Search

Purpose: Financial toxicity is an adverse outcome of cancer care and is often quantified by patient-reported validated survey tools, such as The Comprehensive Score for Financial Toxicity (COST). We aimed to examine the association of objective financial measures of hospital out-of-pocket (OOP) expenses and write-offs with the patient derived COST scores in patients with gynecologic cancer. Methods: We identified individuals who completed our cross-sectional survey in discrete periods between 2017 and 2021. Response rates for these periods ranged from 75 to 95%. Hospital financial data was abstracted for respondents, including OOP payments and write-offs in the year before survey completion. Write-offs occurred when patients did not complete payments and included bills forgiven by the hospital or sent to collections. Chi-square, Fisher’s exact, Kruskal–Wallis, and Cochran-Armitage tests were used to compare variables. Results: Among 323 respondents, median COST score was 29 (IQR 22–36) and 13% had severe, 25% moderate and 62% mild financial toxicity. Increased financial toxicity was associated with age, race, partner, employment status, insurance type, and income (p < 0.05). Most (63%) respondents had OOP payments and 31% had write-offs. The moderate financial toxicity group had the highest median OOP payment ($799 ($246–$2,004)) as compared to those with severe and mild financial toxicity (p = 0.01). Meanwhile, those with severe financial toxicity were more likely to have a write-off (44%), compared to the moderate and mild financial toxicity groups (p trend = 0.02) and had the highest median write-off amount ($417 ($150–$827), p = 0.03). Conclusion: Patient-reported financial toxicity is associated with objective financial measures of hospital out-of-pocket costs and write-offs. [ABSTRACT FROM AUTHOR]

Flooding is a pervasive natural hazard with wide-ranging impacts on society. Using a high-resolution global flood model considering coastal, fluvial, and pluvial hazards, we clarify the role of climate effects versus population growth effects in changing flood exposure. Between 2020 and 2100, the population likely exposed to 1% annual risk (100-year) flood hazard will increase from 1.6 to 1.9 billion people. Of this change from the 2020 exposure, we attribute 21.1% to climate change, 76.8% to population change, and 2.1% to both climate and population change. The largest driver of uncertainty in exposure is population change, while climate change remains a smaller but still important driver. The global increase in exposure between 2020 and 2100 is primarily driven by low-GDP regions, and by 2100 the lowest GDP areas will make up 63% of the exposure both overall and in urban areas. Urban areas are especially vulnerable in nearly all global regions, and urban areas sensitive to extreme events are expected to see a 33% increase in population exposure. This study highlights the vast inequities in flood exposure, and future work should direct resources and strategies toward sustainable risk mitigation in these areas. This study explores how climate change and population growth shape flood exposure. By 2100, exposure could rise from 1.6 to 1.9 billion people, driven 21% by climate change and 77% by population growth, with low-income and urban regions most affected. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate right ventricular (RV) uptake measured by quantitative [99mTc]Tc-DPD SPECT/CT to investigate its role in predicting and evaluating prognosis and therapeutic outcomes in patients with transthyretin amyloid cardiomyopathy (ATTR-CA). Methods: Patients with ATTR-CA were consecutively enrolled for quantitative [99mTc]Tc-DPD SPECT/CT. Ventricular amyloid burden was quantified by SUVmax and TBR. Differences in RV uptake (focal or diffuse) and associations with clinical characteristics and CMR data were evaluated. The primary endpoint was major adverse cardiac events (MACEs), including all-cause deaths, heart failure hospitalizations, complete atrioventricular block, sustained ventricular tachycardia, and atrial fibrillation/flutter. Prognostic associations were evaluated using Cox regression and Kaplan-Meier survival analysis. A secondary endpoint involved a longitudinal SPECT/CT analysis during Tafamidis therapy. Results: The study included 76 patients, all showing both RV and LV uptake on SPECT imaging. Compared with patients with focal RV uptake, patients with diffuse RV uptake had higher serum troponin T levels (P < 0.05), septal thickness (P < 0.01), and external cardiac circulation volume (ECV) (P < 0.05). RV uptake was correlated with septal thickness, ECV, LV uptake, NT-proBNP and troponin-T (all P < 0.05). Among 53 patients, high LV and RV uptake significantly predicted MACEs (P < 0.001), with a median follow-up time of 16 months. A subgroup of 20 patients showed significant reductions in LV and RV uptake after Tafamidis treatment (P < 0.001). Conclusion: Increasing RV amyloid burden quantified by SPECT/CT is associated with advanced disease stage and predicts MACEs, serving as valuable markers for prognosis and treatment monitoring in ATTR-CA. [ABSTRACT FROM AUTHOR]

Aim: The combination of positron emission tomography (PET) and magnetic resonance imaging (MRI) provides an innovation leap in the use of fertilized chicken eggs (in ovo model) in preclinical imaging as PET/MRI enables the investigation of the chick embryonal organ-specific distribution of PET-tracers. However, hybrid PET/MRI inheres technical challenges in quantitative in ovo PET such as attenuation correction (AC) for the object as well as for additional hardware parts present in the PET field-of-view, which potentially contribute to quantification biases in the PET images if not accounted for. This study aimed to investigate the influence of the different sources of attenuation on in ovo PET/MRI and assess the accuracy of MR-based AC for in ovo experiments. Method: An in-house made chicken egg phantom was used to investigate the magnitude of self-attenuation and the influence of the MRI hardware on the PET signal. The phantom was placed in a preclinical PET/MRI system and PET acquisitions were performed without, and after subsequently adding the different hardware parts to the setup. Reconstructions were performed without any AC for the different setups and with subsequently incorporating the hardware parts into the AC. In addition, in ovo imaging was performed using [18F]FDG and [68Ga]Ga-Pentixafor, and PET data was reconstructed with the different AC combinations. Quantitative accuracy was assessed for the phantom and the in ovo measurements. Results: In general, not accounting for the self-attenuation of the egg and the hardware parts caused an underestimation of the PET signal of around 49% within the egg. Accounting for all sources of attenuation allowed a proper quantification with global offsets of 2% from the true activity. Quantification based on % injected dose per cc (%ID/cc) was similar for the in ovo measurements, regardless of whether hardware parts were included in AC or not, when the injected activity was extracted from the PET images. However, substantial quantification biases were found when the self-attenuation of the egg was not taken into account. Conclusion: Self-attenuation of the egg and PET signal attenuation within the hardware parts of the MRI substantially influence quantitative accuracy in in ovo measurements. However, when compensating for the self-attenuation of the egg by a respective AC, a reliable quantification using %ID/cc can be performed even if not accounting for the attenuation of the hardware parts. [ABSTRACT FROM AUTHOR]

Gut microbiota affect transplantation outcomes; however, the influence of immunosuppression and cell therapy on the gut microbiota in cardiovascular care remains unexplored. We investigated gut microbiota dynamics in a nonhuman primate (NHP) cardiac ischemia/reperfusion model while under immunosuppression and receiving cell therapy with human induced pluripotent stem cell (hiPSC)-derived endothelial cells (EC) and cardiomyocytes (CM). Both immunosuppression and EC/CM co-treatment increased gut microbiota alpha diversity. Immunosuppression promoted anaerobes, such as Faecalibacterium, Streptococcus, Anaerovibrio and Dialister, and altered amino acid metabolism and nucleosides/nucleotides biosynthesis in host plasma. EC + CM cotreatment favors Phascolarctobacterium, Fusicatenibacter, Erysipelotrichaceae UCG-006, Veillonella and Mailhella. Remarkably, gut microbiota of the EC/CM co-treatment group resembled that of the pre-injury group, and the NHPs exhibited a metabolic shift towards amino acid and fatty acid/lipid biosynthesis in plasma following cell therapy. The interplay between shift in microbial community and host homeostasis during treatment suggests gut microbiome modulation could improve cell therapy outcomes. [ABSTRACT FROM AUTHOR]

