Development and Outcomes of Returning Polycyclic Aromatic Hydrocarbon Exposure Results in the Washington Heights, NYC Community.

Report-back of research results (RBRR) is becoming standard practice for environmental health research studies. RBRR is thought to increase environmental health literacy (EHL), although standardized measurements are limited. For this study, we developed a report back document on exposure to air pollutants, Polycyclic Aromatic Hydrocarbons, during pregnancy through community engaged research and evaluated whether the report increased EHL. We used focus groups and surveys to gather feedback on the report document from an initial group of study participants (Group 1, n = 22) and then sent the revised report to a larger number of participants (Group 2, n = 168). We conducted focus groups among participants in Group 1 and discussed their suggested changes to the report and how those changes could be implemented. Participants in focus groups demonstrated multiple levels of EHL. While participant engagement critically informed report development, a survey comparing feedback from Group 1 (initial report) and Group 2 (revised report) did not show a significant difference in the ease of reading the report or knowledge gained about air pollutants. We acknowledge that our approach was limited by a lack of EHL tools that assess knowledge and behavior change, and a reliance on quantitative methodologies. Future approaches that merge qualitative and quantitative methodologies to evaluate RBRR and methodologies for assessing RBRR materials and subsequent changes in knowledge, attitudes, and behavior, may be necessary.

A structure-function analysis shows SARS-CoV-2 BA.2.86 balances antibody escape and ACE2 affinity.

BA.2.86, a recently described sublineage of SARS-CoV-2 Omicron, contains many mutations in the spike gene. It appears to have originated from BA.2 and is distinct from the XBB variants responsible for many infections in 2023. The global spread and plethora of mutations in BA.2.86 has caused concern that it may possess greater immune-evasive potential, leading to a new wave of infection. Here, we examine the ability of BA.2.86 to evade the antibody response to infection using a panel of vaccinated or naturally infected sera and find that it shows marginally less immune evasion than XBB.1.5. We locate BA.2.86 in the antigenic landscape of recent variants and look at its ability to escape panels of potent monoclonal antibodies generated against contemporary SARS-CoV-2 infections. We demonstrate, and provide a structural explanation for, increased affinity of BA.2.86 to ACE2, which may increase transmissibility.

Estimation of the optimal radiotherapy utilization rate for childhood neuroblastoma.

BACKGROUND AND PURPOSE: The optimal utilization rate of radiotherapy (oRUR) serves as a benchmark for assessing service demand and improving access to cancer care. While it is estimated that approximately 50 % of adult cancer patients require external beam radiotherapy during their treatment, there is a scarcity of data regarding the optimal use of radiotherapy in pediatric cancer. In this study, we adopted an established method and developed a model to estimate the oRUR in childhood neuroblastoma. MATERIALS AND METHODS: We developed a decision tree model to calculate the oRUR using indications for radiotherapy and corresponding epidemiological data collected through systematic review and meta-analysis. Sensitivity analyses were performed to evaluate the impact of variations in radiotherapy indications between treatment protocols and variables in the model. We calculated and compared the oRUR for global, high-income, and low- and middle-income settings. RESULTS: The oRUR for pediatric neuroblastoma was 64 % (95 % CI: 58 %-71 %) in the global setting, 50 % in high-income countries, and 68 % in low- and middle-income countries. The impact of variation in radiotherapy indications between major international treatment protocols was negligible. CONCLUSION: The knowledge of oRUR is crucial for evaluating current practices, identifying gaps in access, and planning future radiotherapy services for treating childhood cancer. Based on our results, 64 % of children with neuroblastoma have an indication for radiotherapy. Patients in low- and middle-income countries have more indications for radiotherapy than those in high-income countries, due to a more adverse tumour stage distribution caused by limited access to healthcare resources.

Unstructured linker regions play a role in the differential splicing activities of paralogous RNA binding proteins PTBP1 and PTBP2.

