"Older people will die of old age. I'll die of climate change": engaging children and young people in climate decision making for public health.

BACKGROUND: The climate crisis is a significant risk to the health and wellbeing of children, young people, and future generations. While there are calls for children and young people's engagement in climate decision making, current power structures limit their participation. This paper aimed to understand children's perspectives about the impact of the climate crisis on their futures, their ability to influence climate decisions, and strategies and mechanisms to facilitate their greater engagement in decisions made about the climate crisis. METHODS: Online in-depth interviews were conducted with n = 28 children (aged 12-16 years) across Australia. Photo elicitation techniques were used to prompt discussion about how the climate crisis impacted their futures, their ability to influence climate decisions, and strategies and mechanisms to engage them in climate decision making. A reflexive approach to thematic analysis was used to construct three themes from data. Images were analysed for ascribed meanings. RESULTS: First, participants stated that they and future generations will inherit the climate crisis from older generations, specifically decision makers. Second, they described a need to address a range of age-related barriers that limit children and young people's engagement in climate decision making, including perceptions about their capabilities. Finally, they discussed strategies and mechanisms to embed children and young people's perspectives within climate decision making, including at civic and political levels. CONCLUSIONS: Children and young people have the right to be involved in decisions made about the climate crisis which significantly impact their futures, including their health and wellbeing. They argue for structural changes to embed their views in climate decision making, and describe a range of engagement strategies and mechanisms to structure their perspectives and knowledge with decision making processes. Furthermore, genuine involvement of children and young people in climate discussions must avoid youthwashing and tokenistic participation. The public health community can help address barriers to youth participation in climate action and should actively engage and collaborate with children and young people to facilitate their political and democratic influence over the climate crisis. This involves making room and creating an accessible seat at the decision making table to ensure their perspectives are embedded in climate decisions.

Utility of Axillary Staging in Older Patients with HER2-Positive Breast Cancer.

BACKGROUND: The utility of sentinel lymph node biopsy (SLNB) in older patients remains controversial. Advancements in human epidermal growth factor receptor 2 (HER2)-directed therapy have revolutionized disease response rates and prognosis, supporting efforts to re-evaluate the utility of SLNB. We aimed to assess the differences in treatment and overall survival (OS) in older patients with HER2-positive breast cancer based on SLNB. METHODS: Using the National Cancer Database (2010-2020), patients ≥ 70 years of age diagnosed with cT1-2/cN0/M0, HER2-positive breast cancer were identified. Logistic regression assessed associations with SLNB, systemic therapy, and radiation. Cox proportional hazard models were used to identify factors associated with OS. Analyses were stratified by treatment sequence, i.e. upfront surgery or neoadjuvant therapy (NAT) followed by surgery. RESULTS: Of the 17,609 patients included, 94% underwent upfront surgery (n = 16,492) and the remaining underwent NAT (n = 1117). Those who underwent SLNB were more likely to receive adjuvant therapy, irrespective of nodal status {upfront surgery/systemic therapy (odds ratio [OR] 2.82, 95% confidence interval [CI] 2.17-3.67); upfront surgery/radiation (OR 3.97, 95% CI 3.03-5.21); NAT/radiation (OR 5.69, 95% CI 1.83-17.69)}. The breast pathologic complete response (pCR) rate was highest among the hormone receptor (HR)-negative/HER2-positive subtype (50.0%), of which none were found to be ypN+. Comorbidity burden was associated with significantly lower rates of adjuvant systemic therapy and worse OS. CONCLUSIONS: Patients who underwent SLNB, regardless of pN status, were more likely to receive adjuvant therapy. Nodal positivity is exceedingly rare for patients with a breast pCR following NAT, especially among the HR-negative/HER2-positive subtype. It is reasonable to consider omission of SLNB in select subgroups of older patients with HER2-positive breast cancer.

Demographics and Clinical Decision Making in Patients with Germline Moderate Penetrance Non-BRCA Mutations in Breast Cancer Related Genes.