Background: Poly (ADP-ribose) polymerase (PARP) enzymes are crucial for the repair of DNA single-strand breaks and have become key therapeutic targets in homologous recombination-deficient cancers, including prostate cancer. To enable non-invasive monitoring of PARP-1 expression, several PARP-1-targeting positron emission tomography (PET) tracers have been developed. Here, we aimed to preclinically investigate [carbonyl-11C]DPQ as an alternative PARP-1 PET tracer as it features a strongly distinct chemotype compared to the frontrunners [18F]FluorThanatrace and [18F]PARPi. Results: [carbonyl-11C]DPQ was synthesised in a GE TracerLab FXC2 module, yielding sufficient activity (940 ± 410 MBq), molar activity (53 ± 16 GBq/µmol) and radiochemical purity (> 97%) for subsequent preclinical evaluation. [carbonyl-11C]DPQ showed high stability in formulation, in human plasma, and when incubated with human liver microsomes. In vitro, similar specific uptake was observed in both PC3 prostate cancer cells and CHO-K1 Chinese hamster ovary cells. However, in vivo studies using fertilised chicken eggs (in ovo model) revealed poor and non-displaceable tumour accumulation in PC3-derived xenografts, despite confirmed vascularisation and PARP-1 expression. Rapid uptake was observed in the liver (10 min), with less than 30% of the intact compound remaining in the liver 70 min post-injection. Conclusions: Although [carbonyl-11C]DPQ demonstrated metabolic stability and specific binding in vitro, suboptimal tumour-targeting properties and pronounced liver metabolism were observed in ovo. Therefore, further animal experiments with mammalian models were not indicated. [ABSTRACT FROM AUTHOR]

The analysis of serum for biomarkers is a standard method in clinical diagnosis and health assessment. The application of Raman spectroscopy to probe biomarkers in serum is increasingly investigated due to its time- and cost-efficiency. However, time-consuming sample preparation is often required to analyze the serum samples. Additionally, hemolyzed samples are commonly discarded due to interference in the measurements. This study focuses on the application of the online coupling of size exclusion chromatography (SEC) to diode array detector (DAD) and capillary-enhanced Raman spectroscopy (CERS) for direct analysis of hemolyzed serum samples. We demonstrate that different protein classes such as serum albumin and immunoglobulin G (IgG) can be identified in hemolyzed serum according to a calculated hit quality index (HQI). Additionally, different oxidation and binding states of the heme prosthetic group are investigated at 532-nm excitation. The online coupling of SEC-DAD-CERS enables the detailed characterization of blood serum proteins, including the differentiation of IgG, serum albumin, and hemoglobin. [ABSTRACT FROM AUTHOR]

Background: Most individuals who come under the care of large healthcare systems will have experienced at least one traumatic incident in their lifetime that may continue to influence their mental and physical health, disease management, and engagement with treatment and medical professionals. Histories of trauma are especially common in patients with gastrointestinal (GI) illness. Trauma reactions can arise in GI settings, but healthcare providers may not recognize these reactions or know how to respond effectively. Aims: We aimed to increase awareness and understanding of the relationship between trauma and GI symptoms, trauma reactions in a healthcare setting, strategies for responding to patients in emotional distress, and opportunities to reduce risk of retraumatization in a GI setting. Methods: Within a larger initiative to enhance behavioral healthcare access and engagement in a GI setting, patient and stakeholder interviews were conducted, and a needs assessment survey was administered. Interview and survey findings informed development of innovative solutions to the identified need for improved trauma services and resources using an iterative, team-based approach. Results: Programs and resources were developed and implemented to increase recognition of the impact of trauma, improve responses to trauma reactions during encounters with patients (e.g., clinical and procedure visits, telephone calls), and provide support to patients receiving GI care. Conclusions: Trauma-focused programming specific to the needs of patients with GI conditions is desired by patients, providers, and staff. Education, intervention, and support initiatives have potential to increase awareness of the effects of trauma and enhance experience of healthcare. [ABSTRACT FROM AUTHOR]

Coastal ecosystems such as mangroves, salt marshes, and seagrasses sequester large amounts of carbon per unit area due to their high productivity and sediment accumulation rates. However, only a handful of studies have examined carbon sequestration in coastal dunes, which are shaped by biophysical feedback between aeolian sediment transport and burial-tolerant vegetation. The goal of this study was to measure carbon storage and identify the factors that influence its variability along the foredunes of the US Outer Banks barrier islands of North Carolina. Specifically, differences in carbon stocks (above- and belowground biomass and sand), dune grass abundance, and sand supply were measured among islands, cross-shore dune profile locations, and dune grass species. Carbon varied among aboveground grass biomass (0.1 ± 0.1 kg C m−2), belowground grass biomass (1.1 ± 1.6 kg C m−3), and sand (0.9 ± 0.6 kg C m−3), with the largest amount in belowground grass stocks. Aboveground grass carbon stocks were comparable to those in eelgrass beds and salt marshes on a per-area basis, while sediment carbon values in our study system were lower than those in other coastal systems, including other dune locations. Additionally, sand carbon density was positively related to patterns in dune sand supply and grass abundance, reflecting a self-reinforcing vegetation-sediment feedback at both high and low sand accumulation rates. [ABSTRACT FROM AUTHOR]

Objectives: Radical prostatectomy (RP) is a common intervention in patients with localized prostate cancer (PCa), with nerve-sparing RP recommended to reduce adverse effects on patient quality of life. Accurate pre-operative detection of extraprostatic extension (EPE) remains challenging, often leading to the application of suboptimal treatment. The aim of this study was to enhance pre-operative EPE detection through multimodal data integration using explainable machine learning (ML). Methods: Patients with newly diagnosed PCa who underwent [68Ga]Ga-PSMA-11 PET/MRI and subsequent RP were recruited retrospectively from two time ranges for training, cross-validation, and independent validation. The presence of EPE was measured from post-surgical histopathology and predicted using ML and pre-operative parameters, including PET/MRI-derived features, blood-based markers, histology-derived parameters, and demographic parameters. ML models were subsequently compared with conventional PET/MRI-based image readings. Results: The study involved 107 patients, 59 (55%) of whom were affected by EPE according to postoperative findings for the initial training and cross-validation. The ML models demonstrated superior diagnostic performance over conventional PET/MRI image readings, with the explainable boosting machine model achieving an AUC of 0.88 (95% CI 0.87–0.89) during cross-validation and an AUC of 0.88 (95% CI 0.75–0.97) during independent validation. The ML approach integrating invasive features demonstrated better predictive capabilities for EPE compared to visual clinical read-outs (Cross-validation AUC 0.88 versus 0.71, p = 0.02). Conclusion: ML based on routinely acquired clinical data can significantly improve the pre-operative detection of EPE in PCa patients, potentially enabling more accurate clinical staging and decision-making, thereby improving patient outcomes. Critical relevance statement: This study demonstrates that integrating multimodal data with machine learning significantly improves the pre-operative detection of extraprostatic extension in prostate cancer patients, outperforming conventional imaging methods and potentially leading to more accurate clinical staging and better treatment decisions. Key Points: Extraprostatic extension is an important indicator guiding treatment approaches. Current assessment of extraprostatic extension is difficult and lacks accuracy. Machine learning improves detection of extraprostatic extension using PSMA-PET/MRI and histopathology. [ABSTRACT FROM AUTHOR]

Background: Stimulation of a specific site in the dorsolateral subthalamic nucleus (STN) was recently associated with slower motor progression in Parkinson's Disease (PD), based on the deep brain stimulation (DBS) in early-stage PD pilot clinical trial. Here, subject-level visualizations are presented of this early-stage PD dataset to further describe the relationship between active contacts and motor progression. This study also evaluates whether stimulation of the sweet spot and connectivity model associated with slower motor progression is also associated with improvements in long-term motor outcomes in patients with advanced-stage PD. Methods: Active contacts of the early-stage PD cohort (N = 14) were analyzed alongside the degree of two-year motor progression. Sweet spot and connectivity models derived from the early-stage PD cohort were then used to determine how well they can estimate the variance in long-term motor outcomes in an independent STN-DBS cohort of advanced-stage PD patients (N = 29). Results: In early-stage PD, proximity of stimulation to the dorsolateral STN was associated with slower motor progression. In advanced-stage PD, stimulation proximity to the early PD connectivity model and sweet spot were associated with better long-term motor outcomes (R = 0.60, P < 0.001; R = 0.37, P = 0.046, respectively). Conclusions: Results suggest stimulation of a specific site in the dorsolateral STN is associated with both slower motor progression and long-term motor improvements in PD. [ABSTRACT FROM AUTHOR]