RNA Binding Proteins regulate, in part, alternative pre-mRNA splicing and, in turn, gene expression patterns. Polypyrimidine tract binding proteins PTBP1 and PTBP2 are paralogous RNA binding proteins sharing 74% amino acid sequence identity. Both proteins contain four structured RNA-recognition motifs (RRMs) connected by linker regions and an N-terminal region. Despite their similarities, the paralogs have distinct tissue-specific expression patterns and can regulate discrete sets of target exons. How two highly structurally similar proteins can exert different splicing outcomes is not well understood. Previous studies revealed that PTBP2 is post-translationally phosphorylated in the unstructured N-terminal, Linker 1, and Linker 2 regions that share less sequence identity with PTBP1 signifying a role for these regions in dictating the paralog's distinct splicing activities. To this end, we conducted bioinformatics analysis to determine the evolutionary conservation of RRMs versus linker regions in PTBP1 and PTBP2 across species. To determine the role of PTBP2 unstructured regions in splicing activity, we created hybrid PTBP1-PTBP2 constructs that had counterpart PTBP1 regions swapped to an otherwise PTBP2 protein and assayed on differentially regulated exons. We also conducted molecular dynamics studies to investigate how negative charges introduced by phosphorylation in PTBP2 unstructured regions can alter their physical properties. Collectively, results from our studies reveal an important role for PTBP2 unstructured regions and suggest a role for phosphorylation in the differential splicing activities of the paralogs on certain regulated exons.

Using CombiCells, a platform for titration and combinatorial display of cell surface ligands, to study T-cell antigen sensitivity modulation by accessory receptors.

Understanding cellular decisions due to receptor-ligand interactions at cell-cell interfaces has been hampered by the difficulty of independently varying the surface density of multiple different ligands. Here, we express the synthetic binder protein SpyCatcher, designed to form spontaneous covalent bonds with interactors carrying a Spytag, on the cell surface. Using this, we show that addition of different concentrations and combinations of native Spytag-fused ligands allows for the combinatorial display of ligands on cells within minutes. We use this combinatorial display of cell surface ligands-called CombiCells-to assess T cell antigen sensitivity and the impact of T cell co-stimulation and co-inhibition receptors. We find that the T cell receptor (TCR) displayed greater sensitivity to peptides on major-histocompatibility complexes (pMHC) than synthetic chimeric antigen receptor (CARs) and bi-specific T cell engager (BiTEs) display to their target antigen, CD19. While TCR sensitivity was greatly enhanced by CD2/CD58 interactions, CAR sensitivity was primarily but more modestly enhanced by LFA-1/ICAM-1 interactions. Lastly, we show that PD-1/PD-L1 engagement inhibited T cell activation triggered solely by TCR/pMHC interactions, as well as the amplified activation induced by CD2 and CD28 co-stimulation. The ability to easily produce cells with different concentrations and combinations of ligands should accelerate the study of receptor-ligand interactions at cell-cell interfaces.

Does Tibial Tuberosity Osteotomy Improve Outcomes When Combined With Medial Patellofemoral Ligament Reconstruction in the Presence of Increased Tibial Tuberosity-Trochlear Groove Distance? A Systematic Review and Meta-analysis.

Background: There has been recent debate regarding the optimal surgical management strategy for recurrent patellofemoral instability in the presence of an increased tibial tuberosity-trochlear groove (TT-TG) distance. In particular, performing a combined tibial tuberosity osteotomy (TTO) and medial patellofemoral ligament reconstruction (MPFLR) for patients with a TT-TG >20 mm has been questioned, with the hypothesis that an isolated MPFLR (iMPFLR) would be just as effective. Purpose: To pool and compare outcomes after MPFLR+TTO versus iMPFLR in patients with a TT-TG >20 mm. Study Design: Systematic review; Level of evidence, 4. Methods: PubMed-MEDLINE, Embase, Web of Science, and Cochrane Central were searched, and a systematic review was performed. Included were studies that reported postoperative redislocation rates and/or functional outcome scores for patients with recurrent patellar instability and a TT-TG >20 mm who underwent either MPFLR+TTO or iMPFLR and had minimum 2-year follow-up data. Methodologic quality was assessed using the modified Coleman Methodology Score (mCMS). A proportional meta-analysis comparing redislocation, subjective instability, and total complication rates was performed, and mean postoperative functional outcome scores were pooled using a random-effects model with a restricted maximum likelihood estimator. Results: In total, 1548 studies were screened, from which 13 were included for analysis. Of the 386 included patients (406 knees), 276 underwent MPFLR+TTO and 110 underwent iMPFLR. The mean mCMS was 61.3 ± 10.5 (range, 48-77). The pooled postoperative redislocation rate was 1.22% (95% CI, 0.22%-7%), with no significant difference between the study groups (P = .9995). The pooled complication rate was 10.17% (95% CI, 6.2%-16.3%) with no difference between groups (P = .9275), although the MPFLR+TTO group had higher heterogeneity in complication rates (I2 = 79.4%) compared with iMPFLR (I2 = 0%). There was no group difference in the pooled postoperative Lysholm scores (P = .5177), but patients who underwent iMPFLR had significantly higher postoperative Kujala scores compared with those who underwent MPFLR+TTO (P = .0283). Conclusion: Even in the presence of previously indicative anatomic factors (TT-TG >20 mm), TTO combined with MPFLR does not seem to confer additional benefit compared with iMPFLR. This finding could be advantageous in minimizing the burden of additional surgery with its associated risks. The study findings should, however, be interpreted with caution given the heterogeneity of the studies.

