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Particle accelerators are invaluable tools for research in the basic and applied sciences, such as materials science, chemistry, the biosciences, particle physics, nuclear physics and medicine. The design, commissioning, and operation of accelerator facilities is a nontrivial task, due to the large number of control parameters and the complex interplay of several conflicting design goals. The Argonne Wakefield Accelerator facility has some unique challenges resulting from its purpose to carry out advanced accelerator R&D. Individual experiments often have challenging beam requirements, and the physical configuration of the beam lines is often changed to accommodate the variety of supported experiments. The need for rapid deployment of different operational settings further complicates the optimization work that must be done for multiple constraints and challenging operational regimes. One example of this is an independently staged two-beam acceleration experiment which requires the construction of an additional beam line (this is now in progress). The high charge drive beam, well into the space charge regime, must be threaded through small aperture (17.6 mm) decelerating structures. In addition, the bunch length must be sufficiently short to maximize power generation in the decelerator. We propose to tackle this problem by means of multiobjective optimization algorithms which also facilitate a parallel deployment. In order to compute solutions in a meaningful time frame, a fast and scalable software framework is required. In this paper, we present a general-purpose framework for simulation-based multiobjective optimization methods that allows the automatic investigation of optimal sets of machine parameters. Using evolutionary algorithms as the optimizer and opal as the forward solver, validation experiments and results of multiobjective optimization problems in the domain of beam dynamics are presented. Optimized solutions for the new high charge drive beam line found by the framework were used to finish the design of a two beam acceleration experiment. The selected solution along with the associated beam parameters is presented.

Idiopathic pulmonary fibrosis (IPF) is the most common and severe form of pulmonary fibrosis, characterized by scar formation in the lung interstitium. Transforming growth factor beta (TGF-β) is known as a key mediator in the fibrotic process, acting on fibroblasts and mediating their proliferation and differentiation into myofibroblasts. Although the immune system is not considered responsible for the initiation of IPF, markers of tolerogenic immunity define the pro-fibrotic microenvironment in the lungs. In homeostatic conditions, regulatory T cells (Tregs) constitute the main lymphoid population responsible for maintaining peripheral tolerance. Similar to Tregs, regulatory B cells (Bregs) represent a recently described subset of B lymphocytes with immunosuppressive functions. In the context of IPF, numerous studies have suggested a role for Tregs in enhancing fibrosis, mainly via the secretion of TGF-β. In humans, most studies show increased percentages of Tregs associated with the severity of IPF, although their exact role remains unclear. In mice, the most commonly used model involves triggering acute lung inflammation with bleomycin, leading to a subsequent fibrotic process. Consequently, data are still conflicting, as Tregs may play a protective role during the inflammatory phase and a deleterious role during the fibrotic phase. Bregs have been less studied in the context of IPF, but their role appears to be protective in experimental models of lung fibrosis. This review presents the latest updates on studies exploring the implication of regulatory lymphoid cells in IPF and compares the different approaches to better understand the origins of conflicting findings.

Abstract Background In patients with resectable stage III non-small cell lung cancer (NSCLC), induction chemoimmunotherapy followed by surgical resection has shown unprecedented rates of pathological response and event-free survival. However, a triple-induction including radiochemotherapy and immunotherapy followed by surgical resection has not been routinely established in clinical practice. Case presentation We report the case of a 47-year-old patient with stage IIIA NSCLC who was treated in a combined concept including induction concurrent radiochemotherapy, followed by 4 cycles of pembrolizumab and subsequent intrapericardial left-sided pneumonectomy. Histological analysis revealed a pathological complete response. Conclusions The case demonstrates that the combination of neoadjuvant chemo-, radio- and immunotherapy in advanced NSCLC may lead to a relevant down-staging and may enable a R0-resection of a borderline resectable tumor. However, the combination of four different treatment modalities requires resilience and a good performance status. A triple induction treatment may be a promising option for selected patients with locally advanced NSCLC and good performance status.

