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A subset of cancer patients treated with immune checkpoint blockade develops colitis. Here the authors show that lower abundance of Bacteroidetes and vitamin B biosynthetic modules in fecal samples of melanoma patients can predict their susceptibility to colitis following anti-CTLA-4 treatment.

Clostridium difficile infection (CDI) is frequently diagnosed in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT). We characterized early-transplant CDI and its associations, and analyzed serially-collected feces to determine intestinal carriage of toxigenic C. difficile. Fecal specimens were collected longitudinally from 94 patients during allo-HSCT hospitalization, from the start of pre-transplant conditioning until up to 35 days after stem cell infusion. Presence of C. difficile 16S rRNA and tcdB genes was determined. Clinical variables and specimen data were analyzed for association with development of CDI. Historical data from an additional 1144 allo-HSCT patients was also used. Fecal specimens from 37 patients (39%) were found to harbor C. difficile. Early-transplant CDI was diagnosed in 16 of 94 (17%) patients undergoing allo-HSCT; cases were generally mild and resembled non-CDI diarrhea associated with transplant conditioning. CDI was associated with preceding colonization with tcdB-positive C. difficile and conditioning regimen intensity. We found no associations between early-transplant CDI and graft-versus-host disease or CDI later in transplant. CDI occurs with high frequency during the early phase of allo-HSCT, where recipients are pre-colonized with toxigenic C. difficile. During this time, CDI incidence peaks during pre-transplant conditioning, and is correlated to intensity of the treatment. In this unique setting, high rates of CDI may be explained by prior colonization and chemotherapy; however, cases were generally mild and resembled non-infectious diarrhea due to conditioning, raising concerns of misdiagnosis. Further study of this unique population with more discriminating CDI diagnostic tests are warranted.

This article focuses on Nordic school leaders and how rural principals experience autonomy and control in current governance regimes using a sample of principals in the very north of Norway and Sweden as a case. An analysis instrument constituting four different schooling domains (educational; social; developmental; administrative) and the ways in which autonomy and control are perceived within each domain structured the analytical work. The analysis showed that both Norwegian and Swedish principals experience a high degree of autonomy within the four domains. Regarding control, principals of the two countries intimated that control is generally more evident within the educational and administrative domains and less evident within the developmental and particularly within the social domain. Regarding differences between the two countries, Norwegian principals experienced more control from regional and local municipal level compared to their Swedish colleagues. The findings add important pieces to the current body of research on rural principals and school system governance.

Abstract Borna disease virus 1 (BoDV-1) is the causative agent of Borna disease, a fatal neurologic disorder of domestic mammals and humans, resulting from spill-over infection from its natural reservoir host, the bicolored white-toothed shrew (Crocidura leucodon). The known BoDV-1-endemic area is remarkably restricted to parts of Germany, Austria, Switzerland and Liechtenstein. To gain comprehensive data on its occurrence, we analysed diagnostic material from suspected BoDV-1-induced encephalitis cases based on clinical and/or histopathological diagnosis. BoDV-1 infection was confirmed by RT-qPCR in 207 domestic mammals, 28 humans and seven wild shrews. Thereby, this study markedly raises the number of published laboratory-confirmed human BoDV-1 infections and provides a first comprehensive summary. Generation of 136 new BoDV-1 genome sequences from animals and humans facilitated an in-depth phylogeographic analysis, allowing for the definition of risk areas for zoonotic BoDV-1 transmission and facilitating the assessment of geographical infection sources. Consistent with the low mobility of its reservoir host, BoDV-1 sequences showed a remarkable geographic association, with individual phylogenetic clades occupying distinct areas. The closest genetic relatives of most human-derived BoDV-1 sequences were located at distances of less than 40 km, indicating that spill-over transmission from the natural reservoir usually occurs in the patient´s home region.

Abstract Introduction Ultraviolet-free (UV-free) blue light phototherapy has emerged as a promising option due to its reported efficacy and minimal adverse effects. This study aims to evaluate the effectiveness of full-body blue light irradiation in both adult and pediatric patients with atopic dermatitis (AD), assessing its impact on skin condition and mood regulation by investigating serum concentrations of serotonin and kynurenine pathway metabolites. Methods 20 patients (age 9–45) with moderate and severe AD were included in the study. Treatment consisted of 10 irradiations with Full Body Blue device (453 nm). Serum concentrations of serotonin, quinolinic acid, kynurenic acid, tryptophan, and kynurenine were measured before and after irradiations. Results After 10 sessions of full blue light therapy (453 nm) statistically significant improvements were observed in Eczema Area Severity Index (EASI 13.16 vs. 8.65; p = 0.00016), SCORing Atopic Dermatitis (SCORAD 44.99 vs. 23.73; p