Integrating participant feedback and concerns to improve community and individual level chemical exposure assessment reports.

BACKGROUND: As exposure assessment has shifted towards community-engaged research there has been an increasing trend towards reporting results to participants. Reports aim to increase environmental health literacy, but this can be challenging due to the many unknowns regarding chemical exposure and human health effects. This includes when reports encompass a wide-range of chemicals, limited reference or health standards exist for those chemicals, and/or incompatibility of data generated from exposure assessment tools with published reference values (e.g., comparing a wristband concentration to an oral reference dose). METHODS: Houston Hurricane Harvey Health (Houston-3H) participants wore silicone wristbands that were analyzed for 1,530 organic compounds at two time-points surrounding Hurricane Harvey. Three focus groups were conducted in separate neighborhoods in the Houston metropolitan area to evaluate response to prototype community and individual level report-backs. Participants (n = 31) evaluated prototype drafts using Likert scales and discussion prompts. Focus groups were audio-recorded, and transcripts were analyzed using a qualitative data analysis program for common themes, and quantitative data (ranking, Likert scales) were statistically analyzed. RESULTS: Four main themes emerged from analysis of the transcripts: (1) views on the report layout; (2) expression of concern over how chemicals might impact their individual or community health; (3) participants emotional response towards the researchers; and (4) participants ability to comprehend and evaluate environmental health information. Evaluation of the report and key concerns differed across the three focus groups. However, there was agreement amongst the focus groups about the desire to obtain personal exposure results despite the uncertainty of what the participant results meant. CONCLUSIONS: The report-back of research results (RBRR) for community and individual level exposure assessment data should keep the following key principles in mind: materials should be accessible (language level, data visualization options, graph literacy), identify known information vs unknown (e.g., provide context for what exposure assessment data means, acknowledge lack of current health standards or guidelines), recognize and respect community knowledge and history, and set participant expectations for what they can expect from the report.

POCUS-first for nephrolithiasis: A Monte Carlo simulation illustrating cost savings, LOS reduction, and preventable radiation.

OBJECTIVES: Non-contrast computed tomography (NCCT) is the gold standard for nephrolithiasis evaluation in the emergency department (ED). However, Choosing Wisely guidelines recommend against ordering NCCT for patients with suspected nephrolithiasis who are <50 years old with a history of kidney stones. Our primary objective was to estimate the national annual cost savings from using a point-of-care ultrasound (POCUS)-first approach for patients with suspected nephrolithiasis meeting Choosing Wisely criteria. Our secondary objectives were to estimate reductions in ED length of stay (LOS) and preventable radiation exposure. METHODS: We created a Monte Carlo simulation using available estimates for the frequency of ED visits for nephrolithiasis and eligibility for a POCUS-first approach. The study population included all ED patients diagnosed with nephrolithiasis. Based on 1000 trials of our simulation, we estimated national cost savings in averted advanced imaging from this strategy. We applied the same model to estimate the reduction in ED LOS and preventable radiation exposure. RESULTS: Using this model, we estimate a POCUS-first approach for evaluating nephrolithiasis meeting Choosing Wisely guidelines to save a mean (±SD) of $16.5 million (±$2.1 million) by avoiding 159,000 (±18,000) NCCT scans annually. This resulted in a national cumulative decrease of 166,000 (±165,000) annual bed-hours in ED LOS. Additionally, this resulted in a national cumulative reduction in radiation exposure of 1.9 million person-mSv, which could potentially prevent 232 (±81) excess cancer cases and 118 (±43) excess cancer deaths annually. CONCLUSION: If adopted widely, a POCUS-first approach for suspected nephrolithiasis in patients meeting Choosing Wisely criteria could yield significant national cost savings and a reduction in ED LOS and preventable radiation exposure. Further research is needed to explore the barriers to widespread adoption of this clinical workflow as well as the benefits of a POCUS-first approach in other patient populations.