Background: Accurate pharmacokinetic modelling in PET necessitates measurements of an input function, which ideally is acquired non-invasively from image data. For hepatic pharmacokinetic modelling two input functions need to be considered, to account for the blood supply from the hepatic artery and portal vein. Image-derived measurements at the portal vein are challenging due to its small size and image artifacts caused by respiratory motion. In this work we seek to demonstrate, using phantom experiments, how a dedicated PET/MR protocol can tackle these challenges and potentially provide input function measurements of the portal vein in a clinical setup. Methods: A custom 3D printed PET/MR phantom was constructed to mimic the liver and portal vein. PET/MR acquisitions were made with emulated respiratory motion. The PET/MR imaging protocol consisted of high-resolution anatomical MR imaging of the portal vein, followed by a PET acquisition in parallel to a dedicated motion-tracking MR sequence. Motion tracking and deformation information were extracted from PET data and subsequently used in PET reconstruction to produce dynamic series of motion-free PET images. Anatomical MR images were used post PET reconstruction for partial volume correction of the input function measurements. Results: Reconstruction of dynamic PET data with motion-compensation provided nearly motion-free series of PET frame data, suitable for image derived input function measurements of the portal vein. After partial volume correction, the individual input function measurements were within a 16.1% error range from the true activity in the portal vein compartment at the time of PET acquisition. Conclusion: The proposed protocol demonstrates clinically feasible PET/MR imaging of the liver for pharmacokinetic studies with accurate quantification of the portal vein input function, including correction for respiratory motion and partial volume effects. [ABSTRACT FROM AUTHOR]

Elite athletes are high-performance outliers within their specific sports. Even though science seeks to understand the nature of expertise and elite performance, much knowledge remains compartmentalized within subdisciplines. Despite this multidimensionality being acknowledged, an interdisciplinary approach to understanding elite athletes is still rare. This paper synthesizes insights across scientific domains in order to describe the population and individual characteristics of elite athletes. We analyzed diagnostic data from approximately 300 German squad athletes across eight different sports (e.g., gymnastics, volleyball, ice hockey, 3 × 3 basketball etc., agefemale = 18.95 ± 4.84 years, agemale = 19.32 ± 4.19 years) with expertise values ranging from 2 (low expertise) to 16 (high expertise). Data covered muscular strength, lower-body dynamics, muscle-power genetics, blood micronutrients, basic cognitive function, mental health, social support, and training conditions. Results of logistic regressions identified basic cognitive function (B = 0.89) and well-balanced blood micronutrients (B = 1.22) as critical factors distinguishing elite athletes. Additionally, multiple linear regressions suggested that lower-body dynamics (ß = 0.72) is related to increasing expertise values. We examined interactions between determinants of elite performance, and found that social support is positively associated with mental health and training conditions, whereas muscular strength correlates with lower-body dynamics. Focusing on top elite athletes in contrast to semi-elite athletes, we found higher within-group similarities in basic cognitive function and blood micronutrients. Findings indicate the need for a systemic, individualized, and comprehensive model using individual-based profiles. [ABSTRACT FROM AUTHOR]

Purpose: Multidrug resistance-associated protein 1 (MRP1) is a transport protein with a widespread tissue distribution, which has been implicated in the pathophysiology of Alzheimer's and chronic respiratory disease. PET with 6-bromo-7-[11C]methylpurine ([11C]BMP) has been used to measure MRP1 function in rodents. In this study, [11C]BMP was for the first time characterised in humans to assess the function of MRP1 and other MRP subtypes in different tissues. Methods: Thirteen healthy volunteers (7 men, 6 women) underwent dynamic whole-body PET scans on a long axial field-of-view (LAFOV) PET/CT system after intravenous injection of [11C]BMP. Three subjects of each sex were scanned a second time to assess reproducibility. Volumes of interest were outlined for MRP-expressing tissues (cerebral cortex, cerebellum, choroid plexus, retina, lungs, myocardium, kidneys, and liver). From the time-activity curves, the elimination rate constant (kE, h− 1) was derived as a parameter for tissue MRP function and its test-retest variability (TRTV, %) was calculated. Radiation dosimetry was calculated using the Medical Internal Radiation Dose (MIRD) methodology. Results: Mean kE and corresponding TRTV values were: cerebral cortex: 0.055 ± 0.010 h− 1 (− 4 ± 24%), cerebellum: 0.033 ± 0.009 h− 1 (1 ± 39%), choroid plexus: 0.292 ± 0.059 h− 1 (0.1 ± 16%), retina: 0.234 ± 0.045 h− 1 (30 ± 38%), lungs: 0.875 ± 0.095 h− 1 (− 3 ± 11%), myocardium: 0.641 ± 0.105 h− 1 (11 ± 25%), kidneys: 1.378 ± 0.266 h− 1 (14 ± 16%), and liver: 0.685 ± 0.072 h− 1 (7 ± 9%). Significant sex differences were found for kE in the cerebellum, lungs and kidneys. Effective dose was 4.67 ± 0.18 µSv/MBq for men and 4.55 ± 0.18 µSv/MBq for women. Conclusion: LAFOV PET/CT with [11C]BMP potentially allows for simultaneous assessment of MRP function in multiple human tissues. Mean TRTV of kE in different tissues was in an acceptable range, except for the retina. The radiation dosimetry of [11C]BMP was in the typical range of 11C-tracers. LAFOV PET/CT holds great potential to assess at a whole-body, multi-tissue level molecular targets relevant for drug disposition in humans. Trial registration: EudraCT 2021-006348-29. Registered 15 December 2021. [ABSTRACT FROM AUTHOR]

Abstract Descartes separated the physical from the mental realm and presupposed a causal relation between conscious experience and neural processes. He denominated conscious experiences ‘thoughts’ and held them to be indubitable. However, the question of how we can bridge the gap between subjective experience and neural activity remained unanswered, and attempts to integrate the Cartesian conception with evolutionary theory has not resulted in explanations and testable hypotheses. It is argued that the alternative neo-Aristotelian conception of the mind as the capacities of intellect and will resolves these problems. We discuss how the neo-Aristotelian conception, extended with the notion that organisms are open thermodynamic systems that have acquired heredity, can be integrated with evolutionary theory, and elaborate how we can explain four different forms of consciousness in evolutionary terms.

Background: Patient-derived tumour organoids (PDOs) are highly advanced in vitro models for disease modelling, yet they lack vascularisation. To overcome this shortcoming, organoids can be inoculated onto the chorioallantoic membrane (CAM); the highly vascularised, not innervated extraembryonic membrane of fertilised chicken eggs. Therefore, we aimed to (1) establish a CAM patient-derived xenograft (PDX) model based on PDOs generated from the liver metastasis of a colorectal cancer (CRC) patient and (2) to evaluate the translational pipeline (patient – in vitro PDOs – in vivo CAM-PDX) regarding morphology, histopathology, expression of C-X-C chemokine receptor type 4 (CXCR4), and radiotracer uptake patterns. Results: The main liver metastasis of the CRC patient exhibited high 2-[18F]FDG uptake and moderate and focal [68Ga]Ga-Pentixafor accumulation in the peripheral part of the metastasis. Inoculation of PDOs derived from this region onto the CAM resulted in large, highly viable, and extensively vascularised xenografts, as demonstrated immunohistochemically and confirmed by high 2-[18F]FDG uptake. The xenografts showed striking histomorphological similarity to the patient's liver metastasis. The moderate expression of CXCR4 was maintained in ovo and was concordant with the expression levels of the patient's sample and in vitro PDOs. Following in vitro re-culturing of CAM-PDXs, growth, and [68Ga]Ga-Pentixafor uptake were unaltered compared to PDOs before transplantation onto the CAM. Although [68Ga]Ga-Pentixafor was taken up into CAM-PDXs, the uptake in the baseline and blocking group were comparable and there was only a trend towards blocking. Conclusions: We successfully established an in vivo CAM-PDX model based on CRC PDOs. The histomorphological features and target protein expression of the original patient's tissue were mirrored in the in vitro PDOs, and particularly in the in vivo CAM-PDXs. The [68Ga]Ga-Pentixafor uptake patterns were comparable between in vitro, in ovo and clinical data and 2-[18F]FDG was avidly taken up in the patient's liver metastasis and CAM-PDXs. We thus propose the CAM-PDX model as an alternative in vivo model with promising translational value for CRC patients. [ABSTRACT FROM AUTHOR]