Introduction: Local tissue destruction following envenomation from North American snakes, particularly those within the Crotalinae subfamily, has the potential to progress to compartment syndrome. The pathophysiology of venom-induced compartment syndrome (VICS) is a debated topic and is distinct from trauma/reperfusion-induced compartment syndrome. Heterogeneity exists in the treatment practices of VICS, particularly regarding the decision to progress to fasciotomy. Associations with functional outcomes and evolution in clinical practice since the introduction of Crotalidae polyvalent immune Fab (FabAV) have not been well defined. Our goal was to identify the potential gaps in the literature regarding this phenomenon, as well as illuminate salient themes in the clinical characteristics and treatment practices of VICS. Methods: We conducted this systematic scoping-style review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Records were included if they contained data surrounding the envenomation and hospital course of one or more patients who were envenomated by a snake species native to North America and were diagnosed with compartment syndrome from 1980–2020. Results: We included 19 papers: 10 single- or two-patient case reports encompassing 12 patients, and nine chart reviews providing summary statistics of the included patients. In case reports, the median compartment pressure when reported was 60 millimeters of mercury (interquartile range 55–68), 66% underwent fasciotomy, and functional outcomes varied. Use of antivenom appeared to be more liberal with FabAV than the earlier antivenin Crotalidae polyvalent. Rapid progression of swelling was the most commonly reported symptom. Among the included retrospective chart reviews, important data such as compartment pressures, consistent laboratory values, and snake species was inconsistently reported. Conclusions: Venom-induced compartment syndrome is relatively rare. Existing papers generally describe good outcomes even in the absence of surgical management. Significant gaps in the literature regarding antivenom dosing practices, serial compartment pressure measurements, and functional outcomes highlight the need for prospective studies and consistent standardized reporting.

Abstract Whether disasters serve as focusing events leading to measures that reduce future disaster risks is contested. Here, we study flood disasters in 23 of the world’s most flood-prone countries to assess whether catastrophic floods, those milestone events with the highest fatalities, have been followed by decreasing mortality in subsequent floods. Results from a trend analysis, controlling for flood magnitude and subtypes, find that reductions in mortality rates have rarely followed the most devastating floods.

Abstract Quantitative structure-activity relationship (QSAR) modeling is a powerful tool for drug discovery, yet the lack of interpretability of commonly used QSAR models hinders their application in molecular design. We propose a similarity-based regression framework, topological regression (TR), that offers a statistically grounded, computationally fast, and interpretable technique to predict drug responses. We compare the predictive performance of TR on 530 ChEMBL human target activity datasets against the predictive performance of deep-learning-based QSAR models. Our results suggest that our sparse TR model can achieve equal, if not better, performance than the deep learning-based QSAR models and provide better intuitive interpretation by extracting an approximate isometry between the chemical space of the drugs and their activity space.

Este artículo debate el emprendimiento como posibilidad de emancipación y reducción de desigualdades a través de la educación. Se trata de un texto crítico-reflexivo fruto de una investigación bibliográfica analizada en diálogo con el marco histórico-crítico sobre el alcance del emprendimiento en poblaciones vulnerables y estados de pobreza. Las discusiones plantean cinco puntos: 1. el emprendimiento social puede contribuir a la articulación de un proceso emancipatorio; 2. existen diferentes perspectivas sobre el emprendimiento y su papel en la transformación social; 3. se entiende que el emprendimiento emancipatorio se basa en ofrecer una educación para la liberación; 4. los organismos financiadores no creen que los sectores más pobres puedan devolver los préstamos y; 5. las universidades deben enfatizar la promoción de una educación emprendedora-emancipadora. Palabras-clave: Educación emancipadora. Teoría histórico-crítico. Desigualdades. Subjetividad.

Regardless of baseline psychiatric symptom severity, individuals can improve from psychotherapy, including from low-intensity psychosocial treatments. We conducted a secondary analysis of a randomized trial of low-intensity mindfulness interventions to explore if and how specific indices of baseline symptom severity were associated with well-being trajectories during treatment and follow-up. In the original study, participants (N = 4, 411) with physical and mental health conditions were randomly assigned to one of two low-intensity mindfulness interventions (eight-session mindfulness-based cognitive therapy or a three-session mindfulness intervention). In this secondary analysis, we pooled across treatment groups and stratified participants into subgroups based on self-reported baseline levels of anxiety, depression, and social functioning. We used linear mixed effects models and descriptive trajectory plots to evaluate differences in well-being trajectories between subgroups. Baseline symptom severity was associated with well-being trajectory such that those with more severe anxiety, depression, or social functioning at baseline had generally lower well-being across time. All subgroups experienced initial improvement in well-being during the treatment period, though individuals with worse symptom severity tended not to sustain improvements and rebounded back towards baseline well-being levels during follow-up. These data suggest that, for individuals with more severe mental health symptoms, eight or three-session mindfulness-based interventions may still be clinically useful (as patients with more severe symptoms in this study were able to experience initial improvement in well-being from such interventions). However, for such patients, offering these mindfulness-based interventions for a longer duration may have prevented symptom rebounding.

