Where the "ruber" Meets the Road: Using the Genome of the Red Diamond Rattlesnake to Unravel the Evolutionary Processes Driving Venom Evolution.

Understanding the proximate and ultimate causes of phenotypic variation is fundamental in evolutionary research, as such variation provides the substrate for selection to act upon. Although trait variation can arise due to selection, the importance of neutral processes is sometimes understudied. We presented the first reference-quality genome of the Red Diamond Rattlesnake (Crotalus ruber) and used range-wide 'omic data to estimate the degree to which neutral and adaptive evolutionary processes shaped venom evolution. We characterized population structure and found substantial genetic differentiation across two populations, each with distinct demographic histories. We identified significant differentiation in venom expression across age classes with substantially reduced but discernible differentiation across populations. We then used conditional redundancy analysis to test whether venom expression variation was best predicted by neutral divergence patterns or geographically variable (a)biotic factors. Snake size was the most significant predictor of venom variation, with environment, prey availability, and neutral sequence variation also identified as significant factors, though to a lesser degree. By directly including neutrality in the model, our results confidently highlight the predominant, yet not singular, role of life history in shaping venom evolution.

A smartphone-based approach for comprehensive soil microbiome profiling.

The soil microbiome is crucial for nutrient cycling, health, and plant growth. This study presents a smartphone-based approach as a low-cost and portable alternative to traditional methods for classifying bacterial species and characterizing microbial communities in soil samples. By harnessing bacterial autofluorescence detection and machine learning algorithms, the platform achieved an average accuracy of 88% in distinguishing common soil-related bacterial species despite the lack of biomarkers, nucleic acid amplification, or gene sequencing. Furthermore, it successfully identified dominant species within various bacterial mixtures with an accuracy of 76% and three-level soil health identification at an accuracy of 80%-82%, providing insights into microbial community dynamics. The influence of other soil conditions (pH and moisture) was relatively minor, showcasing the platform's robustness. Various field soil samples were also tested with this platform at 80% accuracy compared with the laboratory analyses, demonstrating the practicality and usability of this approach for on-site soil analysis. This study highlights the potential of the smartphone-based system as a valuable tool for soil assessment, microbial monitoring, and environmental management.

Impact of socioeconomic status on open globe injuries during the COVID-19 pandemic.

PURPOSE: We explored the associations between socioeconomic status, as evaluated by the Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry Social Vulnerability Index (SVI), and characteristics of open globe injury (OGI) in a Level I trauma center during the COVID-19 pandemic. METHODS: Retrospective review of electronic medical records of patients who underwent OGI evaluation and repair at Harborview Medical Center between March/2017 and March/2021. Demographic data and patient characteristics were recorded. The SVI was obtained based on the patient's home address. Patients were grouped into the "historical" (pre-COVID) cohort, including dates from March 2017 - March 2020, and the "COVID" cohort, including dates from March 2020 - March 2021. RESULTS: 318 patients (77.4% male) were included. Average ± S.D. age (years) and SVI scores were 44.7 ± 22.7 and 0.413 ± 0.195, respectively. SVI scores were significantly higher (more vulnerable) during the COVID-19 pandemic compared to years prior (p = 0.017), however when compared to scores for the same patients prior to the pandemic, no difference was found (p = 0.609). There was no significant difference between intentional and non-intentional trauma, work-related injuries, OGI type, presence of endophthalmitis, or ocular trauma score (p ≥ 0.293). Still, significantly fewer motor vehicle-associated (MVA) OGIs occurred during the pandemic (p = 0.041). CONCLUSIONS: Patients with OGI during the COVID-19 pandemic had higher SVI scores, however when considering the overall effect of the pandemic, our findings are likely reflective of the societal changes at large. There was no identifiable impact on the mechanisms or characteristics of ocular injuries, except for fewer MVA injuries.

Rebound Hyperthermia in Exertional Heat Stroke.