A study published in EJNMMI Research examines the use of 11C-Choline PET/CT imaging for prognostic evaluation in recurrent glioma, a type of brain tumor. The study finds that this imaging technology provides valuable information about tumor characteristics, aids in personalized treatment planning, and improves overall prognosis. The research analyzes 38 patients with recurrent glioma and demonstrates the significant prognostic value of 11C-Choline PET/CT imaging in assessing glioma outcomes. The study serves as a reliable reference for prognosis evaluations in clinical settings. The study also highlights the benefits of 11C-Choline PET/CT in understanding the metabolic activity of glioma cells, which can inform clinical decision-making and treatment planning. However, the study acknowledges limitations such as a small sample size and the need for larger trials to validate the findings. [Extracted from the article]

Purpose: Determine if the SPIKES method was associated with less distress and more compassion than current modes of delivering negative pregnancy test results to patients undergoing in vitro fertilization. Methods: Twenty-seven nurses from two centers were randomized to use the modified SPIKES script or continue their standard of care; 136 patients with a negative hCG following embryo transfer were included. SPIKES nurses received 1 h of training by a study psychologist; nurses in the control group were instructed to deliver the news as done previously. Patients who underwent embryo transfer and received a call by a participating nurse with a negative test result received an email invitation on the following day. Results: Control patients reported significantly less distress than SPIKES patients; 33% of SPIKES patients reported that they had felt "extremely sad," compared to 15.2% of the control patients (p = 0.01). Perceived compassion did not differ between the groups (all p ≥ 0.22). Conclusion: Patients who received a negative pregnancy test result from the nurses who received a brief training and a script on how to deliver bad news via the modified SPIKES protocol reported significantly more distress than patients receiving negative results from nurses utilizing their standard of care. It is unclear whether a modified SPIKES method to deliver negative pregnancy test results will benefit patients undergoing in vitro fertilization. Trial registration: Clinical trials.gov NCT04917445. [ABSTRACT FROM AUTHOR]

Background: Previous studies have initially reported accompanying elevated 2-deoxy-2[18F]fluoro-D-glucose ([18F]F-FDG) inflammatory activity in the remote area and its prognostic value after acute myocardial infarction (AMI). Non-invasive characterization of the accompanying inflammation in the remote myocardium may be of potency in guiding future targeted theranostics. [68Ga]Ga-Pentixafor targeting chemokine receptor 4 (CXCR4) on the surface of inflammatory cells is currently one of the promising inflammatory imaging agents. In this study, we sought to focus on the longitudinal evolution of [68Ga]Ga-Pentixafor activities in the remote myocardium following AMI and its association with cardiac function. Methods: Twelve AMI rats and six Sham rats serially underwent [68Ga]Ga-Pentixafor imaging at pre-operation, and 5, 7, 14 days post-operation. Maximum and mean standard uptake value (SUV) and target-to-background ratio (TBR) were assessed to indicate the uptake intensity. Gated [18F]F-FDG imaging and immunofluorescent staining were performed to obtain cardiac function and responses of pro-inflammatory and reparative macrophages, respectively. Results: The uptake of [68Ga]Ga-Pentixafor in the infarcted myocardium peaked at day 5 (all P = 0.003), retained at day 7 (all P = 0.011), and recovered at day 14 after AMI (P > 0.05), paralleling with the rise-fall pro-inflammatory M1 macrophages (P < 0.05). Correlated with the peak activity in the infarct territory, [68Ga]Ga-Pentixafor uptake in the remote myocardium on day 5 early after AMI significantly increased (AMI vs. Sham: SUVmean, SUVmax, and TBRmean: all P < 0.05), and strongly correlated with contemporaneous EDV and/or ESV (SUVmean and TBRmean: both P < 0.05). The transitory remote activity recovered as of day 7 post-AMI (AMI vs. Sham: P > 0.05). Conclusions: Corresponding with the peaked [68Ga]Ga-Pentixafor activity in the infarcted myocardium, the activity in the remote region elevated accordingly and led to contemporaneous left ventricular remodelling early after AMI. Further studies are warranted to clarify its clinical application potential. [ABSTRACT FROM AUTHOR]

Practical wisdom is the sine qua non of good conduct for Aristotelian virtue ethicists. Aristotelians conceive it as the virtue responsible for the intellectual side of good conduct, which involves having the right goal and deliberating well about what fulfils that goal, among other tasks. But is there any such trait as practical wisdom? Given the diversity of jobs practical wisdom is asked to do (seven goals are often enumerated), there may be a cluster of traits corresponding to what Aristotelians are talking about, so there really isn't one trait. In this paper, I defend a traditional Aristotelian position on practical wisdom, arguing that it is one thing despite having different functions. Following Thomas Aquinas, we can see practical wisdom as having parts. Those parts may be psychological components (integral parts) of the trait, or they may be derivative functions (virtual parts), things that someone with practical wisdom is also able to do because they have practical wisdom. Still, practical wisdom is one because it is a trait that functions to enable us to pursue the good as good; it possesses what I will call here 'practical unity' as the master virtue of praxis or acting well full stop. [ABSTRACT FROM AUTHOR]

Purpose: Functional PET (fPET) is a novel technique for studying dynamic changes in brain metabolism and neurotransmitter signaling. Accurate quantification of fPET relies on measuring the arterial input function (AIF), traditionally achieved through invasive arterial blood sampling. While non-invasive image-derived input functions (IDIF) offer an alternative, they suffer from limited spatial resolution and field of view. To overcome these issues, we developed and validated a scan protocol for brain fPET utilizing cardiac IDIF, aiming to mitigate known IDIF limitations. Methods: Twenty healthy individuals underwent fPET/MR scans using [18F]FDG or 6-[18F]FDOPA, utilizing bed motion shuttling to capture cardiac IDIF and brain task-induced changes. Arterial and venous blood sampling was used to validate IDIFs. Participants performed a monetary incentive delay task. IDIFs from various blood pools and composites estimated from a linear fit over all IDIF blood pools (3VOI) and further supplemented with venous blood samples (3VOIVB) were compared to the AIF. Quantitative task-specific images from both tracers were compared to assess the performance of each input function to the gold standard. Results: For both radiotracer cohorts, moderate to high agreement (r: 0.60–0.89) between IDIFs and AIF for both radiotracer cohorts was observed, with further improvement (r: 0.87–0.93) for composite IDIFs (3VOI and 3VOIVB). Both methods showed equivalent quantitative values and high agreement (r: 0.975–0.998) with AIF-derived measurements. Conclusion: Our proposed protocol enables accurate non-invasive estimation of the input function with full quantification of task-specific changes, addressing the limitations of IDIF for brain imaging by sampling larger blood pools over the thorax. These advancements increase applicability to any PET scanner and clinical research setting by reducing experimental complexity and increasing patient comfort. [ABSTRACT FROM AUTHOR]

Background: Circulating-tumor DNA (ctDNA) and prostate-specific membrane antigen (PSMA) ligand positron-emission tomography (PET) enable minimal-invasive prostate cancer (PCa) detection and survival prognostication. The present study aims to compare their tumor discovery abilities and prognostic values. Methods: One hundred thirty men with confirmed PCa (70.5 ± 8.0 years) who underwent [68Ga]Ga-PSMA-11 PET/CT (184.8 ± 19.7 MBq) imaging and plasma sample collection (March 2019–August 2021) were included. Plasma-extracted cell-free DNA was subjected to whole-genome-based ctDNA analysis. PSMA-positive tumor lesions were delineated and their quantitative parameters extracted. ctDNA and PSMA PET/CT discovery rates were compared, and the prognostic value for overall survival (OS) was evaluated. Results: PSMA PET discovery rates according to castration status and PSA ranges did differ significantly (P = 0.013, P < 0.001), while ctDNA discovery rates did not (P = 0.311, P = 0.123). ctDNA discovery rates differed between localized and metastatic disease (P = 0.013). Correlations between ctDNA concentrations and PSMA-positive tumor volume (PSMA-TV) were significant in all (r = 0.42, P < 0.001) and castration-resistant (r = 0.65, P < 0.001), however not in hormone-sensitive patients (r = 0.15, P = 0.249). PSMA-TV and ctDNA levels were associated with survival outcomes in the Logrank (P < 0.0001, P < 0.0001) and multivariate Cox regression analysis (P = 0.0023, P < 0.0001). Conclusion: These findings suggest that PSMA PET imaging outperforms ctDNA analysis in detecting prostate cancer across the whole spectrum of disease, while both modalities are independently highly prognostic for survival outcomes. [ABSTRACT FROM AUTHOR]