ABSTRACT Emergomyces africanus is a highly fatal fungal pathogen affecting individuals with advanced HIV disease. Molecular patterns and ultrastructural aspects of E. africanus are unknown, and pathogenic models have not been investigated in detail. Since the cell wall of fungi is a determinant for interaction with the host and antifungal development, we characterized the ultrastructural aspects of E. africanus and the general properties of cell wall components under different conditions of growth in vitro and in vivo. We also tested the pathogenic potential of E. africanus in a Galleria mellonella model of infection. Transmission electron microscopy revealed the common intracellular, ultrastructural features of fungi in association with a thick cell wall. Scanning electron microscopy revealed a smooth cell surface, with no apparent decorative structures. Yeast cultures of E. africanus showed the distribution of chitin, chitooligomers, and mannoproteins commonly observed in fungi. However, in mixed microenvironments containing yeast and filamenting forms of E. africanus, the detection of chitooligomers was increased in comparison with isolated yeast cells, while the detection of these components in filamenting forms was markedly reduced. These observations were suggestive of the ability of E. africanus to change its cell wall composition in response to different microenvironments. Although E. africanus was unable to kill G. mellonella, this infection model allowed us to isolate infected hemocytes for further analysis of mannoproteins, chitin, and chitooligomers. Once again, the detection of E. africanus chitooligomers was markedly increased. These results reveal previously unknown ultrastructural features of E. africanus and suggest a high plasticity in the cell wall of this lethal pathogen.IMPORTANCEThe epidemiology of fungal infections is very dynamic, and novel health emergencies are hard to predict. New fungal pathogens have been continuously emerging for the last few decades, and Emergomyces africanus is one of these threats to human health. This complex scenario points to the need for generating knowledge about emerging pathogens so that new therapeutic strategies can be designed. In this study, we characterized the general cellular and pathogenic properties of the emerging fungal pathogen E. africanus. Our results reveal that E. africanus manifests some of the typical properties of fungal cells but also exhibits some unique characteristics that might be helpful for the future development of therapeutic strategies.

PIWI, from the German word Pilzwiderstandsfähig, meaning “fungus-resistant”, refers to grapevine cultivars bred for resistance to fungal pathogens such as Erysiphe necator (the causal agent of powdery mildew) and Plasmopara viticola (the causal agent of downy mildew), two major diseases in viticulture. These varieties are typically developed through traditional breeding, often crossbreeding European Vitis vinifera with American or Asian species that carry natural disease resistance. This study investigates the transcriptional profiles of exocarp tissues in mature berries from four PIWI grapevine varieties compared to their elite parental counterparts using RNA-seq analysis. We performed RNA-seq on four PIWI varieties (two red and two white) and their noble parents to identify differential gene expression patterns. Comprehensive analyses, including Differential Gene Expression (DEGs), Gene Set Enrichment Analysis (GSEA), Weighted Gene Co-expression Network Analysis (WGCNA), and tau analysis, revealed distinct gene clusters and individual genes characterizing the transcriptional landscape of PIWI varieties. Differentially expressed genes indicated significant changes in pathways related to organic acid metabolism and membrane transport, potentially contributing to enhanced resilience. WGCNA and k-means clustering highlighted co-expression modules linked to PIWI genotypes and their unique tolerance profiles. Tau analysis identified genes uniquely expressed in specific genotypes, with several already known for their defense roles. These findings offer insights into the molecular mechanisms underlying grapevine resistance and suggest promising avenues for breeding strategies to enhance disease resistance and overall grape quality in viticulture.

Abstract This study aimed to evaluate the diagnostic accuracy of Node Reporting and Data System (Node-RADS) in discriminating between normal, reactive, and metastatic axillary LNs in patients with melanoma who underwent SARS-CoV-2 vaccination. Patients with proven melanoma who underwent a 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (2-[18F]-FDG PET/CT) between February and April 2021 were included in this retrospective study. Primary melanoma site, vaccination status, injection site, and 2-[18F]-FDG PET/CT were used to classify axillary LNs into normal, inflammatory, and metastatic (combined classification). An adapted Node-RADS classification (A-Node-RADS) was generated based on LN anatomical characteristics on low-dose CT images and compared to the combined classification. 108 patients were included in the study (54 vaccinated). HALNs were detected in 42 patients (32.8%), of whom 97.6% were vaccinated. 172 LNs were classified as normal, 30 as inflammatory, and 14 as metastatic using the combined classification. 152, 22, 29, 12, and 1 LNs were classified A-Node-RADS 1, 2, 3, 4, and 5, respectively. Hence, 174, 29, and 13 LNs were deemed benign, equivocal, and metastatic. The concordance between the classifications was very good (Cohen’s k: 0.91, CI 0.86–0.95; p-value

Abstract Immune checkpoint inhibitor treatment has the potential to prolong survival in non-small cell lung cancer (NSCLC), however, some of the patients develop resistance following initial response. Here, we analyze the immune phenotype of matching tumor samples from a cohort of NSCLC patients showing good initial response to immune checkpoint inhibitors, followed by acquired resistance at later time points. By using imaging mass cytometry and whole exome and RNA sequencing, we detect two patterns of resistance¨: One group of patients is characterized by reduced numbers of tumor-infiltrating CD8+ T cells and reduced expression of PD-L1 after development of resistance, whereas the other group shows high CD8+ T cell infiltration and high expression of PD-L1 in addition to markedly elevated expression of other immune-inhibitory molecules. In two cases, we detect downregulation of type I and II IFN pathways following progression to resistance, which could lead to an impaired anti-tumor immune response. This study thus captures the development of immune checkpoint inhibitor resistance as it progresses and deepens our mechanistic understanding of immunotherapy response in NSCLC.