Exertional heat stroke (EHS) is a life-threatening condition requiring rapid reversal of hyperthermia to prevent poor health outcomes. Current treatment protocols aim for a cooling rate of 0.15 C/min using various modalities. This case report details a 22-year-old male who, despite initial successful cooling measures, experienced rebound hyperthermia, necessitating the use of endovascular cooling (EVC). The patient collapsed during a 19.3 km (12-mile) ruck march in Fort Moore, Georgia, with an initial core temperature of 41.6ºC. Conventional cooling methods, including ice sheets and chilled intravenous saline, adequately cooled the patient to target temperatures; however, discontinuation of cooling methods resulted in rebound hyperthermia. Endovascular cooling was eventually initiated, resulting in euthermia after 36 hours of continued use. During his hospital admission, the patient was evaluated thoroughly for underlying etiologies contributing to his rebound hyperthermia. This workup did not yield any concerning pathology, except for bilateral foot cellulitis noted on physical examination, which was subsequently managed with antibiotics. Despite initial complications, the patient recovered within 5 days and returned to duty after 2 months. Several case reports have been published regarding the use of EVC in the management of EHS. These reports, however, describe its use in initial management of EHS or in cases where hyperthermia was refractory to other conventional cooling methods. To our knowledge, this is the first report of its kind highlighting its successful implementation in rebound hyperthermia. Early recognition and initiation of cooling measures are critical in EHS cases. Future directions include developing EHS-specific EVC protocols for patients experiencing refractory or rebound hyperthermia.

G Protein-Coupled Receptors: A Century of Research and Discovery.

GPCRs (G protein-coupled receptors), also known as 7 transmembrane domain receptors, are the largest receptor family in the human genome, with ≈800 members. GPCRs regulate nearly every aspect of human physiology and disease, thus serving as important drug targets in cardiovascular disease. Sharing a conserved structure comprised of 7 transmembrane α-helices, GPCRs couple to heterotrimeric G-proteins, GPCR kinases, and ß-arrestins, promoting downstream signaling through second messengers and other intracellular signaling pathways. GPCR drug development has led to important cardiovascular therapies, such as antagonists of ß-adrenergic and angiotensin II receptors for heart failure and hypertension, and agonists of the glucagon-like peptide-1 receptor for reducing adverse cardiovascular events and other emerging indications. There continues to be a major interest in GPCR drug development in cardiovascular and cardiometabolic disease, driven by advances in GPCR mechanistic studies and structure-based drug design. This review recounts the rich history of GPCR research, including the current state of clinically used GPCR drugs, and highlights newly discovered aspects of GPCR biology and promising directions for future investigation. As additional mechanisms for regulating GPCR signaling are uncovered, new strategies for targeting these ubiquitous receptors hold tremendous promise for the field of cardiovascular medicine.

Embedding patient and public involvement into a doctoral study: developing a point-of-care HIV testing intervention for dental settings.

Introduction: Patient and Public Involvement (PPI) can have a positive impact on research. PPI can make research more meaningful and appropriate as well as preventing research waste. For decades, patient advocates with HIV have played a key part in public health and research. This article presents the PPI activity undertaken during a doctoral study. The aim of this article is to demonstrate how PPI was embedded into a doctoral study that explored the feasibility of HIV testing in dental settings. Methods: Patients and the public were invited to be involved with the feasibility study through various organisations and charities. A comprehensive PPI activity strategy was devised, and appropriate funding was obtained. Patients and the public were predominantly consulted or collaboratively involved with several aspects of the study. Findings: Patients and the public positively contributed to the intervention development and the resources supporting its implementation. As a result, the study resources (i.e., questionnaire and information leaflets) were easier to read, and the intervention was more appropriate to the needs of patients. Furthermore, the training and focus groups conducted with dental patients and people with HIV benefitted from input of people with lived experience. Conclusions: PPI can be embedded within doctoral studies provided there is sufficient funding, flexibility, and supervisory support. However, PPI activity may be impacted by limited resource and a priori research protocol and funding agreements.

Few-shot Tumor Bud Segmentation Using Generative Model in Colorectal Carcinoma.