BACKGROUND: Management of pathogenic variants in high penetrance genes related to breast cancer (BC), such as BRCA1 and BRCA2, are well established. However, moderate penetrance mutations are understudied. We aim to compare risk reduction decision-making patterns in patients with a moderate penetrance BC-related genetic mutations, without a prior BC diagnosis. PATIENTS AND METHODS: Female patients aged ≥ 18 years who tested positive for a BRCA1/2, high penetrance, or moderate penetrance mutation related to BC between 1996 and 2023 without a concurrent or prior BC diagnosis were retrospectively identified from a single academic center's database. Groups were stratified by mutation type: BRCA1/2 mutations (BRCA1, BRCA2), high penetrance mutations (HPM; CDH1, PALB2, PTEN, STK11, TP53), or moderate penetrance mutations (MPM; ATM, BARD1, CHEK2, NF1, RAD51C, RAD51D). Demographics and clinical outcomes were compared. RESULTS: A total of 528 patients met the inclusion criteria, with 66% (n = 350) having a BRCA1/2 mutation, 8% (n = 44) having HPM, and 25% (n = 134) having MPM; the median follow-up was 56.0 months. In our cohort, 20.9% of patients with BRCA mutations, 9.1% with HPM, and 7.5% with MPM chose to undergo risk-reducing mastectomies (RRM). Within the moderate penetrance cohort, patients who chose to undergo RRM were younger at the time of genetic testing (39.4 vs. 47.5 years, p = 0.03) and had a higher number of family members with BC (2 vs. 1, p = 0.05). CONCLUSIONS: Our findings provide insights into the demographic characteristics and family history of patients with moderate penetrance mutations and those who pursue risk-reducing surgery.

Cardiomyocyte PANX1 Controls Glycolysis and Neutrophil Recruitment in Hypertrophy.

BACKGROUND: PANX1 (pannexin 1), a ubiquitously expressed ATP release membrane channel, has been shown to play a role in inflammation, blood pressure regulation, and myocardial infarction. However, the possible role of PANX1 in cardiomyocytes in the progression of heart failure has not yet been investigated. METHOD: We generated a novel mouse line with constitutive deletion of PANX1 in cardiomyocytes (Panx1MyHC6). RESULTS: PANX1 deletion in cardiomyocytes had no effect on unstressed heart function but increased the glycolytic metabolism and resulting glycolytic ATP production, with a concurrent decrease in oxidative phosphorylation, both in vivo and in vitro. In vitro, treatment of H9c2 cardiomyocytes with isoproterenol led to PANX1-dependent release of ATP and Yo-Pro-1 uptake, as assessed by pharmacological blockade with spironolactone and siRNA-mediated knockdown of PANX1. To investigate nonischemic heart failure and the preceding cardiac hypertrophy, we administered isoproterenol, and we demonstrated that Panx1MyHC6 mice were protected from systolic and diastolic left ventricle volume increases as a result of cardiomyocyte hypertrophy. Moreover, we found that Panx1MyHC6 mice showed decreased isoproterenol-induced recruitment of immune cells (CD45+), particularly neutrophils (CD11b+, Ly6g+), to the myocardium. CONCLUSIONS: Together, these data demonstrate that PANX1 deficiency in cardiomyocytes increases glycolytic metabolism and protects against cardiac hypertrophy in nonischemic heart failure at least in part by reducing immune cell recruitment. Our study implies PANX1 channel inhibition as a therapeutic approach to ameliorate cardiac dysfunction in patients with heart failure.

Improving symptom management for survivors of young adult cancer: rationale and study protocol for a pilot randomized controlled trial.