Abstract To evaluate whether a machine learning classifier can evaluate image quality of maximum intensity projection (MIP) images from F18-FDG-PET scans. A total of 400 MIP images from F18-FDG-PET with simulated decreasing acquisition time (120 s, 90 s, 60 s, 30 s and 15 s per bed-position) using block sequential regularized expectation maximization (BSREM) with a beta-value of 450 and 600 were created. A machine learning classifier was fed with 283 images rated “sufficient image quality” and 117 images rated “insufficient image quality”. The classification performance of the machine learning classifier was assessed by calculating sensitivity, specificity, and area under the receiver operating characteristics curve (AUC) using reader-based classification as the target. Classification performance of the machine learning classifier was AUC 0.978 for BSREM beta 450 and 0.967 for BSREM beta 600. The algorithm showed a sensitivity of 89% and 94% and a specificity of 94% and 94% for the reconstruction BSREM 450 and 600, respectively. Automated assessment of image quality from F18-FDG-PET images using a machine learning classifier provides equivalent performance to manual assessment by experienced radiologists.

Introduction Many studies have explored the food environment to characterise it and understand its role in food practices. Assessment of the organisational food environment can contribute to the development of more effective interventions to promote adequate and healthy eating. However, few instruments and indicators have been developed and validated for assessing this type of setting. The systematisation of those can be useful to support the planning of future assessments and the development of wide-ranging instruments. This study aims to conduct a scoping review to systematise evidence on instruments and indicators for assessing organisational food environments.Methods and analysis This scoping review was planned according to the methodological framework for scoping reviews proposed by Arksey and O’Malley and subsequently enhanced by Levac et al. For the report of the review, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses—Extension for Scoping Reviews (PRISMA-ScR) checklist and guidelines will be used. The search will be conducted using PubMed, Embase, Web of Science, PsycINFO, Scopus and Google Scholar databases. The studies to be included were required to have been published in peer-reviewed journals since January 2005. No geographical, population or language restrictions will be applied given the desired breadth of the review. Two researchers will select the articles and extract the data independently. The conceptual model proposed by Castro and Canella will guide the data extraction and analysis. The results will be presented with narrative synthesis for the extracted data accompanying the tabulated and charted results.Ethics and dissemination This study is based on the analysis of published scientific literature and did not involve patients, medical research, or any type of personal information; therefore, no ethical approval was obtained for this study. The results of this scoping review will be submitted for publication in an international peer-reviewed journal, preferably open access.

Abstract Background Carcinoid heart disease is a rare disease which develops in patients with functional neuroendocrine tumors in an advanced tumor state. Patients diagnosed with carcinoid heart disease have a poor longtime prognosis with respect to morbidity and mortality and long-term data on patient outcomes are lacking. Methods and results In this retrospective study, we analyzed outcomes of 23 patients with carcinoid heart disease enrolled into the SwissNet database. We observed that early diagnosis with echocardiographic surveillance of carcinoid heart disease during the course of the neuroendocrine tumor disease was beneficial to overall survival of patients. Conclusion Through nationwide patient enrollment, the SwissNet registry is a powerful data tool to identify, follow-up and evaluate long-term patient outcomes in patients with rare neuroendocrine tumor driven pathologies including carcinoid heart syndrome with observational methods enabling better therapy optimization to improve patient`s long-term perspectives and survival. In line with the current ESMO recommendations, our data proposes that heart echocardiography should be included as part of the general physical assessment in patients with newly diagnosed NET.