Abstract Optimizing early breast cancer (BC) detection requires effective risk assessment tools. This retrospective study from Brazil showcases the efficacy of machine learning in discerning complex patterns within routine blood tests, presenting a globally accessible and cost-effective approach for risk evaluation. We analyzed complete blood count (CBC) tests from 396,848 women aged 40–70, who underwent breast imaging or biopsies within six months after their CBC test. Of these, 2861 (0.72%) were identified as cases: 1882 with BC confirmed by anatomopathological tests, and 979 with highly suspicious imaging (BI-RADS 5). The remaining 393,987 participants (99.28%), with BI-RADS 1 or 2 results, were classified as controls. The database was divided into modeling (including training and validation) and testing sets based on diagnostic certainty. The testing set comprised cases confirmed by anatomopathology and controls cancer-free for 4.5–6.5 years post-CBC. Our ridge regression model, incorporating neutrophil–lymphocyte ratio, red blood cells, and age, achieved an AUC of 0.64 (95% CI 0.64–0.65). We also demonstrate that these results are slightly better than those from a boosting machine learning model, LightGBM, plus having the benefit of being fully interpretable. Using the probabilistic output from this model, we divided the study population into four risk groups: high, moderate, average, and low risk, which obtained relative ratios of BC of 1.99, 1.32, 1.02, and 0.42, respectively. The aim of this stratification was to streamline prioritization, potentially improving the early detection of breast cancer, particularly in resource-limited environments. As a risk stratification tool, this model offers the potential for personalized breast cancer screening by prioritizing women based on their individual risk, thereby indicating a shift from a broad population strategy.

In recent years, the sports communication landscape has seen changes in terms of who occupies the role of sports reporter. In-house reporters, or sports communicators employed by specific clubs, teams, or leagues, now contribute content to the sports media landscape. This study explores the complicated relationship between in-house reporters’ self-perceived professional identities and in-houses reporters’ perceptions of their audiences through the lens of Bourdieusian field theory. As such, it sees in-house reporters as peripheral actors negotiating the boundaries of the sports journalism field. Through semi-structured interviews with 28 in-house sports reporters from the United States and Austria, our findings suggest that in-house reporters conceive of themselves both in relation to professional journalism and as members of the sports establishment. Furthermore, they note an ambiguous relationship to their audience, which is both reliant upon the reporters’ work, and, at times, highly critical of it.

Nicaragua is a biodiverse country, but documented herpetological specimens are underrepresented compared to neighboring countries. In 2018 we conducted a collaborative expedition between the University of Michigan Museum of Zoology and Nicaraguan biologists. We visited sites in the Pacific Low‑ lands, Caribbean Lowlands, and the Central Highlands, representing the three major biogeographic regions of Nicaragua. We collected specimens of 100 species from a total of 106 encountered. We provide acces‑ sion numbers and morphological, genetic, and ecological information for these specimens. We recorded 23 new departmental records and the first country record of Metlapilcoatlus indomitus (Smith & Ferrari‑Castro, 2008), filling gaps in the known distribution of the species within Nicaragua and across Central America. When available for each species, we provide range maps and comparative genetic trees including conspecific reference sequences from the region, making this work a significant addition to existing checklists of the herpetofauna in Nicaragua.

Abstract Using material distribution-based topology optimization, we optimize the bandpass design of a loudspeaker cabinet targeting low frequencies. The objective is to maximize the loudspeaker’s output power for a single frequency as well as a range of frequencies. To model the loudspeaker’s performance, we combine a linear electromechanical transducer model with a computationally efficient hybrid 2D–3D model for sound propagation. The adjoint variable approach computes the gradients of the objective function with respect to the design variables, and the Method of Moving Asymptotes (MMA) solves the topology optimization problem. To manage intermediate values of the material indicator function, a quadratic penalty is added to the objective function, and a non-linear filter is used to obtain a mesh independent design. By carefully selecting the target frequency range, we can guide the optimization algorithm to successfully generate a loudspeaker design with the required bandpass character. To the best of our knowledge, this study constitutes the first successful attempt to design the interior structure of a loudspeaker cabinet using topology optimization.

AbstractIntroduction: Whole Bowel Irrigation (WBI) is used as a method of gastrointestinal decontamination for poisoned patients and may have low compliance when recommended by poison centers (PC). We set out to determine WBI compliance and analyze trends and possible associations between WBI compliance and clinical outcomes. Methods: We conducted a single-center retrospective chart review of PC data from 1/1/2011 to 12/31/2019 and included cases in which WBI was recommended. We collected demographic data, exposure history, therapies recommended and performed, and clinical outcomes. Compliance rate was calculated. Chi-squared and Mann-Whitney U tests were performed to look for differences in compliance based on case characteristics such as compliance rate by year, compliance based medication ingested and presence of intubation. We also looked for a possible association between WBI compliance and clinical outcome. Results: Four hundred and eighty-three cases met inclusion criteria. Fifty-five percent of patients were male and the median age was 32.5 years. Compliance to WBI recommendations was 58.2%. There was no significant difference in compliance when comparing by age, gender, medication ingested, or year. There was no association between compliance to WBI and clinical outcomes. Conclusions: We calculated a compliance rate of 58% when WBI was recommended. Compliance to WBI does not appear to be associated with changes in clinical outcome.