BACKGROUND: Young adult (YA) cancer survivors are a growing, yet underserved population who often face significant and long-lasting cancer-related physical (e.g., pain, fatigue) and emotional (e.g., psychological distress) symptoms. Post-treatment symptoms can persist, disrupting YA's abilities to complete goals consistent with their developmental stage (e.g., completing their education, achieving autonomy and independence, building their careers, establishing peer and romantic relationships, building their families). While symptom management has been identified as a significant issue in YA's transitions to survivorship, the symptom management needs of this population largely go unmet. METHODS: We developed an eight-session, group-based behavioral intervention that is delivered using videoconferencing to address the unique symptom management needs of YA cancer survivors. The intervention was developed in conjunction with YA survivors, leading to the novel combination of traditional behavioral symptom coping strategies, home-based physical activity, strategies from contemporary cognitive-behavioral approaches (e.g., those derived from acceptance and commitment therapy, strategies to foster self-compassion), concepts from meaning centered psychotherapy, and behavioral strategies to improve communication and health care engagement. Participants receive printed intervention materials and access to a study-specific mobile application, both of which are used throughout the program. Herein, we report on a pilot study that is in progress. Recruitment has been completed. YA cancer survivors were recruited in cohorts of n = 10 or n = 11 (n = 61) and randomized to the intervention or waitlist control arms. All participants completed a baseline assessment and four additional assessments over 1 year, with each involving a battery of self-report measures. DISCUSSION: The primary objective is to evaluate intervention feasibility and acceptability. As a secondary objective, we will examine patterns of change in intervention targets (i.e., pain, fatigue, emotional distress, symptom interference). Changes from baseline among intervention targets will be estimated for each patient and compared between arms using unadjusted statistical testing. Unadjusted and adjusted multilevel modeling will be used to estimate the effect of the intervention on changes in intervention targets. Interaction models will be used to compare the trajectory of change over time between arms. We expect that this pilot trial will inform our future approach to identify, recruit, and retain participants and provide preliminary data to support a larger, fully powered randomized controlled trial evaluating the intervention. TRIAL REGISTRATION: NCT04035447 at clinicaltrials.gov; registered July 29, 2019.

Methodological and practical guidance for designing and conducting online qualitative surveys in public health.

Online qualitative surveys-those surveys that prioritise qualitative questions and interpretivist values-have rich potential for researchers, particularly in new or emerging areas of public health. However, there is limited discussion about the practical development and methodological implications of such surveys, particularly for public health researchers. This poses challenges for researchers, funders, ethics committees, and peer reviewers in assessing the rigour and robustness of such research, and in deciding the appropriateness of the method for answering different research questions. Drawing and extending on the work of other researchers, as well as our own experiences of conducting online qualitative surveys with young people and adults, we describe the processes associated with developing and implementing online qualitative surveys and writing up online qualitative survey data. We provide practical examples and lessons learned about question development, the importance of rigorous piloting strategies, use of novel techniques to prompt detailed responses from participants, and decisions that are made about data preparation and interpretation. We consider reviewer comments, and some ethical considerations of this type of qualitative research for both participants and researchers. We provide a range of practical strategies to improve trustworthiness in decision-making and data interpretation-including the importance of using theory. Rigorous online qualitative surveys that are grounded in qualitative interpretivist values offer a range of unique benefits for public health researchers, knowledge users, and research participants.

Three-Dimensional Fractional Moving Blood Volume: A Robust Bedside Tool for Evaluation of Fetal Multiorgan Perfusion.

INTRODUCTION: Three-dimensional fractional moving blood volume (3D-FMBV) may provide superior noninvasive measurement of feto-placental perfusion compared to current methods. This study investigated the feasibility and repeatability of producing 3D-FMBV measurements of the placenta, fetal liver, kidney, and brain in a single ultrasound consultation. METHODS: The placenta, fetal liver, kidney, and brain were scanned in triplicate using 3D power Doppler ultrasound (3D-PDU) in 48 women ≥22 weeks of gestation with healthy fetuses. 3D-FMBV was calculated by two analyzers. Feasibility was assessed as the percentage of cases where 3D-FMBV could be evaluated; repeatability (intraobserver and interobserver) using two-way mixed measure intraclass correlation coefficients (ICCs). RESULTS: 3D-FMBV was calculated for 100% of scanned organs. Intraobserver ICCs (95% CI) were good to excellent; 0.93 (0.88-0.96) and 0.87 (0.78-0.92) for placenta, 0.95 (0.92-0.97) and 0.98 (0.96-0.99) for fetal liver, 0.96 (0.94-0.98) and 0.91 (0.85-0.95) for fetal kidney, and 0.98 (0.97-0.99) and 0.97 (0.95-0.98) for fetal brain. Interobserver ICCs (95% CI) were 0.50 (0.08-0.73), 0.92 (0.85-0.96), 0.89 (0.78-0.94), and 0.71 (0.46-0.85) for placenta, fetal liver, kidney, and brain. CONCLUSION: Feto-placental perfusion assessment with 3D-FMBV is highly reliable in healthy pregnancies ≥22 weeks of gestation and can be feasibly calculated in four feto-placental vascular beds in a single ultrasound consultation.