Current deep learning methods in histopathology are limited by the small amount of available data and time consumption in labeling the data. Colorectal cancer (CRC) tumor budding quantification performed using H&E-stained slides is crucial for cancer staging and prognosis but is subject to labor-intensive annotation and human bias. Thus, acquiring a large-scale, fully annotated dataset for training a tumor budding (TB) segmentation/detection system is difficult. Here, we present a DatasetGAN-based approach that can generate essentially an unlimited number of images with TB masks from a moderate number of unlabeled images and a few annotated images. The images generated by our model closely resemble the real colon tissue on H&E-stained slides. We test the performance of this model by training a downstream segmentation model, UNet++, on the generated images and masks. Our results show that the trained UNet++ model can achieve reasonable TB segmentation performance, especially at the instance level. This study demonstrates the potential of developing an annotation-efficient segmentation model for automatic TB detection and quantification.

A case study to engage students in the research design and ethics of high-throughput metagenomics.

Case studies present students with an opportunity to learn and apply course content through problem solving and critical thinking. Supported by the High-throughput Discovery Science & Inquiry-based Case Studies for Today's Students (HITS) Research Coordination Network, our interdisciplinary team designed, implemented, and assessed two case study modules entitled "You Are What You Eat." Collectively, the case study modules present students with an opportunity to engage in experimental research design and the ethical considerations regarding microbiome research and society. In this manuscript, we provide instructors with tools for adopting or adapting the research design and/or the ethics modules. To date, the case has been implemented using two modalities (remote and in-person) in three courses (Microbiology, Physiology, and Neuroscience), engaging over 200 undergraduate students. Our assessment data demonstrate gains in content knowledge and students' perception of learning following case study implementation. Furthermore, when reflecting on our experiences and student feedback, we identified ways in which the case study could be modified for different settings. In this way, we hope that the "You Are What You Eat" case study modules can be implemented widely by instructors to promote problem solving and critical thinking in the traditional classroom or laboratory setting when discussing next-generation sequencing and/or metagenomics research.

Words or code first? Is the legacy document or a code statement the better starting point for complexity-reducing legal automation?

Law is a critical tool that humans have created to assist them in managing complex social interactions. Computational Law holds the potential to significantly enhance our capacity to express and manage legal complexity, and a number of advantages can result from restating public and private legal rules in computable form. Capturing that potential depends in part on the approaches taken to automation. One set of choices involves whether to translate directly into code from existing natural language statements of laws, regulations and contracts or whether to step back, envision the basic structure underlying those statements and build a software approach that reflects that structure in a code-native manner. We argue that many advantages can flow from the second approach, and we present a specific use case of a simplified insurance policy as an example of this approach. Large language models may assist in this process, but are not yet a replacement for a code-native utility. This article is part of the theme issue 'A complexity science approach to law and governance'.

Disruption of nontuberculous mycobacteria biofilms induces a highly vulnerable to antibiotic killing phenotype.

Objectives: Structural or mucus hypersecretory pulmonary diseases such as cystic fibrosis (CF), wherein viscous mucus accumulates and clearance functions are impaired, predispose people to lung infection by inhaled bacteria that form biofilm aggregates. Nontuberculous mycobacteria (NTM), primarily Mycobacterium abscessus and Mycobacterium avium, are the growing cause of these lung infections and are extremely challenging to treat due to antibiotic recalcitrance. Better therapeutic approaches are urgently needed. We developed a humanized monoclonal antibody (HuTipMab) directed against a biofilm structural linchpin, the bacterial DNABII proteins, that rapidly disrupts biofilms and generates highly vulnerable newly released bacteria (NRel). Methods: HuTipMab's ability to recognize HupB, NTM's DNABII homologue was determined by ELISA. Relative ability of HuTipMab to disrupt biofilms formed by lab-passaged and clinical isolates of NTM was assessed by CLSM. Relative sensitivity of NTM NRel to antibiotic killing compared to when grown planktonically was evaluated by plate count. Results: HuTipMab recognized HupB and significantly disrupted NTM biofilms in a time- and dose-dependent manner. Importantly, NTM NRel of lab-passaged and clinical isolates were now highly sensitive to killing by amikacin and azithromycin. Conclusions: If successful, this combinatorial treatment strategy would empower existing antibiotics to more effectively kill NTM newly released from a biofilm by HuTipMab and thereby both improve clinical outcomes and perhaps decrease length of antibiotic treatment for people that are NTM culture-positive.