Development of an age- and comorbidity- adjusted optimal radiotherapy utilisation rate for lung, rectal, prostate and cervical cancers.

INTRODUCTION: Optimal radiotherapy utilisation (RTU) modelling estimates the proportion of people with cancer who would benefit from radiotherapy. Assessment of comorbidities is an important component of the assessment of suitability for radiotherapy in addition to chronological age and life expectancy. Comorbidities have not been considered in previous optimal RTU models. We aimed to develop an age- and comorbidity- adjusted optimal RTU model for patients with lung, rectal, prostate, and cervical cancer, and compare them to actual RTU rates, with a particular focus on those aged 80+ years, METHODS: New South Wales (NSW) Cancer Registry data (2010-2014) linked to radiotherapy data (2010-2015) and hospitalisation data (2008-2015) were used to determine the number of patients diagnosed with lung, rectal, prostate and cervical cancer. The Cancer Specific C3 'all sites' comorbidity index was calculated from hospital diagnosis data for each patient to determine suitability for radiotherapy. The index was then incorporated into a tumour site-specific decision tree model. The actual RTU was also calculated using the linked datasets. RESULTS: 14,696 patients were diagnosed with non-small cell lung cancer (NSCLC), 1839 with small cell lung cancer (SCLC), 5551 with rectal cancer, 30,935 with prostate cancer and 1216 with cervical cancer in New South Wales from 2010-2014. The proportion of patients aged 80+ years at cancer diagnosis was 25% (3603 patients), 15% (279 patients), 17% (943 patients), 12% (3745 patients), and 7% (88 patients) respectively. The age- and comorbidity- adjusted optimal RTU rates for patients aged 80+ years using the C3 index were 49% (NSCLC), 49% (SCLC), 43% (rectal), 51% (prostate) and 40% (cervical). The corresponding actual RTU rates for patients aged 80+ years were 25%, 32%, 27%, 16%, and 56%. CONCLUSION: Even after adjusting for age and comorbidities, the actual radiotherapy utilisation rates were lower than optimal radiotherapy utilisation rates in patients aged 80+ years except for patients with cervical cancer. This warrants further assessment and research into reasons and solutions.

Mindfulness-Based Interventions for the Reduction of Postoperative Pain in Hip and Knee Arthroplasty Patients: A Systematic Review and Meta-Analysis.

PURPOSE: The aim of this systematic review and meta-analysis is to evaluate the effect of mindfulness-based interventions (MBIs) on post-surgical pain in patients undergoing a total hip replacement (THR) or total knee replacement (TKR). METHODS: We performed a systematic review and meta-analysis in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. A search of multiple databases, including PubMed and EMBASE, was performed for studies from database inception through March 2nd, 2022. Data were extracted, and pooled estimates of standardized mean differences in pain scores were calculated using a random effects model and inverse probability weighting. RESULTS: Two randomized control trials were eligible for inclusion (299 patients). The average ages of participants in each study were similar at 65.5 and 64.8 years, and both studies were predominantly female at 72.4% and 61.9%. The mindfulness intervention ranged from an eight-week program to a 20-minute session. Both individual studies reported statistically significant reductions in postoperative pain for MBI groups. The pooled standardized mean difference in pain scores for the MBI groups compared to the control groups was -1.94 (-3.39; -0.48). CONCLUSIONS: There exists preliminary evidence for the beneficial effect of MBIs on reducing the postoperative pain experience in this patient population. Given the significant consequences of postoperative pain and the necessity for non-opioid forms of analgesia, this topic represents a promising area of research that warrants future randomized control trials to better understand the role of MBIs for postoperative analgesia.