Guideline-Concordant Surgical Care for Lobular Versus Ductal Inflammatory Breast Cancer.

INTRODUCTION: Quality of surgical care is understudied for lobular inflammatory breast cancer (IBC), which is less common, more chemotherapy-resistant, and more mammographically occult than ductal IBC. We compared guideline-concordant surgery (modified radical mastectomy [MRM] without immediate reconstruction following chemotherapy) for lobular versus ductal IBC. METHODS:  Female individuals with cT4dM0 lobular and ductal IBC were identified in the National Cancer Database (NCDB) from 2010-2019. Modified radical mastectomy receipt was identified via codes for "modified radical mastectomy" or "mastectomy" and "≥10 lymph nodes removed" (proxy for axillary lymph node dissection). Descriptive statistics, chi-square tests, and t-tests were used. RESULTS: A total of 1456 lobular and 10,445 ductal IBC patients were identified; 599 (41.1%) with lobular and 4859 (46.5%) with ductal IBC underwent MRMs (p = 0.001). Patients with lobular IBC included a higher proportion of individuals with cN0 disease (20.5% lobular vs. 13.7% ductal) and no lymph nodes examined at surgery (31.2% vs. 24.5%) but were less likely to be node-negative at surgery (12.7% vs. 17.1%, all p < 0.001). Among those who had lymph nodes removed at surgery, patients with lobular IBC also had fewer lymph nodes excised versus patients with ductal IBC (median [interquartile range], 7 (0-15) vs. 9 (0-17), p = 0.001). CONCLUSIONS: Lobular IBC patients were more likely to present with node-negative disease and less likely to be node-negative at surgery, despite having fewer, and more frequently no, lymph nodes examined versus ductal IBC patients. Future studies should investigate whether these treatment disparities are because of surgical approach, pathologic assessment, and/or data quality as captured in the NCDB.

Does matrix transducer technology improve quality and repeatability of four-dimensional tricuspid annular plane systolic excursion and mitral annular plane systolic excursion measurements?

Background: Novel ultrasound technology and software processing allow offline evaluation of tricuspid annular plane systolic excursion and mitral annular plane systolic excursion measurements. We wished to compare both novel 4D matrix (eM6C) and conventional (RAB6-D) transducers with variable settings (electronic spatiotemporal image correlation, spatiotemporal image correlation and four-dimensional real time) to determine if there was a significant difference in absolute value, quality and repeatability of the resultant reconstructed image and M-mode trace. Methods: A blinded prospective cross-sectional study of normal fetuses from 23 to 38 weeks' gestation were recruited. After routine sonography, four-dimensional volumes were stored and analysed using GE 4DView™ software. Statistical analysis explored variability, correlations and repeatability of the measurements with chi-square analysis, intraclass correlations and the Bland-Altman comparison plots. A scoring system was devised for image quality. Results: Eighteen participants generated 282 data volumes. Absolute values demonstrated some inconsistencies for both tricuspid annular plane systolic excursion and mitral annular plane systolic excursion measurements with variations between transducers: the highest for the RAB6-D/spatiotemporal image correlation setting and the lowest for the four-dimensional real-time settings. The RAB6-D/spatiotemporal image correlation setting was the most repeatable combination (intraclass correlation coefficient = 0.85). Poorest image quality (M-mode trace, four-chamber view, annuli) came from the RAB6-D/four-dimensional real-time combination with the eM6C/electronic spatiotemporal image correlation and RAB6-D/spatiotemporal image correlation settings being nearly identical. Conclusion: We show that transducer and setting combinations influence absolute tricuspid annular plane systolic excursion/mitral annular plane systolic excursion measurements, so need to be articulated in future research. The transducer setting (electronic spatiotemporal image correlation/spatiotemporal image correlation/four-dimensional real time) was a more significant factor than the type of transducer (conventional vs matrix). Subjective image evaluation does not correlate well with repeatability of image acquisition. Further studies are needed to compare measurements using four-dimensional post-processing tools against conventional real-time measurements.