Myelodysplastic neoplasms (MDS) are a heterogenous group of clonal stem cell disorders characterized by dysplasia and cytopenia in one or more cell lineages. Anemia is a very common symptom that is often treated with blood transfusions and/or erythropoiesis stimulating factors. Iron overload results from a combination of these factors together with the disease-associated ineffective erythropoiesis, that is seen especially in MDS cases with SF3B1 mutations. A growing body of research has shown that erythroferrone is an important regulator of hepcidin, the master regulator of systemic iron homeostasis. Consequently, it is of interest to understand how this molecule contributes to regulating the iron balance in MDS patients. This short review evaluates our current understanding of erythroferrone in general, but more specifically in MDS and seeks to place in context how the current knowledge could be utilized for prognostication and therapy.

BackgroundSerious games, which are gaming applications used for purposes beyond entertainment to educate users on, and address, specific issues, may present a timely approach to promote healthy diabetes management behaviors among children with type 1 diabetes mellitus (T1DM). The lasting benefits associated with these serious games encompass improved patient education; enhanced glycemic control; the reinforcement of bonds within the community of people with diabetes; the facilitation of meaningful dialogues with caregivers, especially within the familial setting; and a significant reduction in the economic burdens associated with subsequent complications. ObjectiveThis paper primarily aims to provide a detailed overview of the iterative design process and the associated evaluation methods used in the development of the educational game. Furthermore, this study aims to enhance motivation for sustained and extended engagement with the game over time. The MyDiabetic game design aims to educate children on various aspects, including the connections among food, insulin, and physical activity. Furthermore, it seeks to impart knowledge related to the operation of a glucometer and an insulin pen, as well as more advanced technologies such as administering glucagon, measuring ketoacidosis, and continuous glucose monitoring. MethodsThe co-design methodology was applied, involving interviews, design workshops, and prototype feedback sessions. A combination of several approaches, such as tailoring, observational learning, social and family support, decision-making practice, and reward systems, was used to support children’s compliance. Moreover, incorporating the literature, guidelines, and current practices into the design ensured that the game was aligned with established health care pathways and included relevant information and best practices for diabetes management. ResultsThe game was tested on 32 children in 3 iterations. Positive responses were received from children who tested the game as well as their parents. The game was also presented to 5 schoolmates of children with T1DM who appreciated a better understanding of the disease and the opportunity to support their friends more efficiently in T1DM compensation. The involvement of children and clinicians in participatory co-design contributed to to the game's high acceptance. With regard to the game’s impact on education, 1 week of testing revealed an enhancement in educational outcomes. ConclusionsThe game is especially suitable for children newly diagnosed with T1DM because it acquaints them in a fun way with new terminology; for example, they can try to measure glycemia levels in an interactive way. The game also caters to children who still need to develop reading skills by including an audio guide. The guide ensures that children of all literacy levels can benefit from the game’s educational content and interactive experiences. The game is available for download on Google Play and the Apple App Store.

Abstract Disease-causing mutations in genes encoding transcription factors (TFs) can affect TF interactions with their cognate DNA-binding motifs. Whether and how TF mutations impact upon the binding to TF composite elements (CE) and the interaction with other TFs is unclear. Here, we report a distinct mechanism of TF alteration in human lymphomas with perturbed B cell identity, in particular classic Hodgkin lymphoma. It is caused by a recurrent somatic missense mutation c.295 T > C (p.Cys99Arg; p.C99R) targeting the center of the DNA-binding domain of Interferon Regulatory Factor 4 (IRF4), a key TF in immune cells. IRF4-C99R fundamentally alters IRF4 DNA-binding, with loss-of-binding to canonical IRF motifs and neomorphic gain-of-binding to canonical and non-canonical IRF CEs. IRF4-C99R thoroughly modifies IRF4 function by blocking IRF4-dependent plasma cell induction, and up-regulates disease-specific genes in a non-canonical Activator Protein-1 (AP-1)-IRF-CE (AICE)-dependent manner. Our data explain how a single mutation causes a complex switch of TF specificity and gene regulation and open the perspective to specifically block the neomorphic DNA-binding activities of a mutant TF.

Abstract Haematopoietic stem cells (HSC) reside in the bone marrow microenvironment (BMM), where they respond to extracellular calcium [eCa2+] via the G-protein coupled calcium-sensing receptor (CaSR). Here we show that a calcium gradient exists in this BMM, and that [eCa2+] and response to [eCa2+] differ between leukaemias. CaSR influences the location of MLL-AF9+ acute myeloid leukaemia (AML) cells within this niche and differentially impacts MLL-AF9+ AML versus BCR-ABL1+ leukaemias. Deficiency of CaSR reduces AML leukaemic stem cells (LSC) 6.5-fold. CaSR interacts with filamin A, a crosslinker of actin filaments, affects stemness-associated factors and modulates pERK, β-catenin and c-MYC signaling and intracellular levels of [Ca2+] in MLL-AF9+ AML cells. Combination treatment of cytarabine plus CaSR-inhibition in various models may be superior to cytarabine alone. Our studies suggest CaSR to be a differential and targetable factor in leukaemia progression influencing self-renewal of AML LSC via [eCa2+] cues from the BMM.