Purpose: Functional positron emission tomography (fPET) with [18F]FDG allows quantification of stimulation-induced changes in glucose metabolism independent of neurovascular coupling. However, the gold standard for quantification requires invasive arterial blood sampling, limiting its widespread use. Here, we introduce a novel fPET method without the need for an input function. Methods: We validated the approach using two datasets (DS). For DS1, 52 volunteers (23.2 ± 3.3 years, 24 females) performed Tetris® during a [18F]FDG fPET scan (bolus + constant infusion). For DS2, 18 participants (24.2 ± 4.3 years, 8 females) performed an eyes-open/finger tapping task (constant infusion). Task-specific changes in metabolism were assessed with the general linear model (GLM) and cerebral metabolic rate of glucose (CMRGlu) was quantified with the Patlak plot as reference. We then estimated simplified outcome parameters, including GLM beta values and percent signal change (%SC), and compared them, region and whole-brain-wise. Results: We observed higher agreement with the reference for DS1 than DS2. Both DS resulted in strong correlations between regional task-specific beta estimates and CMRGlu (r = 0.763...0.912). %SC of beta values exhibited strong agreement with %SC of CMRGlu (r = 0.909...0.999). Average activation maps showed a high spatial similarity between CMRGlu and beta estimates (Dice = 0.870...0.979) as well as %SC (Dice = 0.932...0.997), respectively. Conclusion: The non-invasive method reliably estimates task-specific changes in glucose metabolism without blood sampling. This streamlines fPET, albeit with the trade-off of being unable to quantify baseline metabolism. The simplification enhances its applicability in research and clinical settings. [ABSTRACT FROM AUTHOR]

FiberLean microfibrillated cellulose (MFC) was assessed against the recent definition of a nanomaterial published by the European Union. FiberLean MFC is made by mechanical grinding with the aim of fibrillating traditional wood pulp fibres to generate a highly networked high surface area structure capable of reinforcing a matrix as a filler or modifying the rheology of liquids and gels. The networked structure is complex; consisting of a broad range of fibre sizes which are challenging for any one characterisation technique to accurately represent. Scanning electron microscopy allows investigators to identify the boundaries of discrete complex fibre structures; the challenge is to represent the whole fibre size range. In this study a method is presented for the unbiased quantification of fibre width size distribution from systematic uniform random sampled high-resolution areas (164 µm × 164 µm) using automated scanning electron microscope software. From such images the boundaries of both large- and small-scale fibres could be identified and measured, thus represent the complete size range. The resulting size distribution of FiberLean MFC generated using this method does not meet the criteria specified in the EU definition of a nanomaterial. [ABSTRACT FROM AUTHOR]

Background: Approaches targeting the sodium-glucose cotransporter (SGLT) could represent a promising future therapeutic strategy for numerous oncological and metabolic diseases. In this study, we evaluated the safety, biodistribution and radiation dosimetry of the glucose analogue positron emission tomography (PET) agent [18F] labeled alpha-methyl-4-deoxy-4-[18F]fluoro-D-glucopyranoside ([18F]Me4FDG) with high sodium-glucose cotransporter and low glucose transporter (GLUT) affinity. For this purpose, five healthy volunteers (1 man, 4 women) underwent multiple whole-body PET/computed tomography (CT) examinations starting with injection and up to 4 h after injection of averaged (2.4 ± 0.1) MBq/kg (range: 2.3–2.5 MBq/kg) administered activity. The PET/CT scans were conducted in 5 separate sessions, blood pressure and temperature were measured, and blood and urine samples were collected before the scans and one hour after injection to assess toxicity. Measurements of [18F]Me4FDG radioactivity in organs of interest were determined from the PET/CT scans at 5 time points. Internal dosimetry was performed on voxel level using a fast Monte Carlo approach. Results: All studied volunteers could well tolerate the [18F]Me4FDG and no adverse event was reported. The calculated effective dose was (0.013 ± 0.003) mSv/MBq. The organs with the highest absorbed dose were the kidneys with 0.05 mSv/MBq per kidney. The brain showed almost no uptake. After 60 min, (12 ± 15) % of the administered dose was excreted into the bladder. Conclusion: Featuring an effective dose of only 0.013 ± 0.003 mSv/MBq and no occurrence of side effects, the glucose analogue [18F]Me4FDG seems to be a safe radio-tracer with a favorable biodistribution for PET imaging and also within several consecutive scans. Trial registration number: NCT03557138, Registered 22 February 2017, https://ichgcp.net/clinical-trials-registry/NCT03557138. [ABSTRACT FROM AUTHOR]

Coastal urban areas like New York City (NYC) are more vulnerable to urban pluvial flooding particularly because the rapid runoff from extreme rainfall events can be further compounded by the co-occurrence of high sea-level conditions either from tide or storm surge leading to compound flooding events. Present-day urban pluvial flooding is a significant challenge for NYC and this challenge is expected to become more severe with the greater frequency and intensity of storms and sea-level rise (SLR) in the future. In this study, we advance NYC's assessment of present and future exposure to urban pluvial flooding through simulating various storm scenarios using a citywide hydrologic and hydraulic model. This is the first citywide analysis using NYC's drainage models focusing on rainfall-induced flooding. We showed that the city's stormwater system is highly vulnerable to high-intensity short-duration "cloudburst" events, with the extent and volume of flooding being the largest during these events. We further showed that rainfall events coupled with higher sea-level conditions, either from SLR or storm surge, could significantly increase the volume and extent of flooding in the city. We also assessed flood exposure in terms of the number of buildings and length of roads exposed to flooding as well as the number of the affected population. This study informs NYC's residents of their current and future flood risk and enables the development of tailored solutions to manage increasing flood risk in the city. [ABSTRACT FROM AUTHOR]

The ability of non-native species to successfully invade new ecosystems sometimes involves evolutionary processes such as hybridization. Hybridization can produce individuals with superior traits that give them a competitive advantage over their parent species, allowing for rapid spread. Here we assess growth, functional morphology, and species interactions between two non-native beachgrass species (Ammophila arenaria and A. breviligulata) and their recently discovered hybrid (A. arenaria × A. breviligulata) on the U.S. Pacific Northwest coast. We asked whether the hybrid beachgrass differs from its parent species in morphology and growth, whether it competes with its parent species, and, if so, what are the potential mechanisms of competition. Plant taxa were grown in low- and high-density monocultures and in two-way interactions in a common garden environment. We show that the hybrid grew taller and more densely, with greater total biomass, than either parent species. The hybrid was also the better competitor, resulting in the model prediction of competitive exclusion against A. breviligulata and, depending on its relative abundance, A. arenaria. The hybrid displays a mixed 'guerilla–phalanx' growth form that allows it to spread laterally and achieve high shoot densities, giving it a competitive advantage. Given the current dominance of A. breviligulata compared to A. arenaria in most of the region where these taxa co-occur, we suggest that the hybrid will grow, compete, and spread quickly with potentially widespread consequences for the two non-native Ammophila congeners and the dunes they build. [ABSTRACT FROM AUTHOR]

Background: 6-Bromo-7-[11C]methylpurine ([11C]BMP) is a radiotracer for positron emission tomography (PET) to measure multidrug resistance-associated protein 1 (MRP1) transport activity in different tissues. Previously reported radiosyntheses of [11C]BMP afforded a mixture of 7- and 9-[11C]methyl regioisomers. To prepare for clinical use, we here report an improved regioselective radiosynthesis of [11C]BMP, the results of a non-clinical toxicity study as well as human dosimetry estimates based on mouse PET data. Results: [11C]BMP was synthesised by regioselective N7-methylation of 6-bromo-7H-purine (prepared under good manufacturing practice) with [11C]methyl triflate in presence of 2,2,6,6-tetramethylpiperidine magnesium chloride in a TRACERlab™ FX2 C synthesis module. [11C]BMP was obtained within a total synthesis time of approximately 43 min in a decay-corrected radiochemical yield of 20.5 ± 5.2%, based on starting [11C]methyl iodide, with a radiochemical purity > 99% and a molar activity at end of synthesis of 197 ± 130 GBq/μmol (n = 28). An extended single-dose toxicity study conducted in male and female Wistar rats under good laboratory practice after single intravenous (i.v.) administration of unlabelled BMP (2 mg/kg body weight) revealed no test item related adverse effects. Human dosimetry estimates, based on dynamic whole-body PET data in female C57BL/6J mice, suggested that an i.v. injected activity amount of 400 MBq of [11C]BMP will deliver an effective dose in the typical range of 11C-labelled radiotracers. Conclusions: [11C]BMP can be produced in sufficient amounts and acceptable quality for clinical use. Data from the non-clinical safety evaluation showed no adverse effects and suggested that the administration of [11C]BMP will be safe and well tolerated in humans. [ABSTRACT FROM AUTHOR]

