine current approaches and gaps in well-established applications. Lynch syndrome (LS) causes 3–5% of colorectal cancers (CRCs). While guidelines commonly recommend LS tumour testing of all CRC patients, implementation in health systems is known to be highly variable. To provide insights on the heterogeneity in practice and current bottlenecks in a high-income country with universal healthcare, we characterise the approaches and gaps in LS testing and referral in seven Australian hospitals across three states. Methods: We obtained surgery, pathology, and genetics services data for 1,624 patients who underwent CRC resections from 01/01/2017 to 31/12/2018 in the included hospitals. Results: Tumour testing approaches differed between hospitals, with 0–19% of patients missing mismatch repair deficiency test results (total 211/1,624 patients). Tumour tests to exclude somatic MLH1 loss were incomplete at five hospitals (42/187 patients). Of 74 patients with tumour tests completed appropriately and indicating high risk of LS, 36 (49%) were missing a record of referral to genetics services for diagnostic testing, with higher missingness for older patients (0% of patients aged ≤ 40 years, 76% of patients aged > 70 years). Of 38 patients with high-risk tumour test results and genetics services referral, diagnostic testing was carried out for 25 (89%) and identified a LS pathogenic/likely pathogenic variant for 11 patients (44% of 25; 0.7% of 1,624 patients). Conclusions: Given the LS testing and referral gaps, further work is needed to identify strategies for successful integration of LS testing into clinical care, and provide a model for hereditary cancers and broader genomic medicine. Standardised reporting may help clinicians interpret tumour test results and initiate further actions. [ABSTRACT FROM AUTHOR]

Summary: Background: 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). Objectives: To evaluate PRS‐based melanoma risk prediction in prospective UK and Australian cohorts with European ancestry. Methods: 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. Results: 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). Conclusions: 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. [ABSTRACT FROM AUTHOR]

Previously published sub-site Australian projections for colon and rectal cancers to 2035 using the World Health Organization's mortality database sourced from the Australian Bureau of Statistics (ABS) predicted mortality rate decreases for colon cancer and increases for rectal cancer. There are complexities related to the interpretation of ABS's Australian colon and rectal cancer mortality rates, which could lead to possible inaccuracies in mortality rates for these sub-sites. The largest Australian population-wide registry, New South Wales Cancer Registry (NSWCR), compares routinely-reported causes of death with the recorded medical history from multiple data sources. Therefore, this study used the NSWCR data to project mortality rates for colon and rectal cancers separately to 2040 in Australia. The mortality rates for colon cancer are projected to continuously decline over the period 2015–2040, from 7.0 to 4.7 per 100,000 males, and from 5.3 to 3.2 per 100,000 females. Similar decreasing trends in mortality rates for rectal cancer were projected over the period 2015–2040, from 4.9 to 3.7 per 100,000 males, and from 2.6 to 2.3 per 100,000 females. These projections provide benchmark estimates for the colorectal cancer burden in Australia against which the effectiveness of cancer control interventions can be measured. [ABSTRACT FROM AUTHOR]

Objective: Menopausal status impacts risk for many health outcomes. However, factors including hysterectomy without oophorectomy and Menopausal Hormone Therapy (MHT) can mask menopause, affecting reliability of self-reported menopausal status in surveys. We describe a step-by-step algorithm for classifying menopausal status using: directly self-reported menopausal status; MHT use; hysterectomy; oophorectomy; intervention timing; and attained age. We illustrate this approach using the Australian 45 and Up Study cohort (142,973 women aged ≥ 45 years). Results: We derived a detailed seven-category menopausal status, able to be further consolidated into four categories ("pre-menopause"/"peri-menopause"/"post-menopause"/"unknown") accounting for participants' ages. 48.3% of women had potentially menopause-masking interventions. Overall, 93,107 (65.1%), 9076 (6.4%), 17,930 (12.5%) and 22,860 (16.0%) women had a directly self-reported "post-menopause", "peri-menopause", "pre-menopause" and "not sure"/missing status, respectively. 61,464 women with directly self-reported "post-menopause" status were assigned a "natural menopause" detailed derived status (menopause without MHT use/hysterectomy/oophorectomy). By accounting for participants' ages, 105,817 (74.0%) women were assigned a "post-menopause" consolidated derived status, including 15,009 of 22,860 women with "not sure"/missing directly self-reported status. Conversely, 3178 of women with directly self-reported "post-menopause" status were assigned "unknown" consolidated derived status. This algorithm is likely to improve the accuracy and reliability of studies examining outcomes impacted by menopausal status. [ABSTRACT FROM AUTHOR]