Cardiac changes in collegiate athletes following SARS-CoV-2 infection and quarantine: a prospective Case-Control study.

OBJECTIVE: Athletes are susceptible to acute respiratory tract infections, including SARS-CoV-2, which can affect cardiovascular function. We aimed to evaluate the impact of COVID-19 infection and quarantine on cardiac function in male and female collegiate athletes. METHODS: We conducted a single-center, prospective, case-control study and performed transthoracic echocardiography in a diverse group of convalescent SARS-CoV-2-positive athletes following a 10-14-day quarantine, matched to non-SARS-CoV-2 athletes. Data collection occurred from August 1, 2020, to May 31, 2021. RESULTS: We evaluated 61 SARS-CoV-2-positive athletes (20 ± 1 years, 39% female) and 61 controls (age 20 ± 2 years, 39% female). Echocardiography in SARS-CoV-2-positive athletes was performed on average 40 ± 38 days after infection diagnosis. All SARS-CoV-2-positive athletes had clinically normal systolic left ventricular function (LVEF > 50%). However, SARS-CoV-2-positive athletes exhibited mildly lower LVEF compared to controls (65 ± 6% vs. 72 ± 8%, respectively, p < 0.001), which remained significant when evaluated separately for female and male athletes. Sub-analysis revealed these differences occurred only when imaging occurred within a mean average of 27 days of infection, with a longer recovery period (≥27 days) resulting in no differences. SARS-CoV-2-positive male athletes exhibited higher left ventricular end-diastolic volume and mitral filling velocities compared to male controls. CONCLUSION: Our study reveals unique sex-specific cardiac changes in collegiate athletes following SARS-CoV-2 infection and quarantine compared to controls. Despite a mild reduction in LVEF, which was only observed in the first weeks following infection, no clinically significant cardiac abnormalities were observed. Further research is required to understand if the changes in LVEF are directly attributed to the infection or indirectly through exercise restrictions resulting from quarantine.

Recent Uses of Paper Microfluidics in Isothermal Nucleic Acid Amplification Tests.

Isothermal nucleic acid amplification tests have recently gained popularity over polymerase chain reaction (PCR), as they only require a constant temperature and significantly simplify nucleic acid amplification. Recently, numerous attempts have been made to incorporate paper microfluidics into these isothermal amplification tests. Paper microfluidics (including lateral flow strips) have been used to extract nucleic acids, amplify the target gene, and detect amplified products, all toward automating the process. We investigated the literature from 2020 to the present, i.e., since the onset of the COVID-19 pandemic, during which a significant surge in isothermal amplification tests has been observed. Paper microfluidic detection has been used extensively for recombinase polymerase amplification (RPA) and its related methods, along with loop-mediated isothermal amplification (LAMP) and rolling circle amplification (RCA). Detection was conducted primarily with colorimetric and fluorometric methods, although a few publications demonstrated flow distance- and surface-enhanced Raman spectroscopic (SERS)-based detection. A good number of publications could be found that demonstrated both amplification and detection on paper microfluidic platforms. A small number of publications could be found that showed extraction or all three procedures (i.e., fully integrated systems) on paper microfluidic platforms, necessitating the need for future work.

Reproducible evaluation of transposable element detectors with McClintock 2 guides accurate inference of Ty insertion patterns in yeast.