Purpose: Positron emission tomography (PET) provides precise molecular information on physiological processes, but its low temporal resolution is a major obstacle. Consequently, we characterized the metabolic response of the human brain to working memory performance using an optimized functional PET (fPET) framework at a temporal resolution of 3 s. Methods: Thirty-five healthy volunteers underwent fPET with [18F]FDG bolus plus constant infusion, 19 of those at a hybrid PET/MRI scanner. During the scan, an n-back working memory paradigm was completed. fPET data were reconstructed to 3 s temporal resolution and processed with a novel sliding window filter to increase signal to noise ratio. BOLD fMRI signals were acquired at 2 s. Results: Consistent with simulated kinetic modeling, we observed a constant increase in the [18F]FDG signal during task execution, followed by a rapid return to baseline after stimulation ceased. These task-specific changes were robustly observed in brain regions involved in working memory processing. The simultaneous acquisition of BOLD fMRI revealed that the temporal coupling between hemodynamic and metabolic signals in the primary motor cortex was related to individual behavioral performance during working memory. Furthermore, task-induced BOLD deactivations in the posteromedial default mode network were accompanied by distinct temporal patterns in glucose metabolism, which were dependent on the metabolic demands of the corresponding task-positive networks. Conclusions: In sum, the proposed approach enables the advancement from parallel to truly synchronized investigation of metabolic and hemodynamic responses during cognitive processing. This allows to capture unique information in the temporal domain, which is not accessible to conventional PET imaging. [ABSTRACT FROM AUTHOR]

The article discusses the impact of cachexia, a condition characterized by weight loss and muscle wasting, on the quality of life and survival of lung cancer patients. It highlights the high prevalence of cachexia in lung cancer patients and the need for effective treatment approaches. The article introduces a research project called LuCaPET, which aims to use advanced imaging techniques and artificial intelligence algorithms to detect metabolic patterns associated with cachexia in lung cancer patients. The project also addresses the ethical challenges of using AI in clinical decision-making and aims to make the AI-driven models transparent and comprehensible for clinicians. The ultimate goal of the project is to improve the diagnosis and treatment of cachexia in lung cancer patients and enhance their quality of life and survival. [Extracted from the article]

Background: Cancer is a leading cause of death worldwide. While routine diagnosis of cancer is performed mainly with biopsy sampling, it is suboptimal to accurately characterize tumor heterogeneity. Positron emission tomography (PET)-driven radiomic research has demonstrated promising results when predicting clinical endpoints. This study aimed to investigate the added value of quantum machine learning both in simulator and in real quantum computers utilizing error mitigation techniques to predict clinical endpoints in various PET cancer patients. Methods: Previously published PET radiomics datasets including 11C-MET PET glioma, 68GA-PSMA-11 PET prostate and lung 18F-FDG PET with 3-year survival, low-vs-high Gleason risk and 2-year survival as clinical endpoints respectively were utilized in this study. Redundancy reduction with 0.7, 0.8, and 0.9 Spearman rank thresholds (SRT), followed by selecting 8 and 16 features from all cohorts, was performed, resulting in 18 dataset variants. Quantum advantage was estimated by Geometric Difference (GDQ) score in each dataset variant. Five classic machine learning (CML) and their quantum versions (QML) were trained and tested in simulator environments across the dataset variants. Quantum circuit optimization and error mitigation were performed, followed by training and testing selected QML methods on the 21-qubit IonQ Aria quantum computer. Predictive performances were estimated by test balanced accuracy (BACC) values. Results: On average, QML outperformed CML in simulator environments with 16-features (BACC 70% and 69%, respectively), while with 8-features, CML outperformed QML with + 1%. The highest average QML advantage was + 4%. The GDQ scores were ≤ 1.0 in all the 8-feature cases, while they were > 1.0 when QML outperformed CML in 9 out of 11 cases. The test BACC of selected QML methods and datasets in the IonQ device without error mitigation (EM) were 69.94% BACC, while EM increased test BACC to 75.66% (76.77% in noiseless simulators). Conclusions: We demonstrated that with error mitigation, quantum advantage can be achieved in real existing quantum computers when predicting clinical endpoints in clinically relevant PET cancer cohorts. Quantum advantage can already be achieved in simulator environments in these cohorts when relying on QML. [ABSTRACT FROM AUTHOR]

Purpose: Anatomical and molecular staging strategies are needed for the personalized treatment of localized pancreatic ductal adenocarcinoma (PDAC). This study evaluated the performance of [68 Ga]Ga–FAPI-04 and [18F]F-FDG PET/CT on the disease staging and prognostic value of patients with localized PDAC on contrast-enhanced (CE)-CT images. Methods: Patients with suspected localized PDAC on CE-CT were recruited for static [68 Ga]Ga-FAPI-04 and 18[F]F-FDG and PET/CT, and select patients underwent simultaneous 60-min dynamic 68 Ga-FAPI-04 PET/CT. The diagnostic and staging performances of the static PET/CT results were evaluated by delineating regions of interest in the primary tumor, whole pancreas, and distal pancreas in both types of scans and then evaluating correlations between the PET/CT findings and clinicopathological characteristics. Furthermore, Kaplan–Meier and hazard ratio (log-rank) methods were used to evaluate the prognostic value of the combined dynamic [68 Ga]Ga-FAPI-04 and static [18F]F-FDG PET/CT method. Results: We included 49 patients with histologically confirmed PDAC adenocarcinomas; 32 underwent 60-min dynamic [68 Ga]Ga-FAPI-04 PET/CT imaging simultaneously. The static [68 Ga]Ga-FAPI-04 method had significantly higher accuracy and uptake values than the static [18F]F-FDG method for primary PDAC lesions, metastatic lymph nodes, and distal metastases. Furthermore, 18.4% and 10.2% of the patients' stages changed after using the [68 Ga]Ga-FAPI-04 and [18F]F-FDG PET/CT methodologies, respectively, compared to the CE-CT-designated stage. The Ki values obtained from dynamic [68 Ga]Ga-FAPI-04 PET/CT did not differ between PDAC and distal obstructive pancreatitis lesions. Pathologically enlarged tumor size, poor differentiation, and perineural invasion were associated with increased [68 Ga]Ga-FAPI-04 uptake but not with [18F]F-FDG uptake. The preoperative prognostic performance of [68 Ga]Ga-FAPI-04 was better than that of [18F]F-FDG. Interestingly, combined [68 Ga]Ga-FAPI-04 and [18F]F-FDG uptake results in the whole pancreas could further stratify patients based on their postoperative prognosis. Conclusion: 6[68 Ga]Ga-FAPI-04 PET/CT was more sensitive and accurate than [18F]F-FDG PET/CT for tumor, node, and metastasis staging of PDAC identified on CE-CT. Additionally, [68 Ga]Ga-FAPI-04 uptake was significantly associated with pathologically aggressive tumor features. Combined [68 Ga]Ga-FAPI-04 and [18F]F-FDG PET/CT findings improved the prognostic value, potentially providing a non-invasive guide for clinical management. Finally, increased fibroblast activity in PDAC-induced obstructive pancreatitis may be associated with poor patient survival rates. [ABSTRACT FROM AUTHOR]

Computational models provide an efficient paradigm for integrating and linking multiple spatial and temporal scales. However, these models are difficult to parameterize and match to experimental data. Recent advances in both data collection and model analyses have helped overcome this limitation. Here, we combine a multiscale, biventricular interaction model with mouse data before and after left ventricular (LV) ischemia. Sensitivity analyses are used to identify the most influential parameters on pressure and volume predictions. The subset of influential model parameters are calibrated to biventricular pressure–volume loop data (n = 3) at baseline. Each mouse underwent left anterior descending coronary artery ligation, during which changes in fractional shortening and RV pressure–volume dynamics were recorded. Using the calibrated model, we simulate acute LV ischemia and contrast outputs at baseline and in simulated ischemia. Our baseline simulations align with the LV and RV data, and our predictions during ischemia complement recorded RV data and prior studies on LV function during myocardial infarction. We show that a model with both biventricular mechanical interaction and systems-level cardiovascular dynamics can quantitatively reproduce in-vivo data and qualitatively match prior findings from animal studies on LV ischemia. [ABSTRACT FROM AUTHOR]