Introduction: Colorectal cancer (CRC) care costs the Australian healthcare system more than any other cancer. We estimated costs and days in hospital for CRC cases, stratified by site (colon/rectal cancer) and disease stage, to inform detailed analyses of CRC-related healthcare. Methods: Incident CRC patients were identified using the Australian 45 and Up Study cohort linked with cancer registry records. We analysed linked hospital admission records, emergency department records, and reimbursement records for government-subsidised medical services and prescription medicines. Cases' health system costs (2020 Australian dollars) and hospital days were compared with those for cancer-free controls (matched by age, sex, geography, smoking) to estimate excess resources by phase of care, analysed by sociodemographic, health, and disease characteristics. Results: 1200 colon and 546 rectal cancer cases were diagnosed 2006–2013, and followed up to June 2016. Eighty-nine percent of cases had surgery, chemotherapy or radiotherapy, and excess costs were predominantly for hospitalisations. Initial phase (12 months post-diagnosis) mean excess health system costs were $50,434 for colon and $60,877 for rectal cancer cases, with means of 16 and 18.5 excess hospital days, respectively. The annual continuing mean excess costs were $6,779 (colon) and $8,336 (rectal), with a mean of 2 excess hospital days each. Resources utilised (costs and days) in these phases increased with more advanced disease, comorbidities, and younger age. Mean excess costs in the year before death were $74,952 (colon) and $67,733 (rectal), with means of 34 and 30 excess hospital days, respectively–resources utilised were similar across all characteristics, apart from lower costs for cases aged ≥75 at diagnosis. Conclusions: Health system costs and hospital utilisation for CRC care are greater for people with more advanced disease. These findings provide a benchmark, and will help inform future cost-effectiveness analyses of potential approaches to CRC screening and treatment. [ABSTRACT FROM AUTHOR]

Objectives: To 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.Methods: We 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.Results: We 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<10-10) and was reproducible in an independent patient cohort (ρ=-0.85, p<10-10).Conclusions: These data support the reproducible stratification of osteoarthritis patients by molecular subtype and the exploration of new avenues for tailored treatments. [ABSTRACT FROM AUTHOR]

Background: Intimate partner violence and differential power dynamics are associated with contraceptive behaviors. This study examines the role of reproductive coercion (RC) by an intimate partner in women's decisions about contraceptive use. Materials and Methods: A self-report survey was administered to a probability sample of a diverse group of women of reproductive age in Delaware's Title X health care facilities. Currently used contraceptive methods were categorized into three effectiveness levels based on typical use failure rates: no method or low effectiveness (>10% failure), moderate effectiveness (>1% and <10% failure), and high effectiveness (<1% failure). The short-form RC scale was used to categorize RC experiences: no RC, verbal only, or behavioral. We conducted multinomial logistic regression to examine the association between types of RC and effectiveness level of current contraceptive method, taking our sampling design into account and adjusting for covariates. Results: Among 240 women (weighted n = 6529) included in the sample, 13.9% reported experiencing only verbal RC, and 16.1% reported behavioral RC. Women who reported behavioral RC were more likely to currently be using highly versus moderately (adjusted relative risk ratio [aRRR]: 26.71, 95% confidence interval [CI]: 4.59–156.0) and low effective methods (aRRR: 3.08, 95% CI: 0.97–9.82), but less likely to be using moderately (aRRR: 0.12, 95% CI: 0.02–0.77) than low effective methods. Conclusions: Using highly and low effective methods may indicate two opposing ways of managing behavioral RC experiences: controlling fertility by choosing less detectable but highly effective methods or feeling disempowered and using no or low effective partner-dependent methods. [ABSTRACT FROM AUTHOR]