ABSTRACTDespite a growing body of research, there is an urgent need for studies on principals’ work during the COVID-19 pandemic. Given that Sweden, unlike most other countries, decided to keep schools open during the pandemic there is plenty to learn from the Swedish case. This article explores how Swedish principals experienced their autonomy before the pandemic and whether and how the experience of autonomy changed over the course of the pandemic. Data from 14 urban principals were integrated in order to analyse principals’ autonomy within four domains of their work. The results indicate that principals experienced a high degree of autonomy in their work, both before and during the pandemic. At the same time, they experienced a significant degree of control from state and local municipal level. The article adds important pieces to the current body of research by showing how autonomy and control impinge upon principals’ work and leadership in times of crisis.

Abstract A muon collider would enable the big jump ahead in energy reach that is needed for a fruitful exploration of fundamental interactions. The challenges of producing muon collisions at high luminosity and 10 TeV centre of mass energy are being investigated by the recently-formed International Muon Collider Collaboration. This Review summarises the status and the recent advances on muon colliders design, physics and detector studies. The aim is to provide a global perspective of the field and to outline directions for future work.

In current digital media landscapes, sports journalism has lost its status as the undisputed playmaker in delivering sports-related information to audiences [...]

Abstract MicroRNAs (miRNAs) are short non-coding RNAs that are involved in post-transcriptional control of gene expression and might be used as biomarkers for diabetes-related complications. The aim of this case–control study was to explore potential differences in circulating miRNAs in young individuals with long-duration type 1 diabetes (T1D) compared to healthy controls, and how identified miRNAs are expressed across different tissues. Twelve adolescents, age 15.0–17.9 years, with T1D duration of more than 8 years (mean 11.1 years), were enrolled from the Swedish diabetes quality registry. An age-matched control group was recruited. Circulating miRNAs (n = 187) were analyzed by quantitative PCR. We observed that 27 miRNAs were upregulated and one was downregulated in T1D. Six of these miRNAs were tissue-enriched (blood cells, gastrointestinal, nerve, and thyroid tissues). Six miRNAs with the largest difference in plasma, five up-regulated (hsa-miR-101-3p, hsa-miR-135a-5p, hsa-miR-143-3p, hsa-miR-223-3p and hsa-miR-410-3p (novel for T1D)) and one down-regulated (hsa-miR-495-3p), with P-values below 0.01, were selected for further in-silico analyses. AKT1, VEGFA and IGF-1 were identified as common targets. In conclusion, 28 of the investigated miRNAs were differently regulated in long-duration T1D in comparison with controls. Several associations with cancer were found for the six miRNAs with the largest difference in plasma.

Abstract Background This study aimed to examine the epidemiology of firework-related injuries within a national population between 2012 and 2022, including the severity of injury by year, patient demographics, body region injured, firework type, and diagnosis category of injury. Methods Data were collected from the Consumer Product Safety Commission’s National Electronic Injury Surveillance System, which is a representative nationwide database that collects data on consumer product-related injuries occurring in the US. Injury rates were calculated based on patient age, sex, body region injured, firework type, and diagnosis category. Results A total of 3219 injuries, representing an estimated 122,912 firework-related injuries, were treated in emergency departments within the US from 2012 to 2022. The overall incidence rate of firework-related injuries in the study rose by over 17% from 2012 [2.61 cases per 100,000 people (95% CI 2.03–3.20)] to 2022 and [3.05 cases per 100,000 people (95% CI 2.29–3.80)]. The rate of injuries was highest in adolescents and young adults (age 20–24; 7.13 cases per 100,000 people). Men experienced firework injuries at more than double the rate of women (4.90 versus 2.25 cases per 100,000 people). The upper extremities (41.62%), head/neck (36.40%), and lower extremities (13.78%) were the most commonly injured regions. Over 20% of cases in patients older than 20 were significant injuries requiring hospitalization. Aerial devices (32.11%) and illegal fireworks (21.05%) caused the highest rates of significant injury of any firework type. Conclusions The incidence of firework-related injuries has risen over the past decade. Injuries remain the most common among adolescents and young adults. In addition, significant injuries requiring hospitalization occur most often during aerial and illegal firework use. Further targeted sale restrictions, distribution, and manufacturing regulations for high-risk fireworks are required to reduce the incidence of significant injury.