Cancer of unknown primary has a dismal prognosis, especially following failure of platinum-based chemotherapy. 10-20% of patients have a high tumor mutational burden (TMB), which predicts response to immunotherapy in many cancer types. In this prospective, non-randomized, open-label, multicenter Phase II trial (EudraCT 2018-004562-33; NCT04131621), patients relapsed or refractory after platinum-based chemotherapy received nivolumab and ipilimumab following TMBhigh vs. TMBlow stratification. Progression-free survival (PFS) represented the primary endpoint; overall survival (OS), response rates, duration of clinical benefit and safety were the secondary endpoints. The trial was prematurely terminated in March 2021 before reaching the preplanned sample size (n = 194). Among 31 evaluable patients, 16% had a high TMB (> 12 mutations/Mb). Overall response rate was 16% (95% CI 6-34%), with 7.7% (95% CI 1-25%) vs. 60% (95% CI 15-95%) in TMBlow and TMBhigh, respectively. Although the primary endpoint was not met, high TMB was associated with better median PFS (18.3 vs. 2.4 months) and OS (18.3 vs. 3.6 months). Severe immune-related adverse events were reported in 29% of cases. Assessing on-treatment dynamics of circulating tumor DNA using combined targeted hotspot mutation and shallow whole genome sequencing as part of a predefined exploratory analysis identified patients benefiting from immunotherapy irrespective of initial radiologic response. Standard of care for unfavorable-risk cancer of unknown primary (CUP) comprises platinum-based chemotherapy as first-line treatment, however therapeutic options remain limited. Here the authors report the results of a phase II trial of combined nivolumab (anti-PD1) and ipilimumab (anti-CTLA4) in patients with unfavorable CUP. [ABSTRACT FROM AUTHOR]

Purpose: This paper presents the results of the first joint survey on the use of SPECT and PET myocardial perfusion imaging (MPI) and cardiac amyloidosis imaging in Austria, Germany, and Switzerland of the year 2021. Methods: A questionnaire was sent in 2022 to centres practicing nuclear medicine. Results: Data from 14 Austrian (10,710 SPECT), 218 German (133,047 SPECT), and 16 Swiss centres (11,601 MPI (6,879 SPECT, 4722 PET)) were analysed. In Austria and Germany, the PET MPI numbers were close to zero and not considered. Official MPS numbers from 2015 to 2021 from Austria and Germany revealed a decline in Austria by about 40% in the pandemic years 2020 to 2021, but an increase in Germany by 9%. Ambulatory care cardiologists represented the major referral group (56–71%). Mostly, stress tests were performed pharmacologically (58–92%). Contrary to Germany, a 1-day protocol was predominant (58–97%) in Austria and Switzerland. The leading camera systems were SPECT-CT in Austria and Switzerland (57–79%) and multi-head systems in Germany (58%). Switzerland had the highest proportion of SPECT MPI with attenuation correction (84%), followed by Austria (43%), and Germany (33%). Electrocardiogram-gated SPECT MPI showed an overall high penetration of 87–99%. Scoring was most frequently applied in Germany (72%), followed by Austria (64%), and Switzerland (60%). Related to the population, the number of cardiac amyloidosis imaging was highest in Austria, followed by Switzerland and Germany. Conclusions: This first joint survey of 2021 shows considerable differences among the countries. The Swiss situation is outstanding due to the wide use of PET MPI. In terms of camera equipment, Switzerland is also leading, followed by Austria and Germany. Despite the differences in procedural issues, the results reveal an overall high standard of MPI imaging. [ABSTRACT FROM AUTHOR]

Abstract In the normal quiescent vasculature, only 0.01% of endothelial cells (ECs) are proliferating. However, this proportion increases dramatically following the angiogenic switch during tumor growth or wound healing. Recent evidence suggests that this angiogenic switch is accompanied by a metabolic switch. Here, we show that proliferating ECs increasingly depend on mitochondrial oxidative phosphorylation (OxPhos) for their increased energy demand. Under growth conditions, ECs consume three times more oxygen than quiescent ECs and work close to their respiratory limit. The increased utilization of the proton motif force leads to a reduced mitochondrial membrane potential in proliferating ECs and sensitizes to mitochondrial uncoupling. The benzoquinone embelin is a weak mitochondrial uncoupler that prevents neoangiogenesis during tumor growth and wound healing by exhausting the low respiratory reserve of proliferating ECs without adversely affecting quiescent ECs. We demonstrate that this can be exploited therapeutically by attenuating tumor growth in syngenic and xenograft mouse models. This novel metabolic targeting approach might be clinically valuable in controlling pathological neoangiogenesis while sparing normal vasculature and complementing cytostatic drugs in cancer treatment.

Background: Recurrent myocardial infarction (RMI) portends an unfavorable outcome, which might be related to diminished hematopoietic-inflammatory activation. We aimed to investigate the hematopoietic-inflammatory activation and the outcome in categorized patients with primary myocardial infarction (PMI) versus RMI as well as chronic stable angina (CSA) by 18F-FDG PET. Results: A total of 105 patients (88 males; 60.1 ± 9.7 years) were included. Target-to-background ratio of bone marrow (TBRBM) was highest in the PMI group (n = 45), intermediate in the RMI group (n = 30), and lowest in the CSA group (n = 30) (P < 0.001). RMI group exhibited larger scar, significantly reduced left ventricular ejection fraction, and enlarged end systolic volume in comparison with the PMI and CSA groups, respectively (P < 0.05). Additionally, there was a significantly positive correlation between TBRBM and TBRaorta (P < 0.001). The cumulative major adverse cardiac events free survival of patients in the RMI group was lower than that in the PMI and CSA groups during a median follow-up of 16.6 months (P = 0.026). Conclusions: RMI conferred relatively decreased hematopoietic-inflammatory activation compared with PMI. Patients with RMI presented subsequent enlarged myocardial scar, worsened cardiac dysfunction, aggravated remodeling, and worse outcomes than that in PMI patients. [ABSTRACT FROM AUTHOR]

Disease surveillance systems are crucial to monitor and predict outbreaks, epidemics and pandemics, as well as to understand the dynamics and trends of diseases over space and time. For zoonotic diseases, i.e., diseases that spread from animals to humans, surveillance systems often rely on complex data collection mechanisms which present particular challenges to the statistician, including sampling processes that commonly violate key assumptions of standard statistical methods. One such mechanism is preferential sampling, referring to a stochastic dependency between a spatial process of interest and the locations at which it is observed, commonly arising out of practical considerations related to a limited sampling budget and a rare outcome. While this sampling strategy can lead to considerably biased spatial predictions, few solutions to address preferential sampling have been proposed in the context of disease surveillance. We propose a novel approach to correct for preferential sampling in disease surveillance applications and show by simulation the practical benefits of reduced bias in parameter estimates and greater accuracy of the estimated risk surface. We conclude with an application of the model to a disease surveillance dataset targeting plague (Yersinia pestis) in the sylvatic rodent populations in California. [ABSTRACT FROM AUTHOR]

Conventional and regulatory T cells (Treg) are dynamic mediators of maternal immune tolerance to the developing feto-placental unit. Functional evaluation of T cells at the maternal-fetal interface is crucial to elucidate the immunologic basis of obstetric complications. Our objective was to define the T cell phenotype and function of uterine intervillous blood (IVB) in pregnancy with and without preeclampsia. We hypothesize that preeclampsia is associated with impaired immune tolerance and a pro-inflammatory uterine T cell microenvironment. In this cross-sectional study, maternal peripheral blood (PB) and uterine IVB (obtained from the surgical sponge used to clean the placental bed during cesarean delivery) were collected from participants with and without preeclampsia. Proportion, activation, and cytokine production of T cell subsets were quantified by flow cytometry. T cell parameters were compared by tissue source and by preeclampsia status. Sixty participants, 26 with preeclampsia, were included. Induced Treg made up a greater proportion of IVB T cells compared to PB and had greater cytokine-producing capacity. Preeclampsia was associated with increased ratio of pro-inflammatory IL-17α to suppressive IL-10 cytokine production by CD4 T cell subsets in IVB, but not in PB. Human uterine IVB is composed of activated, cytokine-producing T cell subsets distinct from maternal PB. Preeclampsia is associated with a pro-inflammatory IVB profile, with increased IL-17α /IL-10 ratio in all CD4 T cell subsets. IVB sampling is a useful tool for investigating human T cell biology at the maternal-fetal interface that may inform immunotherapeutic strategies for preeclampsia. [ABSTRACT FROM AUTHOR]