PTEN inhibition promotes robust growth of bulbospinal respiratory axons and partial recovery of diaphragm function in a chronic model of cervical contusion spinal cord injury.

High spinal cord injury (SCI) leads to persistent and debilitating compromise in respiratory function. Cervical SCI not only causes the death of phrenic motor neurons (PhMNs) that innervate the diaphragm, but also damages descending respiratory pathways originating in the rostral ventral respiratory group (rVRG) located in the brainstem, resulting in denervation and consequent silencing of spared PhMNs located caudal to injury. It is imperative to determine whether interventions targeting rVRG axon growth and respiratory neural circuit reconnection are efficacious in chronic cervical contusion SCI, given that the vast majority of individuals are chronically-injured and most cases of SCI involve contusion-type damage to the cervical region. We therefore employed a rat model of chronic cervical hemicontusion to test therapeutic manipulations aimed at reconstructing damaged rVRG-PhMN-diaphragm circuitry to achieve recovery of respiratory function. At a chronic time point post-injury, we systemically administered: an antagonist peptide directed against phosphatase and tensin homolog (PTEN), a central inhibitor of neuron-intrinsic axon growth potential; an antagonist peptide directed against receptor-type protein tyrosine phosphatase sigma (PTPσ), another important negative regulator of axon growth capacity; or a combination of these two peptides. PTEN antagonist peptide (PAP4) promoted partial recovery of diaphragm motor activity out to nine months post-injury (though this effect depended on the anesthetic regimen used during recording), while PTPσ peptide did not impact diaphragm function after cervical SCI. Furthermore, PAP4 promoted robust growth of descending bulbospinal rVRG axons caudal to the injury within the denervated portion of the PhMN pool, while PTPσ peptide did not affect rVRG axon growth at this location that is critical to control of diaphragmatic respiratory function. In conclusion, we find that, when PTEN inhibition is targeted at a chronic time point following cervical contusion, our non-invasive PAP4 strategy can successfully promote significant regrowth of damaged respiratory neural circuitry and also partial recovery of diaphragm motor function.

Patient Characteristics Impact Performance of AI Algorithm in Interpreting Negative Screening Digital Breast Tomosynthesis Studies.

Background Artificial intelligence (AI) is increasingly used to manage radiologists' workloads. The impact of patient characteristics on AI performance has not been well studied. Purpose To understand the impact of patient characteristics (race and ethnicity, age, and breast density) on the performance of an AI algorithm interpreting negative screening digital breast tomosynthesis (DBT) examinations. Materials and Methods This retrospective cohort study identified negative screening DBT examinations from an academic institution from January 1, 2016, to December 31, 2019. All examinations had 2 years of follow-up without a diagnosis of atypia or breast malignancy and were therefore considered true negatives. A subset of unique patients was randomly selected to provide a broad distribution of race and ethnicity. DBT studies in this final cohort were interpreted by a U.S. Food and Drug Administration-approved AI algorithm, which generated case scores (malignancy certainty) and risk scores (1-year subsequent malignancy risk) for each mammogram. Positive examinations were classified based on vendor-provided thresholds for both scores. Multivariable logistic regression was used to understand relationships between the scores and patient characteristics. Results A total of 4855 patients (median age, 54 years [IQR, 46-63 years]) were included: 27% (1316 of 4855) White, 26% (1261 of 4855) Black, 28% (1351 of 4855) Asian, and 19% (927 of 4855) Hispanic patients. False-positive case scores were significantly more likely in Black patients (odds ratio [OR] = 1.5 [95% CI: 1.2, 1.8]) and less likely in Asian patients (OR = 0.7 [95% CI: 0.5, 0.9]) compared with White patients, and more likely in older patients (71-80 years; OR = 1.9 [95% CI: 1.5, 2.5]) and less likely in younger patients (41-50 years; OR = 0.6 [95% CI: 0.5, 0.7]) compared with patients aged 51-60 years. False-positive risk scores were more likely in Black patients (OR = 1.5 [95% CI: 1.0, 2.0]), patients aged 61-70 years (OR = 3.5 [95% CI: 2.4, 5.1]), and patients with extremely dense breasts (OR = 2.8 [95% CI: 1.3, 5.8]) compared with White patients, patients aged 51-60 years, and patients with fatty density breasts, respectively. Conclusion Patient characteristics influenced the case and risk scores of a Food and Drug Administration-approved AI algorithm analyzing negative screening DBT examinations. © RSNA, 2024.