Abstract Background Robust and reliable in vitro and in vivo models of primary cells are necessary to study the pathomechanisms of Myelodysplastic Neoplasms (MDS) and identify novel therapeutic strategies. MDS-derived hematopoietic stem and progenitor cells (HSPCs) are reliant on the support of bone marrow (BM) derived mesenchymal stroma cells (MSCs). Therefore, isolation and expansion of MCSs are essential for successfully modeling this disease. For the clinical use of healthy MSCs isolated from human BM, umbilical cord blood or adipose tissue, several studies showed that xeno-free (XF) culture conditions resulted in superior growth kinetics compared to MSCs cultured in the presence of fetal bovine serum (FBS). In this present study, we investigate, whether the replacement of a commercially available MSC expansion medium containing FBS with a XF medium is beneficial for the expansion of MSCs derived from BM of MDS patients which are often difficult to cultivate. Methods MSCs isolated from BM of MDS patients were cultured and expanded in MSC expansion medium with FBS or XF supplement. Subsequently, the impact of culture media on growth kinetics, morphology, immunophenotype, clonogenic potential, differentiation capacity, gene expression profiles and ability to engraft in immunodeficient mouse models was evaluated. Results Significant higher cell numbers with an increase in clonogenic potential were observed during culture of MDS MSCs with XF medium compared to medium containing FBS. Differential gene expression showed an increase in transcripts associated with MSC stemness after expansion with XF. Furthermore, immunophenotypes of the MSCs and their ability to differentiate into osteoblasts, adipocytes or chondroblasts remained stable. MSCs expanded with XF media were similarly supportive for creating MDS xenografts in vivo as MSCs expanded with FBS. Conclusion Our data indicate that with XF media, higher cell numbers of MDS MSCs can be obtained with overall improved characteristics in in vitro and in vivo experimental models.

[This corrects the article DOI: 10.1371/journal.pone.0298320.].

Abstract Major trauma is a condition that can result in severe bone damage. Customised orthopaedic reconstruction allows for limb salvage surgery and helps to restore joint alignment. For the best possible outcome three dimensional (3D) medical imaging is necessary, but its availability and access, especially in developing countries, can be challenging. In this study, 3D bone shapes of the femur reconstructed from planar radiographs representing bone defects were evaluated for use in orthopaedic surgery. Statistical shape and appearance models generated from 40 cadaveric X-ray computed tomography (CT) images were used to reconstruct 3D bone shapes. The reconstruction simulated bone defects of between 0% and 50% of the whole bone, and the prediction accuracy using anterior–posterior (AP) and anterior–posterior/medial–lateral (AP/ML) X-rays were compared. As error metrics for the comparison, measures evaluating the distance between contour lines of the projections as well as a measure comparing similarities in image intensities were used. The results were evaluated using the root-mean-square distance for surface error as well as differences in commonly used anatomical measures, including bow, femoral neck, diaphyseal–condylar and version angles between reconstructed surfaces from the shape model and the intact shape reconstructed from the CT image. The reconstructions had average surface errors between 1.59 and 3.59 mm with reconstructions using the contour error metric from the AP/ML directions being the most accurate. Predictions of bow and femoral neck angles were well below the clinical threshold accuracy of 3°, diaphyseal–condylar angles were around the threshold of 3° and only version angle predictions of between 5.3° and 9.3° were above the clinical threshold, but below the range reported in clinical practice using computer navigation (i.e., 17° internal to 15° external rotation). This study shows that the reconstructions from partly available planar images using statistical shape and appearance models had an accuracy which would support their potential use in orthopaedic reconstruction.

Abstract Melanoma is the deadliest form of skin cancer showing rising incidence over the past years. New insights into the mechanisms of melanoma progression contributed to the development of novel treatment options, such as immunotherapies. However, acquiring resistance to treatment poses a big problem to therapy success. Therefore, understanding the mechanisms underlying resistance could improve therapy efficacy. Correlating expression levels in tissue samples of primary melanoma and metastases revealed that secretogranin 2 (SCG2) is highly expressed in advanced melanoma patients with poor overall survival (OS) rates. By conducting transcriptional analysis between SCG2-overexpressing (OE) and control melanoma cells, we detected a downregulation of components of the antigen presenting machinery (APM), which is important for the assembly of the MHC class I complex. Flow cytometry analysis revealed a downregulation of surface MHC class I expression on melanoma cells that showed resistance towards the cytotoxic activity of melanoma-specific T cells. IFNγ treatment partially reversed these effects. Based on our findings, we suggest that SCG2 might stimulate mechanisms of immune evasion and therefore be associated with resistance to checkpoint blockade and adoptive immunotherapy.

Hypomethylating agents, such as 5-Azacytidine (5-AZA), are standard of care for patients with myelodysplastic and myeloid malignancies, however response rates are limited and risk of relapses high. Here the authors show that inhibition of lysyl oxidases synergizes with 5-AZA to improve erythropoiesis and reduce disease burden in myelodysplastic neoplasms models.

The requirements placed on the foundry industry are mainly related to the need to maintain an appropriate quality–price ratio of the product and to maintain an appropriate production regime that takes into account modern legal solutions related to environmental protection. This work is part of the trend of searching for new or previously unused materials from renewable sources in moulding sand technology. This article concerns the possibility of using barley malt in moulding material technology as a binding material. The presented work contains the results of research on the release of gases during casting, where high temperatures cause the decomposition of chemical substances. The tests confirmed that moulding sands with barley malt as a binder do not cause excessive emissions of harmful gaseous products when pouring moulds with liquid casting alloy. The volume of gases formed was smaller than that of commonly used moulding sands with other binders. The total volume of gases produced and the kinetics of their release indicate that casting in this type of moulding sand did not cause any technological inconvenience or casting defects of gaseous origin. This was confirmed by research involving obtaining iron castings in industrial conditions using barley malt as a binder in moulding sand technology, which were then subjected to visual assessment and roughness analysis.