Background: Globally, radon is the leading risk factor for lung cancer in never-smokers (LCINS). In this study, we systematically reviewed and meta-analysed the evidence of the risk of LCINS associated with residential radon exposure. Methods: Medline and Embase databases were searched using predefined inclusion and exclusion criteria to identify relevant studies published from 1 January 1990 to 5 March 2020 focused on never-smokers. We identified four pooled collaborative studies (incorporating data from 24 case–control studies), one case– control study and one cohort study for systematic review. Meta-analysis was performed on the results of the four pooled studies due to different measures of effect and outcome reported in the cohort study and insufficient information reported for the case–control study. In a post hoc analysis, the corresponding risk for ever-smokers was also examined. Results: Risk estimates of lung cancer from residential radon exposure were pooled in the meta-analysis for 2341 never-smoker cases, 8967 never-smoker controls, 9937 ever-smoker cases and 12 463 ever-smoker controls. Adjusted excess relative risks (aERRs) per 100 Bq·m−3 of radon level were 0.15 (95% CI 0.06– 0.25) for never-smokers and 0.09 (95% CI 0.03–0.16) for ever-smokers, and the difference between them was statistically insignificant ( p=0.32). The aERR per 100 Bq·m−3 was higher for men (0.46; 95% CI 0.15– 0.76) than for women (0.09; 95% CI −0.02–0.20) among never-smokers ( p=0.027). Conclusion: This study provided quantified risk estimates for lung cancer from residential radon exposure among both never-smokers and ever-smokers. Among never-smokers in radon-prone areas, men were at higher risk of lung cancer than women. [ABSTRACT FROM AUTHOR]

Osteoarthritis causes pain and functional disability for over 500 million people worldwide. To develop disease-stratifying tools and modifying therapies, we need a better understanding of the molecular basis of the disease in relevant tissue and cell types. Here, we study primary cartilage and synovium from 115 patients with osteoarthritis to construct a deep molecular signature map of the disease. By integrating genetics with transcriptomics and proteomics, we discover molecular trait loci in each tissue type and omics level, identify likely effector genes for osteoarthritis-associated genetic signals and highlight high-value targets for drug development and repurposing. These findings provide insights into disease aetiopathology, and offer translational opportunities in response to the global clinical challenge of osteoarthritis. Understanding the molecular effects of disease variants in relevant tissues is essential to understanding and treating disease. Here, the authors discover expression and protein quantitative trait loci in cartilage and synovium from 115 osteoarthritis patients to pinpoint genes of action and potential drug treatments. [ABSTRACT FROM AUTHOR]

Exposures to cancer risk factors such as smoking and alcohol are not mutually independent. We aimed to identify risk factor exposure patterns and their associations with sociodemographic characteristics and cancer incidence. We considered 120,771 female and, separately, 100,891 male participants of the Australian prospective cohort 45 and Up Study. Factor analysis grouped 36 self-reported variables into 8 combined factors each for females (largely representing 'smoking', 'alcohol', 'vigorous exercise', 'age at childbirth', 'Menopausal Hormone Therapy', 'parity and breastfeeding', 'standing/sitting', 'fruit and vegetables') and males (largely representing 'smoking', 'alcohol', 'vigorous exercise', 'urology and health', 'moderate exercise', 'standing/sitting', 'fruit and vegetables', 'meat and BMI'). Associations with cancer incidence were investigated using multivariable logistic regression (4–8 years follow-up: 6193 females, 8749 males diagnosed with cancer). After multiple-testing correction, we identified 10 associations between combined factors and cancer incidence for females and 6 for males, of which 14 represent well-known relationships (e.g. bowel cancer: females 'smoking' factor Odds Ratio (OR) 1.16 (95% Confidence Interval (CI) 1.08–1.25), males 'smoking' factor OR 1.15 (95% CI 1.07–1.23)), providing evidence for the validity of this approach. The catalogue of associations between exposure patterns, sociodemographic characteristics, and cancer incidence can help inform design of future studies and targeted prevention programmes. [ABSTRACT FROM AUTHOR]