BACKGROUND: Many computational methods have been developed to detect non-reference transposable element (TE) insertions using short-read whole genome sequencing data. The diversity and complexity of such methods often present challenges to new users seeking to reproducibly install, execute, or evaluate multiple TE insertion detectors. RESULTS: We previously developed the McClintock meta-pipeline to facilitate the installation, execution, and evaluation of six first-generation short-read TE detectors. Here, we report a completely re-implemented version of McClintock written in Python using Snakemake and Conda that improves its installation, error handling, speed, stability, and extensibility. McClintock 2 now includes 12 short-read TE detectors, auxiliary pre-processing and analysis modules, interactive HTML reports, and a simulation framework to reproducibly evaluate the accuracy of component TE detectors. When applied to the model microbial eukaryote Saccharomyces cerevisiae, we find substantial variation in the ability of McClintock 2 components to identify the precise locations of non-reference TE insertions, with RelocaTE2 showing the highest recall and precision in simulated data. We find that RelocaTE2, TEMP, TEMP2 and TEBreak provide consistent estimates of [Formula: see text]50 non-reference TE insertions per strain and that Ty2 has the highest number of non-reference TE insertions in a species-wide panel of [Formula: see text]1000 yeast genomes. Finally, we show that best-in-class predictors for yeast applied to resequencing data have sufficient resolution to reveal a dyad pattern of integration in nucleosome-bound regions upstream of yeast tRNA genes for Ty1, Ty2, and Ty4, allowing us to extend knowledge about fine-scale target preferences revealed previously for experimentally-induced Ty1 insertions to spontaneous insertions for other copia-superfamily retrotransposons in yeast. CONCLUSION: McClintock ( https://github.com/bergmanlab/mcclintock/ ) provides a user-friendly pipeline for the identification of TEs in short-read WGS data using multiple TE detectors, which should benefit researchers studying TE insertion variation in a wide range of different organisms. Application of the improved McClintock system to simulated and empirical yeast genome data reveals best-in-class methods and novel biological insights for one of the most widely-studied model eukaryotes and provides a paradigm for evaluating and selecting non-reference TE detectors in other species.

Distinct types of multicellular aggregates in Pseudomonas aeruginosa liquid cultures.

Pseudomonas aeruginosa forms suspended multicellular aggregates when cultured in liquid media. These aggregates may be important in disease, and/or as a pathway to biofilm formation. The polysaccharide Psl and extracellular DNA (eDNA) have both been implicated in aggregation, but previous results depend strongly on the experimental conditions. Here we develop a quantitative microscopy-based method for assessing changes in the size distribution of suspended aggregates over time in growing cultures. For exponentially growing cultures of P. aeruginosa PAO1, we find that aggregation is mediated by cell-associated Psl, rather than by either eDNA or secreted Psl. These aggregates arise de novo within the culture via a growth process that involves both collisions and clonal growth, and Psl non-producing cells do not aggregate with producers. In contrast, we find that stationary phase (overnight) cultures contain a different type of multicellular aggregate, in which both eDNA and Psl mediate cohesion. Our findings suggest that the physical and biological properties of multicellular aggregates may be very different in early-stage vs late-stage bacterial cultures.

Priorities in Chronic nonbacterial osteomyelitis (CNO) - results from an international survey and roundtable discussions.

OBJECTIVE: Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disorder that predominantly affects children and young people. The pathophysiology and molecular mechanisms of CNO remain poorly understood, and diagnostic criteria and biomarkers are lacking. As a result, treatment is empiric and follows personal experience, case series and expert consensus plans. METHODS: A survey was designed to gain insight on clinician and patient experiences of diagnosing and treating CNO and to collate opinions on research priorities. A version containing 24 questions was circulated among international expert clinicians and clinical academics (27 contacted, 21 responses). An equivalent questionnaire containing 20 questions was shared to explore the experience and priorities of CNO patients and family members (93 responses). RESULTS: Responses were used to select topics for four moderated roundtable discussions at the "International Conference on CNO and autoinflammatory bone disease" (Liverpool, United Kingdom, May 25-26th, 2022). The group identified deciphering the pathophysiology of CNO to be the highest priority, followed by clinical trials, necessary outcome measures and classification criteria. Surprisingly, mental wellbeing scored behind these items. CONCLUSIONS: Agreement exists among clinicians, academics, patients and families that deciphering the pathophysiology of CNO is of highest priority to inform clinical trials that will allow for the approval of medications for the treatment of CNO by regulatory agencies.

