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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]

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]

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]

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]

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]

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]

Fundus autofluorescence (FAF) imaging allows for topographic mapping of intrisnic fluorophores in the retinal pigment epithelial cell monolayer, as well as mapping of other fluorophores that may occur with disease in the outer retina and the sub-neurosensory space. FAF imaging provides information not obtainable with other imaging modalities. Near-infrared fundus autofluorescence images can also be obtained in vivo, and may be largely melanin-derived. FAF imaging has been shown to be useful in a wide spectrum of macular and retinal diseases. The scope of applications now includes identification of diseased RPE in macular/retinal diseases, elucidating pathophysiological mechanisms, identification of early disease stages, refined phenotyping, identification of prognostic markers for disease progression, monitoring disease progression in the context of both natural history and interventional therapeutic studies, and objective assessment of luteal pigment distribution and density as well as RPE melanin distribution. Here, we review the use of FAF imaging in various phenotypic manifestations of dry AMD. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to assess the effects of obtaining an abortion versus being denied an abortion on self-esteem and life satisfaction. Methods: We present the first 2.5 years of a 5-year longitudinal telephone-interview study that follows 956 women who sought an abortion from 30 facilities across the USA. We examine the self-esteem and life satisfaction trajectories of women who sought and received abortions just under the facility's gestational age limit, of women who sought and received abortions in their first trimester of pregnancy, and of women who sought abortions just beyond the facility gestational limit and were denied an abortion. We use adjusted mixed effects linear regression analyses to assess whether the trajectories of women who sought and obtained an abortion differ from those who were denied one. Results: Women denied an abortion initially reported lower self-esteem and life satisfaction than women who sought and obtained an abortion. For all study groups, except those who obtained first trimester abortions, self-esteem and life satisfaction improved over time. The initially lower levels of self-esteem and life satisfaction among women denied an abortion improved more rapidly reaching similar levels as those obtaining abortions at 6 months to one year after abortion seeking. For women obtaining first trimester abortions, initially higher levels of life satisfaction remained steady over time. Conclusions: There is no evidence that abortion harms women's self-esteem or life satisfaction in the short term. [ABSTRACT FROM AUTHOR]

Objectification theory contends that women are socialized to view their body as an object to be evaluated by others (Fredickson and Roberts ). In contrast, pregnancy may be a time that women are more attuned to their body's functionality. Extending objectification theory, we investigate relationships among body surveillance, awareness and appreciation of body functionality, depressive symptoms, and prenatal health behaviors among an on-line sample of 156 predominantly White, middle-class pregnant women from throughout the U.S recruited through maternity stores, message boards, listservs, and snowballing techniques. We examine whether higher levels of awareness and appreciation of body functionality may attenuate, and thereby possibly protect women from the negative effects of high body surveillance. We found that higher body surveillance was associated with depressive symptoms and, although not significant, tended to be associated with engagement in unhealthy prenatal behaviors. Awareness and appreciation of body functionality were each associated with fewer depressive symptoms and less engagement in unhealthy prenatal behaviors. Supporting our hypotheses, we found that at higher levels of appreciation of body functionality, the relationship between body surveillance and engagement in unhealthy behaviors was attenuated. However, in contrast to our hypotheses, the relationship between body surveillance and depression was stronger at higher levels of awareness of body functionality, and attenuated at lower levels. These findings suggest appreciation of body functionality may buffer negative effects of body surveillance. Future research examining these relationships over the course of pregnancy, and among ethnically and socioeconomically diverse women, is needed. [ABSTRACT FROM AUTHOR]

These authors contributed equally: Graham R. Williams, J. H. Duncan Bassett. The original version of this Article contained private information in the Data Availability statement, which was used by reviewers to access Proteomics datasets. [Extracted from the article]

Developmental dysplasia of the hip (DDH) is the most common skeletal developmental disease. However, its genetic architecture is poorly understood. We conduct the largest DDH genome-wide association study to date and replicate our findings in independent cohorts. We find the heritable component of DDH attributable to common genetic variants to be 55% and distributed equally across the autosomal and X-chromosomes. We identify replicating evidence for association between GDF5 promoter variation and DDH (rs143384, effect allele A, odds ratio 1.44, 95% confidence interval 1.34–1.56, P = 3.55 × 10−22). Gene-based analysis implicates GDF5 (P = 9.24 × 10−12), UQCC1 (P = 1.86 × 10−10), MMP24 (P = 3.18 × 10−9), RETSAT (P = 3.70 × 10−8) and PDRG1 (P = 1.06 × 10−7) in DDH susceptibility. We find shared genetic architecture between DDH and hip osteoarthritis, but no predictive power of osteoarthritis polygenic risk score on DDH status, underscoring the complex nature of the two traits. We report a scalable, time-efficient recruitment strategy and establish for the first time to our knowledge a robust DDH genetic association locus at GDF5. Konstantinos Hatzikotoulas et al. report the largest genome-wide association study to date for developmental dysplasia of the hip using national clinical audit data from the UK. They find a significant association with the GDF5 locus and evidence for shared genetic architecture with hip osteoarthritis. [ABSTRACT FROM AUTHOR]