Osteoarthritis causes debilitating pain and disability, resulting in a considerable socioeconomic burden, yet no drugs are available that prevent disease onset or progression. Here, we develop, validate and use rapid-throughput imaging techniques to identify abnormal joint phenotypes in randomly selected mutant mice generated by the International Knockout Mouse Consortium. We identify 14 genes with functional involvement in osteoarthritis pathogenesis, including the homeobox gene Pitx1, and functionally characterize 6 candidate human osteoarthritis genes in mouse models. We demonstrate sensitivity of the methods by identifying age-related degenerative joint damage in wild-type mice. Finally, we phenotype previously generated mutant mice with an osteoarthritis-associated polymorphism in the Dio2 gene by CRISPR/Cas9 genome editing and demonstrate a protective role in disease onset with public health implications. We hope this expanding resource of mutant mice will accelerate functional gene discovery in osteoarthritis and offer drug discovery opportunities for this common, incapacitating chronic disease. Osteoarthritis is a chronic, heritable disease with no available treatment. Here, the authors show that a validated, rapid-throughput joint phenotyping pipeline detects osteoarthritis in the mouse knee following surgical provocation, in aging and after single gene deletion or point mutation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: We examined whether experiencing more types of lifetime intimate partner violence (IPV) was independently associated with the effectiveness level of the contraceptive method women chose following an abortion. Materials and Methods: Using data on 245 women who were attending an urban hospital abortion clinic, we assessed whether women had ever experienced emotional, physical, or sexual IPV. Effectiveness of women's post-abortion contraceptive method selection was categorized into high (intrauterine device [IUD] and implant), moderate (pill, patch, ring, and shot), and low (condoms, emergency contraception, and none) effectiveness. Using multinomial logistic regression, we examined the relationship between number of types of IPV experienced and post-abortion contraceptive method effectiveness, adjusting for sociodemographics, prior abortion, having children, abortion trimester, importance of avoiding pregnancy in the next year, pre-abortion psychological distress, and effectiveness level of the contraceptive method women were planning to use before contraceptive counseling. Results: Twenty-seven percent (27%) of women experienced two or three types of IPV, 35% experienced one IPV type, and 38% experienced no IPV. Compared to women with no histories of IPV, women who experienced two or more types of IPV during their lifetimes were more likely to choose contraceptive methods with moderate effectiveness (adjusted odds ratio [AOR] = 5.23, 95% confidence interval [CI]: 1.13–24.23, p = 0.035) and high effectiveness (AOR = 5.01, 95% CI: 1.12–22.39, p = 0.035) than those with low effectiveness. Conclusion: Women who experienced two or more types of lifetime IPV selected more effective contraceptive methods post-abortion. Access to contraceptives that are not partner dependent, including long-acting reversible contraceptives (LARC), may be particularly important for women who have experienced multiple types of IPV. [ABSTRACT FROM AUTHOR]

Background: We examined whether experiencing more types of lifetime intimate partner violence (IPV) was independently associated with the effectiveness level of the contraceptive method women chose following an abortion. Materials and Methods: Using data on 245 women who were attending an urban hospital abortion clinic, we assessed whether women had ever experienced emotional, physical, or sexual IPV. Effectiveness of women’s post-abortion contraceptive method selection was categorized into high (intrauterine device [IUD] and implant), moderate (pill, patch, ring, and shot), and low (condoms, emergency contraception, and none) effectiveness. Using multinomial logistic regression, we examined the relationship between number of types of IPV experienced and post-abortion contraceptive method effectiveness, adjusting for sociodemographics, prior abortion, having children, abortion trimester, importance of avoiding pregnancy in the next year, pre-abortion psychological distress, and effectiveness level of the contraceptive method women were planning to use before contraceptive counseling. Results: Twenty-seven percent (27%) of women experienced two or three types of IPV, 35% experienced one IPV type, and 38% experienced no IPV. Compared to women with no histories of IPV, women who experienced two or more types of IPV during their lifetimes were more likely to choose contraceptive methods with moderate effectiveness (adjusted odds ratio [AOR] = 5.23, 95% confidence interval [CI]: 1.13–24.23, p = 0.035) and high effectiveness (AOR= 5.01, 95% CI: 1.12–22.39, p = 0.035) than those with low effectiveness. Conclusion: Women who experienced two or more types of lifetime IPV selected more effective contraceptive methods post-abortion. Access to contraceptives that are not partner dependent, including long-acting reversible contraceptives (LARC), may be particularly important for women who have experienced multiple types of IPV. [ABSTRACT FROM AUTHOR]