Evaluating fetal tricuspid and mitral annular plane systolic excursion (TAPSE and MAPSE) using spatiotemporal image correlation (STIC) M-mode.

OBJECTIVES: This study aimed to evaluate the feasibility and reliability of tricuspid and mitral annular plane systolic excursion measurements (TAPSE and MAPSE) applying M-mode spatiotemporal image correlation (STIC) technology in low-risk pregnancies. METHODS: An initial retrospective pilot study was carried out to assess repeatability, followed by a larger mixed cross-sectional and prospective longitudinal study, both evaluating low-risk singleton pregnancies between 22+6 and 39+1 weeks. As only annuli capture was necessary, STIC acquisition parameters were set to the minimum volume angle of 15° and acquisition time of 7.5 s. RESULTS: A total of 330 volumes were analysed offline applying STIC M-mode. Acquisition rates were 96.9 % for TAPSE and 93.7 % MAPSE in the pilot study (n=32) and 98.0 % for both in the longitudinal study (n=102). Both study designs revealed good repeatability for both sides of the heart, with higher intraclass correlation coefficients (ICCs) for TAPSE (0.84-0.94) compared to MAPSE (0.80-0.88). Good repeatability was demonstrated for both sides of the heart, more so for TAPSE than MAPSE, with ICCs for TAPSE 0.84-0.91 and MAPSE 0.75-0.76, comparable to prior ICCs for STIC repeatability. CONCLUSIONS: Modified STIC acquisition settings specifically tailored for capturing the longitudinal annular displacement may improve STIC TAPSE and MAPSE acquisition rates, optimising image quality for precise measurement and potentially bringing these modalities closer to clinical application.

Health Care Cost Reductions with Machine Learning-Directed Evaluations during Radiation Therapy - An Economic Analysis of a Randomized Controlled Study.

BACKGROUND: Machine learning (ML) may cost-effectively direct health care by identifying patients most likely to benefit from preventative interventions to avoid negative and expensive outcomes. System for High-Intensity Evaluation During Radiation Therapy (SHIELD-RT; NCT04277650) was a single-institution, randomized controlled study in which electronic health record-based ML accurately identified patients at high risk for acute care (emergency visit or hospitalization) during radiotherapy (RT) and targeted them for supplemental clinical evaluations. This ML-directed intervention resulted in decreased acute care utilization. Given the limited prospective data showing the ability of ML to direct interventions cost-efficiently, an economic analysis was performed. METHODS: A post hoc economic analysis was conducted of SHIELD-RT that included RT courses from January 7, 2019, to June 30, 2019. ML-identified high-risk courses (≥10% risk of acute care during RT) were randomized to receive standard of care weekly clinical evaluations with ad hoc supplemental evaluations per clinician discretion versus mandatory twice-weekly evaluations. The primary outcome was difference in mean total medical costs during and 15 days after RT. Acute care costs were obtained via institutional cost accounting. Physician and intervention costs were estimated via Medicare and Medicaid data. Negative binomial regression was used to estimate cost outcomes after adjustment for patient and disease factors. RESULTS: A total of 311 high-risk RT courses among 305 patients were randomized to the standard (n=157) or the intervention (n=154) group. Unadjusted mean intervention group supplemental visit costs were $155 per course (95% confidence interval, $142 to $168). The intervention group had fewer acute care visits per course (standard, 0.47; intervention, 0.31; P=0.04). Total mean adjusted costs were $3110 per course for the standard group and $1494 for the intervention group (difference in means, $1616 [95% confidence interval, $1450 to $1783]; P=0.03). CONCLUSIONS: In this economic analysis of a randomized controlled, health care ML study, mandatory supplemental evaluations for ML-identified high-risk patients were associated with both reduced total medical costs and improved clinical outcomes. Further study is needed to determine whether economic results are generalizable. (Funded in part by The Duke Endowment, The Conquer Cancer Foundation, the Duke Department of Radiation Oncology, and the National Cancer Institute of the National Institutes of Health [R01CA277782]; ClinicalTrials.gov number, NCT04277650.).