Reproducible evaluation of transposable element detectors with McClintock 2 guides accurate inference of Ty insertion patterns in yeast.

BACKGROUND: Many computational methods have been developed to detect non-reference transposable element (TE) insertions using short-read whole genome sequencing data. The diversity and complexity of such methods often present challenges to new users seeking to reproducibly install, execute, or evaluate multiple TE insertion detectors. RESULTS: We previously developed the McClintock meta-pipeline to facilitate the installation, execution, and evaluation of six first-generation short-read TE detectors. Here, we report a completely re-implemented version of McClintock written in Python using Snakemake and Conda that improves its installation, error handling, speed, stability, and extensibility. McClintock 2 now includes 12 short-read TE detectors, auxiliary pre-processing and analysis modules, interactive HTML reports, and a simulation framework to reproducibly evaluate the accuracy of component TE detectors. When applied to the model microbial eukaryote Saccharomyces cerevisiae, we find substantial variation in the ability of McClintock 2 components to identify the precise locations of non-reference TE insertions, with RelocaTE2 showing the highest recall and precision in simulated data. We find that RelocaTE2, TEMP, TEMP2 and TEBreak provide a consistent and biologically meaningful view of non-reference TE insertions in a species-wide panel of ∻1000 yeast genomes, as evaluated by coverage-based abundance estimates and expected patterns of tRNA promoter targeting. Finally, we show that best-in-class predictors for yeast have sufficient resolution to reveal a dyad pattern of integration in nucleosome-bound regions upstream of yeast tRNA genes for Ty1, Ty2, and Ty4, allowing us to extend knowledge about fine-scale target preferences first revealed experimentally for Ty1 to natural insertions and related copia-superfamily retrotransposons in yeast. CONCLUSION: McClintock (https://github.com/bergmanlab/mcclintock/) provides a user-friendly pipeline for the identification of TEs in short-read WGS data using multiple TE detectors, which should benefit researchers studying TE insertion variation in a wide range of different organisms. Application of the improved McClintock system to simulated and empirical yeast genome data reveals best-in-class methods and novel biological insights for one of the most widely-studied model eukaryotes and provides a paradigm for evaluating and selecting non-reference TE detectors for other species.

Economic impact of using risk models for eligibility selection to the International lung screening Trial.

OBJECTIVES: Using risk models as eligibility criteria for lung screening can reduce race and sex-based disparities. We used data from the International Lung Screening Trial(ILST; NCT02871856) to compare the economic impact of using the PLCOm2012 risk model or the US Preventative Services' categorical age-smoking history-based criteria (USPSTF-2013). MATERIALS AND METHODS: The cost-effectiveness of using PLCOm2012 versus USPSTF-2013 was evaluated with a decision analytic model based on the ILST and other screening trials. The primary outcomes were costs in 2020 International Dollars ($), quality-adjusted life-years (QALY) and incremental net benefit (INB, in $ per QALY). Secondary outcomes were selection characteristics and cancer detection rates (CDR). RESULTS: Compared with the USPSTF-2013 criteria, the PLCOm2012 risk model resulted in $355 of cost savings per 0.2 QALYs gained (INB=$4294 at a willingness-to-pay threshold of $20 000/QALY (95 %CI: $4205-$4383). Using the risk model was more cost-effective in females at both a 1.5 % and 1.7 % 6-year risk threshold (INB=$6616 and $6112, respectively), compared with males ($5221 and $695). The PLCOm2012 model selected more females, more individuals with fewer years of formal education, and more people with other respiratory illnesses in the ILST. The CDR with the risk model was higher in females compared with the USPSTF-2013 criteria (Risk Ratio = 7.67, 95 % CI: 1.87-31.38). CONCLUSION: The PLCOm2012 model saved costs, increased QALYs and mitigated socioeconomic and sex-based disparities in access to screening.

Colon and rectal cancer treatment patterns and their associations with clinical, sociodemographic and lifestyle characteristics: analysis of the Australian 45 and Up Study cohort.

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.

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

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