Background/Aims To analyse the retest reliability of visual field indices and to describe patterns of visual field deficits in mesopic and dark-adapted two-colour fundus-controlled perimetry (FCP) in macular diseases. Methods Seventy-seven eyes (30 eyes with macular diseases and 47 normal eyes) underwent duplicate mesopic and dark-adapted two-colour FCP (Scotopic Macular Integrity Assessment, CenterVue). Non-weighted (mean defect, loss variance), variability-weighted (mean deviation, pattern standard deviation (PSD)) and graphical (cumulative defect (Bebie) curves) indices were computed. Reproducibility (coefficient of repeatability, CoR) of these indices was assessed. Cluster analysis was carried out to identify patterns of visual field deficits. Results The intrasession reproducibility was lower for the mean defect as compared with the mean deviation (CoR (dB) 2.67 vs 2.57 for mesopic, 1.71 vs 1.45 for dark-adapted cyan, 1.94 vs 1.87 for dark-adapted red testing) and lower for the square-root loss variance as compared with the PSD (CoR (dB) 1.48 vs 1.34, 0.77 vs 0.65, 1.23 vs 1.03). Hierarchical cluster analysis of the indices disclosed six patterns of visual field deficits (approximately unbiased P value>0.95) with varying degrees of global versus focal defect and rod versus cone dysfunction. These were also reflected by the cumulative defect curves. Conclusion FCP with mesopic and dark-adapted two-colour testing allows for reproducible assessment of different types of retinal sensitivity, whereby mean deviation and PSD exhibited the better retest reliability of the tested indices. Distinct patterns of retinal dysfunction can be identified using this setup, reflecting variable degrees of rod and cone dysfunction in different macular diseases. Dark-adapted two-colour FCP provides additional diagnostic information and allows for refined structure--function correlation in macular diseases. [ABSTRACT FROM AUTHOR]

Objectives To identify molecular differences between chondrocytes from osteophytic and articular cartilage tissue from OA patients. Methods We investigated genes and pathways by combining genome-wide DNA methylation, RNA sequencing and quantitative proteomics in isolated primary chondrocytes from the cartilaginous layer of osteophytes and matched areas of low- and high-grade articular cartilage across nine patients with OA undergoing hip replacement surgery. Results Chondrocytes from osteophytic cartilage showed widespread differences to low-grade articular cartilage chondrocytes. These differences were similar to, but more pronounced than, differences between chondrocytes from osteophytic and high-grade articular cartilage, and more pronounced than differences between high- and low-grade articular cartilage. We identified 56 genes with significant differences between osteophytic chondrocytes and low-grade articular cartilage chondrocytes on all three omics levels. Several of these genes have known roles in OA, including ALDH1A2 and cartilage oligomeric matrix protein, which have functional genetic variants associated with OA from genome-wide association studies. An integrative gene ontology enrichment analysis showed that differences between osteophytic and low-grade articular cartilage chondrocytes are associated with extracellular matrix organization, skeletal system development, platelet aggregation and regulation of ERK1 and ERK2 cascade. Conclusion We present a first comprehensive view of the molecular landscape of chondrocytes from osteophytic cartilage as compared with articular cartilage chondrocytes from the same joints in OA. We found robust changes at genes relevant to chondrocyte function, providing insight into biological processes involved in osteophyte development and thus OA progression. [ABSTRACT FROM AUTHOR]