Dietary Nitrate Metabolism in Porcine Ocular Tissues Determined Using 15N-Labeled Sodium Nitrate Supplementation.

Nitrate (NO3-) obtained from the diet is converted to nitrite (NO2-) and subsequently to nitric oxide (NO) within the body. Previously, we showed that porcine eye components contain substantial amounts of nitrate and nitrite that are similar to those in blood. Notably, cornea and sclera exhibited the capability to reduce nitrate to nitrite. To gain deeper insights into nitrate metabolism in porcine eyes, our current study involved feeding pigs either NaCl or Na15NO3 and assessing the levels of total and 15N-labeled NO3-/NO2- in various ocular tissues. Three hours after Na15NO3 ingestion, a marked increase in 15NO3- and 15NO2- was observed in all parts of the eye; in particular, the aqueous and vitreous humor showed a high 15NO3- enrichment (77.5 and 74.5%, respectively), similar to that of plasma (77.1%) and showed an even higher 15NO2- enrichment (39.9 and 35.3%, respectively) than that of plasma (19.8%). The total amounts of NO3- and NO2- exhibited patterns consistent with those observed in 15N analysis. Next, to investigate whether nitrate or nitrite accumulate proportionally after multiple nitrate treatments, we measured nitrate and nitrite contents after supplementing pigs with Na15NO3 for five consecutive days. In both 15N-labeled and total nitrate and nitrite analysis, we did not observe further accumulation of these ions after multiple treatments, compared to a single treatment. These findings suggest that dietary nitrate supplementation exerts a significant influence on nitrate and nitrite levels and potentially NO levels in the eye and opens up the possibility for the therapeutic use of dietary nitrate/nitrite to enhance or restore NO levels in ocular tissues.

Critical updates in neuroendocrine tumors: Version 9 American Joint Committee on Cancer staging system for gastroenteropancreatic neuroendocrine tumors.

The American Joint Committee on Cancer (AJCC) staging system for all cancer sites, including gastroenteropancreatic neuroendocrine tumors (GEP-NETs), is meant to be dynamic, requiring periodic updates to optimize AJCC staging definitions. This entails the collaboration of experts charged with evaluating new evidence that supports changes to each staging system. GEP-NETs are the second most prevalent neoplasm of gastrointestinal origin after colorectal cancer. Since publication of the AJCC eighth edition, the World Health Organization has updated the classification and separates grade 3 GEP-NETs from poorly differentiated neuroendocrine carcinoma. In addition, because of major advancements in diagnostic and therapeutic technologies for GEP-NETs, AJCC version 9 advocates against the use of serum chromogranin A for the diagnosis and monitoring of GEP-NETs. Furthermore, AJCC version 9 recognizes the increasing role of endoscopy and endoscopic resection in the diagnosis and management of NETs, particularly in the stomach, duodenum, and colorectum. Finally, T1NXM0 has been added to stage I in these disease sites as well as in the appendix.

'You can't really separate these risks, our environment, our animals and us': Australian children's perceptions of the risks of the climate crisis.