Inhibitors of anti-apoptotic BCL-2 family proteins in combination with chemotherapy and hypomethylating agents (HMA) are promising therapeutic approaches in acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS). Alvocidib, a cyclin-dependent kinase 9 (CDK9) inhibitor and indirect transcriptional repressor of the anti-apoptotic factor MCL-1, has previously shown clinical activity in AML. Availability of biomarkers for response to the alvocidib + 5-azacytidine (5-AZA) could also extend the rationale of this treatment concept to high-risk MDS. In this study, we performed a comprehensive in vitro assessment of alvocidib and 5-AZA effects in N=45 high-risk MDS patients. Our data revealed additive cytotoxic effects of the combination treatment. Mutational profiling of MDS samples identified ASXL1 mutations as predictors of response. Further, increased response rates were associated with higher gene expression of the pro-apoptotic factor NOXA in ASXL1-mutated samples. The higher sensitivity of ASXL1 mutant cells to the combination treatment was confirmed in vivo in ASXL1Y588X transgenic mice. Overall, our study demonstrated augmented activity for the alvocidib + 5-AZA combination in higher-risk MDS and identified ASXL1 mutations as a biomarker of response for potential stratification studies.

Outdoor recreation benefits local economies, environmental education, and public health and wellbeing, but it can also adversely affect local ecosystems. Human presence in natural areas alters feeding and reproductive behaviors, physiology, and population structure in many wildlife species, often resulting in cascading effects through entire ecological communities. As outdoor recreation gains popularity, existing trails are becoming overcrowded and new trails are being built to accommodate increasing use. Many recreation impact studies have investigated effects of the presence or absence of humans while few have investigated recreation effects on wildlife using a gradient of disturbance intensity. We used camera traps to quantify trail use by humans and mid- to large-sized mammals in an area of intense outdoor recreation–the Upper East River Valley, Colorado, USA. We selected five trails with different types and intensities of human use and deployed six cameras on each trail for five weeks during a COVID-enhanced 2020 summer tourism season. We used occupancy models to estimate detectability and habitat use of the three most common mammal species in the study area and determined which human activities affect the habitat use patterns of each species. Human activities affected each species differently. Mule deer (Odocoileus hemionus) tended to use areas with more vehicles, more predators, and greater distances from the trailhead, and they were more likely to be detected where there were more bikers. Coyotes (Canis latrans) and red foxes (Vulpes vulpes) were most likely to use areas where their prey species occurred, and foxes were more likely to be detected where the vegetation was shorter. Humans and their recreational activities differentially influence different species. More generally, these results reinforce that it is unlikely that a single management policy is suitable for all species and management should thus be tailored for each target species.

In a domain of a safety increasing of railway and road traffic, hydraulic barrier drives installed at level crossings have an important role. Frequent traffic accidents at level crossings, involving road vehicles and trains, are result of inappropriately equipped level crossings with signalling and safety equipment. Limited use of hydraulic barrier drives is the result of complicated adaptation in the process of implementing such systems to the existing infrastructure of some of the equipment manufacturers and railway operators. Hydraulic barrier drive PBH21, which uses a modular architecture, was developed and designed in this paper. Applying modular design principles and functional modeling methods, using functional flow diagrams, PBH21 has ability to adapt on the technologies and infrastructures of other major manufacturers of such equipment within EU countries and other countries in the world that have developed railway infrastructure. Due to the protection of certain design solutions from competition, certain details are not presented in this paper.

Major Depressive Disorder (MDD) - can be evaluated by advanced neurocomputing and traditional machine learning techniques. This study aims to develop an automatic system based on a Brain-Computer Interface (BCI) to classify and score depressive patients by specific frequency bands and electrodes. In this study, two Residual Neural Networks (ResNets) based on electroencephalogram (EEG) monitoring are presented for classifying depression (classifier) and for scoring depressive severity (regression). Significant frequency bands and specific brain regions are selected to improve the performance of the ResNets. The algorithm, which is estimated by 10-fold cross-validation, attained an average accuracy rate ranging from 0.371 to 0.571 and achieved average Root-Mean-Square Error (RMSE) from 7.25 to 8.41. After using the beta frequency band and 16 specific EEG channels, we obtained the best-classifying accuracy at 0.871 and the smallest RMSE at 2.80. It was discovered that signals extracted from the beta band are more distinctive in depression classification, and these selected channels tend to perform better on scoring depressive severity. Our study also uncovered the different brain architectural connections by relying on phase coherence analysis. Increased delta deactivation accompanied by strong beta activation is the main feature of depression when the depression symptom is becoming more severe. We can therefore conclude that the model developed here is acceptable for classifying depression and for scoring depressive severity. Our model can offer physicians a model that consists of topological dependency, quantified semantic depressive symptoms and clinical features by using EEG signals. These selected brain regions and significant beta frequency bands can improve the performance of the BCI system for detecting depression and scoring depressive severity.