Monitoring systems are recognized worldwide as fundamental tools for landslide risk management. However, monitoring can be difficult when dealing with large slopes in forested areas. In these situations, dendrogeomorphology can offer a low-cost and low-impact alternative for providing distributed information with an annual temporal resolution. The present study is a first attempt to integrate dendrometric and dendrogeomorphic data into a numerical finite difference model, in order to simulate the stress–strain behavior of the tree-slope system. By using a parametrical approach, the capability of the numerical model to effectively reproduce the tree stem anomalies (i.e., tilting angle, J-shaped feature, and internal stresses causing tree-ring growth anomalies such as eccentric growth and reaction wood) was verified, and the target parameters for the model calibration were identified based on a sensitivity analysis, which emphasized the relevance of the wood deformability; moreover, the interpretation of results allowed to point out different peculiarities (in terms of type of deformation, falling direction, and distribution of internal stresses) for different slope conditions (kinematics and depth of the failure surface) and different zones of the landslide (head scarp, main body, and toe). Afterwards, the modeling approach was applied to the Val Roncaglia landslide (Northen Italy), which involves a complex roto-translational kinematics, characterized by multiple sliding surfaces. The simulated stem anomalies showed good agreement with the ones arising from onsite dendrometric surveys, and they confirmed the conceptual model of the landslide, enabling the planning of further specific investigations. Moreover, the capability of the model in reproducing the tilting angle of trees, if correlated to their eccentricity, could provide a quite long time series (over more than 50–60 years) of the landslide reactivation and allow the use of dendrochronological data for the model calibration, thereby enhancing slope dynamic monitoring and landslide risk management.

Background Few tissue biomarkers exist to date that could enrich patient with cancer populations to benefit from immune checkpoint blockade by programmed cell death protein 1/ligand-1 (PD-/L-1) inhibitors. PD-L1 expression has value in this context in some tumor types but is an imperfect predictor of clinical benefit. In malignant pleural mesothelioma, PD-L1 expression is not predictive of the benefit from PD-1 blockade. We aimed to identify novel markers in malignant pleural mesothelioma to select patients better.Methods We performed a multiplex-immune histochemistry analysis of tumor samples from the phase III PROMISE-meso study, which randomized 144 pretreated patients to receive either pembrolizumab or standard second-line chemotherapy. Our panel focused on CD8+T cell, CD68+macrophages, and the expression of PD-1 and PD-L1 on these and cancer cells. We analyzed single and double positive cells within cancer tissues (infiltrating immune cells) and in the stroma. In addition, we performed cell neighborhood analysis. The cell counts were compared with clinical outcomes, including responses, progression-free and overall survivals.Results We confirmed the absence of predictive value for PD-L1 in this cohort of patients. Furthermore, total CD8 T cells, CD68+macrophages, or inflammatory subtypes (desert, excluded, inflamed) did not predict outcomes. In contrast, PD-1-expressing CD8+T cells (exhausted T cells) and PD-1-expressing CD68+macrophages were both independent predictors of progression-free survival benefit from pembrolizumab. Patients with tumors simultaneously harboring PD1+T cells and PD-1+macrophages benefited the most from immune therapy.Conclusion We analyzed a large cohort of patients within a phase III study and found that not only PD-1+CD8 T cells but also PD-1+CD68+ macrophages are predictive. This data provides evidence for the first time for the existence of PD-1+macrophages in mesothelioma and their clinical relevance for immune checkpoint blockade.

Predicting others’ actions and inferring preferences from theirchoices is indispensable for successfully navigating socialenvironments. Yet, the cognitive tools agents employ for predictionand decision may differ when involved in social interactions. Whenpursuing a goal individually, humans maximize utility byminimizing costs, while when engaged in joint actions utilitymaximization might not be the only heuristic in place. Weinvestigate if human adults represent costs and rewards of joint vs.individual actions, and how do they decide whether to engage in ajoint action. We test participants’ decisions when solving a taskalone or together with a partner as a function of the cost ofcoordination. Our results show that human adults decide based on apreference for joint actions, despite engaging in coordinationreduces their individual utility. We discuss a framework fordecision-making which accounts for cognitive heuristics andpreferences for joint actions characterizing agents’ cooperativebehavior.

Information transmission between individuals through sociallearning is a foundational component of cultural evolution.However, how this transmission occurs is still debated. Thecopying account draws parallels with biological mechanismsfor genetic inheritance, arguing that learners copy what theyobserve as they see it. On the other hand, the reconstructionaccount argues that learners recreate only what is relevant andreconstruct it using pragmatic inference, environmental andcontextual cues. Distinguishing these two accounts empiricallyusing typical transmission chain studies is difficult becausethey generate overlapping predictions. In this study we presentan innovative methodological approach that generates differentpredictions of these accounts by manipulating the task contextbetween model and learner in a transmission episode. Weprovide an empirical proof-of-concept showing that, when amodel introduces embedded signals to their actions that are notintended to be transmitted, learners’ reproductions are moreconsistent with a process of reconstruction than copying.