Perceptions of the risks associated with the climate crisis are shaped by a range of social and political contexts and information sources. While some have expressed concerns about the impact of the spread of climate misinformation through social media platforms on young people, others have shown that the youth climate movement has played a key role in countering misinformation. Despite this, there has been very limited research with children about how they conceptualize the risks associated with the climate crisis, how they receive climate information, and how they understand and apply this to their own and others' lives. The following qualitative study used photo-elicitation techniques and in-depth interviews with Australian children to address this gap. A total of n = 28 children (12-16 years) participated, with four themes constructed from the data using a reflexive approach to thematic analysis. Children were concerned about how the climate crisis would continue to harm their futures and the health of planet and people. They recognized that some groups and countries would experience more risks associated with the climate crisis as compared to others. While they received information from a range of different sources (school, family, social media), they mostly used social media to seek out climate information. They recognized that social media sites could be a source of climate misinformation, and argued that a range of strategies were needed to identify and counter false information about the climate crisis. Children's perspectives must be harnessed to improve information about climate risks and action.

Survival among patients with untreated metastatic breast cancer: "What if I do nothing?"

PURPOSE: We sought to assess survival outcomes of patients with de novo metastatic breast cancer (dnMBC) who did not receive treatment irrespective of the reason. METHODS: Adults with dnMBC were selected from the NCDB (2010-2016) and stratified based on receipt of treatment (treated = received at least one treatment and untreated = received no treatments). Overall survival (OS) was estimated using the Kaplan-Meier method, and groups were compared. Cox proportional hazards models were used to identify factors associated with OS. RESULTS: Of the 53,240 patients with dnMBC, 92.1% received at least one treatment (treated), and 7.9% had no documented treatments, irrespective of the reason (untreated). Untreated patients were more likely to be older (median 68 y vs 61 y, p < 0.001), have higher comorbidity scores (p < 0.001), have triple-negative disease (17.8% vs 12.6%), and a higher disease burden (≥ 2 metastatic sites: 38.2% untreated vs 29.2% treated, p < 0.001). The median unadjusted OS in the untreated subgroup was 2.5 mo versus 36.4 mo in the treated subgroup (p < 0.001). After adjustment, variables associated with a worse OS in the untreated cohort included older age, higher comorbidity scores, higher tumor grade, and triple-negative (vs HR + /HER2-) subtype (all p < 0.05), while the number of metastatic sites was not associated with survival. CONCLUSIONS: Patients with dnMBC who do not receive treatment are more likely to be older, present with comorbid conditions, and have clinically aggressive disease. Similar to those who do receive treatment, survival in an untreated population is associated with select patient and disease characteristics. However, the prognosis for untreated dnMBC is dismal.

Anatomy Versus Biology: What Guides Chemotherapy Decisions in Older Patients With Breast Cancer?

INTRODUCTION: With the increasing utilization of genomic assays, such as the Oncotype DX recurrence score (RS), the relevance of anatomic staging has been questioned for select older patients with breast cancer. We sought to evaluate differences in chemotherapy receipt and/or survival among older patients based on RS and sentinel lymph node biopsy (SLNB) receipt/result. METHODS: Patients aged ≥ 65 diagnosed with pT1-2/cN0/M0 hormone-receptor-positive (HR+)/HER2-breast cancer (2010-2019) were selected from the National Cancer Database. Logistic regression was used to identify factors associated with chemotherapy receipt. Cox proportional hazards models were used to estimate the association of RS/SLNB group with overall survival. A cost-benefit study was also performed. RESULTS: Of the 75,428 patients included, the majority had an intermediate RS (58.2% versus 27.9% low, 13.8% high) and were SLNB- (85.1% versus 11.6% SLNB+, 3.3% none). Chemotherapy was recommended for 13,442 patients (17.8%). After adjustment, chemotherapy receipt was more likely with higher RS and SLNB+. After adjustment, SLNB receipt/result was only associated with overall survival among those with an intermediate RS. However, returning to the OR for SLNB is not cost-effective. CONCLUSIONS: SLNB receipt/result was associated with survival for those with an intermediate RS, but not a low or high RS, suggesting that an SLNB may indeed be unnecessary for select older patients with breast cancer.