Global application of National Comprehensive Cancer Network resource-stratified guidelines for systemic treatment of colon cancer: a population-based, customisable model for cost, demand, and procurement.

BACKGROUND: Resource-stratified guidelines (RSGs) can inform systemic treatment decisions in the face of limited resources. The objective of this study was to develop a customisable modelling tool to predict the demand, cost, and drug procurement needs of delivering National Comprehensive Cancer Network (NCCN) RSG-based systemic treatment for colon cancer. METHODS: We developed decision trees for first-course systemic therapy for colon cancer based on the NCCN RSGs. Decision trees were merged with data from the Surveillance, Epidemiology, and End Results programme, the International Agency for Research on Cancer's GLOBOCAN 2020 national estimates for colon cancer incidence, country-level income data, and data on drug costs from Redbook (USA), the Pharmaceutical Benefits Scheme (Australia), and the Management Sciences for Health 2015 International Medical Products price guide to estimate global treatment needs and costs, and forecast drug procurement. Simulations and sensitivity analyses were used to explore the effect of scaling up services globally and the effect of alternative stage distributions on treatment demand and cost. We generated a customisable model, in which estimates can be tailored to local incidence, epidemiological, and costing data. FINDINGS: First-course systemic therapy is indicated in 608 314 (53·6%) of 1 135 864 colon cancer diagnoses in 2020. Indications for first-course systemic therapy are projected to rise to 926 653 in 2040; the indications in 2020 might be as high as 826 123 (72·7%), depending on stage distribution assumptions. Adhering to NCCN RSGs, patients with colon cancer in low-income and middle income countries (LMICs) would constitute 329 098 (54·1%) of 608 314 global systemic therapy demands, but only 10% of global expenditure on systemic therapies. The total cost of NCCN RSG-based first-course systemic therapy for colon cancer in 2020 would be between about US$4·2 and about $4·6 billion, depending on stage distribution. If all patients with colon cancer in 2020 were treated according to maximal resources, global expenditure on systemic therapy for colon cancer would rise to around $8·3 billion. INTERPRETATION: We have developed a customisable model that can be applied at global, national, and subnational levels to estimate systemic treatment needs, forecast drug procurement, and calculate expected drug costs on the basis of local data. This tool can be used to plan resource allocation for colon cancer globally. FUNDING: None.

Diffusive fluxes of persistent organic pollutants between Arctic atmosphere, surface waters and sediments.

Arctic communities are disproportionately exposed to pollutants from sources including global atmospheric transport and formerly used defense sites (FUDS). The effects of climate change and increasing development in the Arctic have the potential to exacerbate this problem. Yupik People of Sivuqaq, or St Lawrence Island, Alaska are one such community with documented exposures to pollutants from FUDS, and their traditional lipid-rich foods such as blubber and rendered oils of marine mammals. Troutman Lake, adjacent to the Yupik community of Gambell, Alaska, was used as a disposal site during the decommission of the adjacent FUDS, leading to community concern about exposure to military pollution and intrusion from historic local dump sites. In collaboration with a local community group, this study utilized passive sampling devices deployed in Troutman Lake. Air, water and sediment deployed samplers were analyzed for unsubstituted and alkylated polycyclic aromatic hydrocarbons (PAHs), brominated and organophosphate flame retardants and polychlorinated biphenyls (PCBs). PAH concentrations were low and comparable to other remote/rural locations. PAHs were generally in deposition from the overlying atmosphere into Troutman Lake. Of the flame retardants, brominated diphenyl ether-47 was detected in all surface water samplers while triphenyl phosphate was detected in all environmental compartments. Both were at concentrations equivalent or lower than other remote locations. Of particular interest, we measured higher atmospheric concentrations of tris(2-chloroethyl) phosphate (TCEP) (0.75-2.8 ng/m3) than previously reported in the literature for remote Arctic sites (<0.017-0.56 ng/m3). TCEP was found to be in deposition to Troutman Lake at magnitudes from 290 to 1300 ng/m2/day. No PCBs were detected in this study. Our findings demonstrate the relevance of both modern and legacy chemicals from local and global sources. These results help us to understand the fate of anthropogenic contaminants in dynamic Arctic systems providing valuable data for communities, policy makers and scientists.