In forests, the residence time of air – the inverse of first-order exchange rates – influences in-canopy chemistry and the exchanges of momentum, energy, and mass with the surrounding atmosphere. Accurate estimates are needed for chemical investigations of reactive trace species, such as volatile organic compounds, some of whose chemical lifetimes are on the order of average residence times. However, very few observational residence-time estimates have been reported. Little is known about even the basic statistics of real-world residence times or how they are influenced by meteorological variables such as turbulence or atmospheric stability. Here, we report opportunistic investigations of residence time of air in a free-air carbon dioxide enrichment (FACE) facility in a mature, broadleaf deciduous forest with canopy height of hc≈25 m. Using nearly 50 million FACE observations, we find that median daytime residence times in the tree crowns range from around 70 s when the trees are in leaf to just over 34 s when they are not. Residence times increase with increasing atmospheric stability, as does the spread around their central value. Residence times scale approximately with the reciprocal of the friction velocity, u∗. During some calm evenings in the growing season, we observe distinctly different behaviour: pooled air being sporadically and unpredictably vented – evidenced by sustained increases in CO2 concentration – when intermittent turbulence penetrates the canopy. In these conditions, the concept of a residence time is less clearly defined. Parameterisations available in the literature underestimate turbulent exchange in the upper half of forest crowns and overestimate the frequency of long residence times. Robust parameterisations of residence times (or, equivalently, fractions of emissions escaping the canopy) may be generated from inverse-gamma distributions, with the parameters 1.4≤α≤1.8 and β=hc/u∗ estimated from widely measured flow variables. In this case, the mean value for τ becomes formally defined as τ‾=β/(α-1). For species released in the canopy during the daytime, chemical transformations are unlikely unless the reaction timescale is on the order of a few minutes or less.

Abstract Background Vitamin B deficiencies are involved with several outcomes in fertility and pregnancy. In Brazil, the national prevalence rates of these micronutrient deficiencies in women of reproductive age were not known. This study aims to systematically identify, select, evaluate, analyze, and report the prevalence rates of vitamin B complex deficiencies in women of reproductive age in Brazil and identify variables that may modify the outcome rates. Methods A systematic review will be conducted guided by the following question: “What is the prevalence of vitamin B deficiencies in women of reproductive age in Brazil?”. The studies will be identified and selected from a literature search using electronic databases, consultation with researchers/specialists, and reference lists of eligible studies and reviews on the topic. Major eligibility criteria include observational cross-sectional and cohort studies carried out in Brazil and performed in women 10–49 years old, or pregnant and lactating mothers, and investigated the deficiency of vitamin B complex by laboratory test. Two reviewers independently will perform the screening and selection of the studies, data extraction, and risk of bias assessment. For the data report, a narrative approach will be used to present the characteristics of the included studies and individual findings. A random meta-analysis model will be implemented to summarize the individual prevalence rates in a global value if the studies are sufficiently homogeneous. Discussion This study aims to identify the national and regional prevalence rates of vitamin B complex deficiencies in women of reproductive age; allow the policymakers discuss, plan, and implement public policies to screen; and prevent and/or treat these malnutrition conditions. This also aims to know the rates of nutritional deficiencies over the years, serving as an indirect indicator of the socioeconomic and dietary patterns of the population. Specifically for folate, this study allows to compare the prevalence rates of deficiency of this vitamin before and after the mandatory fortification of wheat and corn flours implemented since 2004 in Brazil, in this specific population. The evidence gathered may highlight the need for population-based studies to investigate the deficiency of these vitamins. Systematic review registration PROSPERO CRD42020188474

Previous research has shown the importance of font type, size, and spacing to facilitate text reading in dyslexia. Great heterogeneity in the population of readers with specific learning disorders suggests that personalized parameters should be preferable compared to one-fits-all ones. A special automatized procedure was designed to select the most favorable parameters for both text visualization and text-to-speech conversion. A total of 78 primary and middle school students (29 typical readers, 49 children with atypical reading skills, either diagnosed as specific reading disorder or as special learning needs) took part in this study, which included the application of the procedure and a validation of its outcomes through a systematic comparison of the use of the personalized versus standard fonts and voices in reading and writing tests. The results show a significant advantage for the personalized parameters. Moreover, in the case of text-to-speech personalization, the advantage is significantly larger for dyslexic readers than for typical readers. These results confirm the usefulness of a personalization approach in providing support to facilitate learning in dyslexic students.