Importance: The repercussions of abortion for mental health have been used to justify state policies that limit access to abortion in the United States. Much earlier research has relied on self-report of abortion or mental health conditions or on convenience samples. This study uses data that rely on neither.Objective: To examine whether first-trimester first abortion or first childbirth is associated with an increase in women's initiation of a first-time prescription for an antidepressant.Design, Setting, and Participants: This study linked data and identified a cohort of women from Danish population registries who were born in Denmark between January 1, 1980, and December 30, 1994. Overall, 396 397 women were included in this study; of these women, 30 834 had a first-trimester first abortion and 85 592 had a first childbirth.Main Outcomes and Measure: First-time antidepressant prescription redemptions were determined and used as indication of an episode of depression or anxiety, and incident rate ratios (IRRs) were calculated comparing women who had an abortion vs women who did not have an abortion and women who had a childbirth vs women who did not have a childbirth.Results: Of 396 397 women whose data were analyzed, 17 294 (4.4%) had a record of at least 1 first-trimester abortion and no children, 72 052 (18.2%) had at least 1 childbirth and no abortions, 13 540 (3.4%) had at least 1 abortion and 1 childbirth, and 293 511 (74.1%) had neither an abortion nor a childbirth. A total of 59 465 (15.0%) had a record of first antidepressant use. In the basic and fully adjusted models, relative to women who had not had an abortion, women who had a first abortion had a higher risk of first-time antidepressant use. However, the fully adjusted IRRs that compared women who had an abortion with women who did not have an abortion were not statistically different in the year before the abortion (IRR, 1.46; 95% CI, 1.38-1.54) and the year after the abortion (IRR, 1.54; 95% CI, 1.45-1.62) (P = .10) and decreased as time from the abortion increased (1-5 years: IRR, 1.24; 95% CI, 1.19-1.29; >5 years: IRR, 1.12; 95% CI, 1.05-1.18). The fully adjusted IRRs that compared women who gave birth with women who did not give birth were lower in the year before childbirth (IRR, 0.47; 95% CI, 0.43-0.50) compared with the year after childbirth (IRR, 0.93; 95% CI, 0.88-0.98) (P < .001) and increased as time from the childbirth increased (1-5 years: IRR, 1.52; 95% CI, 1.47-1.56; >5 years: IRR, 1.99; 95% CI, 1.91-2.09). Across all women in the sample, the strongest risk factors associated with antidepressant use in the fully adjusted model were having a previous psychiatric contact (IRR, 3.70; 95% CI, 3.62-3.78), having previously obtained an antianxiety medication (IRR, 3.03; 95% CI, 2.99-3.10), and having previously obtained antipsychotic medication (IRR, 1.88; 95% CI, 1.81-1.96).Conclusions and Relevance: Women who have abortions are more likely to use antidepressants compared with women who do not have abortions. However, additional aforementioned findings from this study support the conclusion that increased use of antidepressants is not attributable to having had an abortion but to differences in risk factors for depression. Thus, policies based on the notion that abortion harms women's mental health may be misinformed. [ABSTRACT FROM AUTHOR]

Objectives: Osteoarthritis (OA) is a complex disease, but its genetic aetiology remains poorly characterised. To identify novel susceptibility loci for OA, we carried out a genome-wide association study (GWAS) in individuals from the largest UK-based OA collections to date.Methods: We carried out a discovery GWAS in 5414 OA individuals with knee and/or hip total joint replacement (TJR) and 9939 population-based controls. We followed-up prioritised variants in OA subjects from the interim release of the UK Biobank resource (up to 12 658 cases and 50 898 controls) and our lead finding in operated OA subjects from the full release of UK Biobank (17 894 cases and 89 470 controls). We investigated its functional implications in methylation, gene expression and proteomics data in primary chondrocytes from 12 pairs of intact and degraded cartilage samples from patients undergoing TJR.Results: We detect a genome-wide significant association at rs10116772 with TJR (P=3.7×10-8; for allele A: OR (95% CI) 0.97 (0.96 to 0.98)), an intronic variant in GLIS3, which is expressed in cartilage. Variants in strong correlation with rs10116772 have been associated with elevated plasma glucose levels and diabetes.Conclusions: We identify a novel susceptibility locus for OA that has been previously implicated in diabetes and glycaemic traits. [ABSTRACT FROM AUTHOR]

ABSTRACT Metal-on-metal (MOM) hip resurfacing has recently been a popular prosthesis choice for the treatment of symptomatic arthritis, but results in the release of cobalt and chromium ions into the circulation that can be associated with adverse clinical effects. The mechanism underlying these effects remains unclear. While chromosomal aneuploidy and translocations are associated with this exposure, the presence of subtle structural epigenetic modifications in patients with MOM joint replacements remains unexplored. Consequently, we analyzed whole blood DNA methylation in 34 OA patients with MOM hip resurfacing (MOM HR) compared to 34 OA patients with non-MOM total hip replacements (non-MOM THR), using the genome-wide Illumina HumanMethylation 450k BeadChip. No probes showed differential methylation significant at 5% false-discovery rate (FDR). We also tested association of probe methylation levels with blood chromium and cobalt levels directly; there were no significant associations at 5% FDR. Finally, we used the 'epigenetic clock' to compare estimated to actual age at sample for all individuals. We found no significant difference between MOM HR and non-MOM THR, and no correlation of age acceleration with blood metal levels. Our results suggest the absence of large methylation differences systemically following metal exposure, however, larger sample sizes will be required to identify potential small effects. Any DNA methylation changes that may occur in the local periprosthetic tissues remain to be elucidated. © 2017 The Authors. Orthopaedic Research Society. Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 35:2323-2328, 2017. [ABSTRACT FROM AUTHOR]