Novel techniques in performing extraoral ultrasound in diagnosing dental abscesses.

INTRODUCTION: Dental abscesses are a common reason patients present to the emergency department (ED). Facial and dental imaging are sometimes necessary to support the clinical diagnosis. While radiographs and computed tomography scans are frequently used, point-of-care ultrasound (US) offers several advantages, including decreased radiation exposure, reduced costs, and shorter patient length of stay. This report outlines the use of US in evaluating patients with suspected dental abscesses in the ED. DISCUSSION: The typical orofacial US techniques include examining the affected area for cobblestoning or fluid collections. To improve the accuracy of diagnoses, novel techniques such as the Oral Hydroscan (OHS) and the Tongue Pointing Techniques (TPT) may be employed in specific cases. The OHS utilizes a water-filled oral cavity to enhance the spatial resolution of ultrasound images, providing improved visualization of near-field structures and preventing air accumulation between the gingiva and the buccal mucosa. The TPT involves asking the patient to extend their tongue towards the affected area, pointing to the painful location, and serving as a visual reference for an extraoral US. CONCLUSION: US presents several advantages as an alternative imaging method for patients with suspected dental abscesses in the ED. Using innovative techniques such as the OHS and the TPT can further increase the visibility of tissue planes and help define the area of interest in these cases.

Racial Equity in Healthcare Machine Learning: Illustrating Bias in Models With Minimal Bias Mitigation.

Background and objective While the potential of machine learning (ML) in healthcare to positively impact human health continues to grow, the potential for inequity in these methods must be assessed. In this study, we aimed to evaluate the presence of racial bias when five of the most common ML algorithms are used to create models with minimal processing to reduce racial bias. Methods By utilizing a CDC public database, we constructed models for the prediction of healthcare access (binary variable). Using area under the curve (AUC) as our performance metric, we calculated race-specific performance comparisons for each ML algorithm. We bootstrapped our entire analysis 20 times to produce confidence intervals for our AUC performance metrics. Results With the exception of only a few cases, we found that the performance for the White group was, in general, significantly higher than that of the other racial groups across all ML algorithms. Additionally, we found that the most accurate algorithm in our modeling was Extreme Gradient Boosting (XGBoost) followed by random forest, naive Bayes, support vector machine (SVM), and k-nearest neighbors (KNN). Conclusion Our study illustrates the predictive perils of incorporating minimal racial bias mitigation in ML models, resulting in predictive disparities by race. This is particularly concerning in the setting of evidence for limited bias mitigation in healthcare-related ML. There needs to be more conversation, research, and guidelines surrounding methods for racial bias assessment and mitigation in healthcare-related ML models, both those currently used and those in development.

The Superfund Research Program Analytics Portal: linking environmental chemical exposure to biological phenotypes.

The OSU/PNNL Superfund Research Program (SRP) represents a longstanding collaboration to quantify Polycyclic Aromatic Hydrocarbons (PAHs) at various superfund sites in the Pacific Northwest and assess their potential impact on human health. To link the chemical measurements to biological activity, we describe the use of the zebrafish as a high-throughput developmental toxicity model that provides quantitative measurements of the exposure to chemicals. Toward this end, we have linked over 150 PAHs found at Superfund sites to the effect of these same chemicals in zebrafish, creating a rich dataset that links environmental exposure to biological response. To quantify this response, we have implemented a dose-response modelling pipeline to calculate benchmark dose parameters which enable potency comparison across over 500 chemicals and 12 of the phenotypes measured in zebrafish. We provide a rich dataset for download and analysis as well as a web portal that provides public access to this dataset via an interactive web site designed to support exploration and re-use of these data by the scientific community at http://srp.pnnl.gov .

Patterns of curative treatment for non-small cell lung cancer in New South Wales, Australia.