Introduction: While most patients with triple negative breast cancer receive radiation therapy to improve outcomes, a significant subset of patients continue to experience recurrence. Macrophage infiltration into radiation-damaged sites has been shown to promote breast cancer recurrence in pre-clinical models. However, the mechanisms that drive recurrence are unknown. Here, we developed a novel spheroid model to evaluate macrophage-mediated tumor cell recruitment. Methods: We characterized infiltrating macrophage phenotypes into irradiated mouse mammary tissue via flow cytometry. We then engineered a spheroid model of radiation damage with primary fibroblasts, macrophages, and 4T1 mouse mammary carcinoma cells using in vivo macrophage infiltration results to inform our model. We analyzed 4T1 infiltration into spheroids when co-cultured with biologically relevant ratios of pro-healing M2:pro-inflammatory M1 macrophages. Finally, we quantified interleukin 6 (IL-6) secretion associated with conditions favorable to tumor cell infiltration, and we directly evaluated the impact of IL-6 on tumor cell invasiveness in vitro and in vivo. Results: In our in vivo model, we observed a significant increase in M2 macrophages in mouse mammary glands 10 days post-irradiation. We determined that tumor cell motility toward irradiated spheroids was enhanced in the presence of a 2:1 ratio of M2:M1 macrophages. We also measured a significant increase in IL-6 secretion after irradiation both in vivo and in our model. This secretion increased tumor cell invasiveness, and tumor cell invasion and recruitment were mitigated by neutralizing IL-6. Conclusions: Our work suggests that interactions between infiltrating macrophages and damaged stromal cells facilitate breast cancer recurrence through IL-6 signaling. [ABSTRACT FROM AUTHOR]

Though childhood maltreatment negatively affects later in life functioning, current interventions do little to mitigate this impact. This ineffectiveness may be exacerbated by deficit-focused models which focus primarily on mental illness, ignoring other indicators of healthy functioning. This paper presents two studies that examine the relationships between childhood maltreatment and later in life functioning, including indicators of mental illness and mental health. In Study 1, network analysis was used as an exploratory tool to examine how childhood maltreatment relates to later in life wellbeing. Study 2 used a different sample of adults to provide a confirmatory test of the network obtained in Study 1 given remaining concerns about the replicability of networks from network analysis. Study 1 included a subset of participants from the Midlife Development in the United States Study 2 (MIDUS 2) Biomarker Project 4, 2004–2009. Study 2 included individuals from the MIDUS Refresher Biomarker Project 4, 2012–2016. Network comparison tests demonstrated that the networks generally replicated as they did not significantly vary in structure, global strength, or measures of strength centrality. In both studies, emotional forms of maltreatment (i.e., emotional abuse, emotional neglect) emerged as particularly influential in the networks. Childhood maltreatment impacts the ability to thrive in adulthood, beyond its impact on diagnosable mental illness, and also affects positive functioning. A stronger focus on emotional abuse and emotional neglect is warranted within maltreatment intervention and education initiatives, as is an emphasis on the impact of maltreatment on positive functioning in adulthood. [ABSTRACT FROM AUTHOR]

Purpose: Sodium-glucose cotransporter 2 inhibitor (SGLT2i) regulation, developed as treatment for patients with type 2 diabetes, can be imaged with the glucose analogue alpha-methyl-4-deoxy-4-[18F]fluoro-d-glucopyranoside (Me4FDG), a positron emission tomography (PET) tracer with a high affinity for SGLT1 and SGLT2 proteins. With regard to therapy effectiveness, we aimed to investigate whether clinical parameters or Me4FDG excretion could predict response to SGLT2i in patients with type 2 diabetes. Methods: In a longitudinal, prospective study, 19 patients with type 2 diabetes underwent Me4FDG combined PET and magnetic resonance imaging (PET/MRI) scans at baseline and 2 weeks after initiation of therapy with SGLT2i, accompanied by the collection of blood and urine samples. Me4FDG-excretion was determined from the Me4FDG uptake in the bladder. Long-term response was determined by HbA1c level after 3 months; a strong response to the therapy was defined as a reduction of HbA1c by at least 10% from baseline. Results: SGLT2i resulted in significantly increased Me4FDG excretion (4.8 vs. 45.0, P < 0.001) and urine glucose (56 vs. 2806 mg/dl, P < 0.001). Baseline urine glucose and baseline Me4FDG excretion correlated both with long-term decline in HbA1c with r = 0.55 (P < 0.05). However, only Me4FDG excretion was a predictor of a strong response to SGLT2i (P = 0.005, OR 1.9). Conclusions: Using Me4FDG-PET, we demonstrated for the first time renal SGLT2-related excretion before and after short-term SGLT2i treatment. In contrary to other clinical parameters, SGLT2-related excretion before treatment was a robust predictor of long-term HbA1c response in patients with type 2 diabetes, suggesting that therapy effectiveness is only dependent of endogenous SGLT2 processes. [ABSTRACT FROM AUTHOR]

Purpose: We evaluated financial toxicity (FT) in patients with gynecologic cancer treated with radiation and assessed the impact of the COVID-19 pandemic on patients’ financial wellbeing. Methods: Patients completed a survey 1 month after completing radiation from August 2019-March 2020 and November 2020-June 2021. The survey included the COmprehensive Score for Financial Toxicity (COST) tool, EQ-5D to measure quality of life (QOL) and pandemic-related questions for the second survey period. High FT was COST score ≤ 23. Results: Of 97 respondents (92% response rate), 49% completed the survey pre-pandemic and 51% after; the majority were white (76%) and had uterine cancer (64%). Sixty percent received external beam radiation with or without brachytherapy; 40% had only brachytherapy. High FT was associated with worse QOL (r = -0.37, P < 0.001), younger age and type of insurance (both p ≤ 0.03). Respondents with high FT were 6.0 (95% CI 1.0–35.9) times more likely to delay/avoid medical care, 13.6 (95% CI 2.9–64.3) times more likely to borrow money, and 6.9 (95% CI 1.7–27.2) times as likely to reduce spending on basic goods. The pandemic cohort had a smaller proportion of respondents with high FT than the pre-pandemic cohort (20% vs. 35%, p = 0.10) and a higher median COST score (32 (IQR 25–35) vs. 27 (IQR 19–34), p = 0.07). Conclusion: Privately insured, younger respondents who received radiation for gynecologic cancer were at risk for FT. High FT was associated with worse QOL and economic cost-coping strategies. We observed less FT in the pandemic cohort, though not statistically different from the pre-pandemic cohort. [ABSTRACT FROM AUTHOR]

During a failure event, electrochemical cells can exhibit such characteristics as extreme high temperatures, deflagration, fire, venting of electrolyte and rapid uncontrolled disassembly. The cell's characteristics prior to, during, and after a destructive event are important in developing preventive and mitigating hazard steps. A novel measuring system based on isothermal calorimetry has been developed and utilized to further understand the worst-case event produced by large format electrochemical cells. This system allows for the containment of the reaction and its products while measuring the pressure and release rate of the gaseous product, as well as a complete thermal profile of the reaction. This paper provides a description of the calorimeter, calibration test results on its performance, test results, and empirical model from a selection of cells tested. The cells utilized in this developmental testing were Lithium Iron Phosphate and Lithium Cobalt Oxide cells ranging from 6 to 38 Ampere hour capacities and approximately 40 mm diameter, 170 mm height, and 0.35 kg each. This analytical system allows for a wide range of cells, chemistries, failure mechanisms and testing environments for lithium-ion cells, static or under load. Empirical models developed from this flexible and adaptive system will enable researchers to compare larger samples across material property boundaries to better predict the outcome of destructive chemical reactions. [ABSTRACT FROM AUTHOR]