INTRODUCTION: There is a lack of large population-based studies examining patterns of curative treatment for non-small cell lung cancer (NSCLC) in Australia. This study aimed to evaluate the utilization of curative treatment for NCSLC at a population level and identify factors associated with its use in New South Wales (NSW), Australia. METHODS: Patients diagnosed with localized or locoregional NSCLC between 2009 and 2014 were identified from the NSW Central Cancer Registry. Curative treatment was defined as surgery or radiotherapy with a 45 Gy minimum dose. Univariate and multivariable analyses were performed to investigate factors associated with the receipt of curative treatment. A Cox proportional-hazards regression model was used to analyze the factors associated with 2-year overall survival (OS). RESULTS: Of the 5722 patients diagnosed with NSCLC in the study period, 3355 (59%) patients received curative treatment and 2367 (41%) patients did not receive curative treatment. The receipt of curative treatment was significantly associated with younger patients, female gender, localized disease, and Charlson Comorbidity Index (CCI) = 0. The use of curative treatment increased significantly over time from 2009 (55%) to 2014 (63%) and varied significantly from 24% to 70% between local health districts (LHDs) of residence. Younger age, female gender, localized disease, CCI = 0, and overseas country of birth were significantly associated with 2-year OS. The 2-year OS significantly improved from 70% in 2009 to 77% in 2014 for patients who received curative treatment. CONCLUSION: The use of curative treatment for patients with potentially curable NSCLC was low at 59%. However, the use of curative treatment and survival have increased over time. Significant variation was noted in the use of curative treatment between LHDs.

Radiotherapy utilisation rates for patients with cancer as a function of age: A systematic review.

INTRODUCTION: There is an increasing incidence of cancer in older people, but limited data on radiotherapy uptake, and in particular, radiotherapy utilisation (RTU) rates. The RTU rate for older adults with cancer may be lower than recommended due to lower tolerance for radiotherapy as well as additional comorbidities, reduced life expectancy and travel for treatment. Radiotherapy use must be aligned with best available, age-specific evidence to ensure older adults with cancer receive optimal benefit without harms. MATERIALS AND METHODS: A systematic review was conducted to synthesise the published data on the actual RTU rate for patients with cancer as a function of age. MEDLINE and EMBASE were systematically searched to identify relevant population-based and hospital-based cohort studies on radiotherapy utilisation for all age groups, published in English, from 1 January 1990 to 1 July 2020. We focused on the following common cancers in older adults for which radiotherapy is recommended: breast, prostate, lung, rectal cancer, glioblastoma multiforme (GBM), and cervical cancer. Age-specific radiotherapy utilisation data were extracted and analysed as a narrative synthesis. RESULTS: From 2606 studies screened, 75 cohort and population-based studies were identified with age-specific radiotherapy utilisation data. The total number of patients in the 75 studies was 4,792,138. The RTU rate decreased with increasing age for all tumour sites analysed, except for patients receiving curative radiotherapy as definitive treatment for prostate or cervical cancer. This reduction with increasing age was demonstrated in both palliative and curative settings. DISCUSSION: There is a global reduction in radiotherapy utilisation with increasing age for most tumour sites. The reduction in delivery of radiotherapy warrants further examination and evidence-based guidelines specific to this population.

Molecular Dynamics Simulations of the Cardiac Ryanodine Receptor Type 2 (RyR2) Gating Mechanism.

Mutations in the cardiac ryanodine receptor type 2 (RyR2) have been linked to fatal cardiac arrhythmias such as catecholaminergic polymorphic ventricular tachycardia (CPVT). While many CPVT mutations are associated with an increase in Ca2+ leak from the sarcoplasmic reticulum, the mechanistic details of RyR2 channel gating are not well understood, and this poses a barrier in the development of new pharmacological treatments. To address this, we explore the gating mechanism of the RyR2 using molecular dynamics (MD) simulations. We test the effect of changing the conformation of certain structural elements by constructing chimera RyR2 structures that are derived from the currently available closed and open cryo-electron microscopy (cryo-EM) structures, and we then use MD simulations to relax the system. Our key finding is that the position of the S4-S5 linker (S4S5L) on a single subunit can determine whether the channel as a whole is open or closed. Our analysis reveals that the position of the S4S5L is regulated by interactions with the U-motif on the same subunit and with the S6 helix on an adjacent subunit. We find that, in general, channel gating is crucially dependent on high percent occupancy interactions between adjacent subunits. We compare our interaction analysis to 49 CPVT1 mutations in the literature and find that 73% appear near a high percent occupancy interaction between adjacent subunits. This suggests that disruption of cooperative, high percent occupancy interactions between adjacent subunits is a primary cause of channel leak and CPVT in mutant RyR2 channels.