O objetivo deste texto é fazer uma breve análise das condições de trabalho, renda e proteção social oferecidas aos trabalhadores da economia solidária com base na categoria marxista do Exército Industrial de Reserva (EIR). Para isso, é feita uma análise dos dados dos empreendimentos solidários no Brasil a partir do Segundo Mapeamento Nacional de Empreendimentos Solidários realizado em 2013. As principais conclusões apontam que uma parcela significativa dos Empreendimentos de Economia Solidária (EES) oferece aos seus membros pouca proteção social e baixos rendimentos. Com isso, apesar de ser uma fonte de subsistência, a economia solidária termina por manter uma parte dos trabalhadores na condição de EIR.

The unprecedented generation of large volumes of biodiversity data is consistently contributing to a wide range of disciplines, including disease ecology. Emerging infectious diseases are usually zoonoses caused by multi-host pathogens. Therefore, their understanding may require the access to biodiversity data related to the ecology and the occurrence of the species involved. Nevertheless, despite several data-mobilization initiatives, the usage of biodiversity data for research into disease dynamics has not yet been fully leveraged.To explore current contribution, trends, and to identify limitations, we characterized biodiversity data usage in scientific publications related to human health, contrasting patterns of studies citing the Global Biodiversity Information Facility (GBIF) with those obtaining data from other sources.We found that the studies mainly obtained data from scientific literature and other not aggregated or standardized sources. Most of the studies explored pathogen species and, particularly those with GBIF-mediated data, tended to explore and reuse data of multiple species (>2). Data sources varied according to the taxa and epidemiological roles of the species involved. Biodiversity data repositories were mainly used for species related to hosts, reservoirs, and vectors, and barely used as a source of pathogens data, which was usually obtained from human and animal-health related institutions. While both GBIF- and not GBIF-mediated data studies explored similar diseases and topics, they presented discipline biases and different analytical approaches.Research on emerging infectious diseases may require the access to geographical and ecological data of multiple species. The One Health challenge requires interdisciplinary collaboration and data sharing, which is facilitated by aggregated repositories and platforms. The contribution of biodiversity data to understand infectious disease dynamics should be acknowledged, strengthened, and promoted.

Continuously global warming and landscape change have aggravated the damage of flood disasters to ecological safety and sustainable development. If the risk of flood disasters under climate and land-use changes can be predicted and evaluated, it will be conducive to flood control, disaster reduction, and global sustainable development. This study uses bias correction and spatial downscaling (BCSD), patch-generating land-use simulation (PLUS) coupled with multi-objective optimization (MOP), and entropy weighting to construct a 1 km resolution flood risk assessment framework for the Guanzhong Plain under multiple future scenarios. The results of this study show that BCSD can process the 6th Climate Model Intercomparison Project (CMIP6) data well, with a correlation coefficient of up to 0.98, and that the Kappa coefficient is 0.85. Under the SSP126 scenario, the change in land use from cultivated land to forest land, urban land, and water bodies remained unchanged. In 2030, the proportion of high-risk and medium-risk flood disasters in Guanzhong Plain will be 41.5% and 43.5% respectively. From 2030 to 2040, the largest changes in risk areas were in medium- and high-risk areas. The medium-risk area decreased by 1256.448 km2 (6.4%), and the high-risk area increased by 1197.552 km2 (6.1%). The increase mainly came from the transition from the medium-risk area to the high-risk area. The most significant change in the risk area from 2040 to 2050 is the higher-risk area, which increased by 337 km2 (5.7%), while the medium- and high-risk areas decreased by 726.384 km2 (3.7%) and 667.488 km2 (3.4%), respectively. Under the SSP245 scenario, land use changes from other land use to urban land use; the spatial distribution of the overall flood risk and the overall flood risk of the SSP126 and SSP245 scenarios are similar. The central and western regions of the Guanzhong Plain are prone to future floods, and the high-wind areas are mainly distributed along the Weihe River. In general, the flood risk in the Guanzhong Plain increases, and the research results have guiding significance for flood control in Guanzhong and global plain areas.

Abstract Non-Standard-Model parity violation may be occurring in LHC collisions. Any such violation would go unseen, however, as searches for it are not currently performed. One barrier to searches for parity violation is the lack of model-independent methods sensitive to all of its forms. We remove this barrier by demonstrating an effective and model-independent way to search for parity-violating physics at the LHC. The method is data-driven and makes no reference to any particular parity-violating model. Instead, it inspects data to construct sensitive parity-odd event variables (using machine learning tools), and uses these variables to test for parity asymmetry in independent data. We demonstrate the efficacy of this method by testing it on data simulated from the Standard Model and from a non-standard parity-violating model. This result enables the possibility of investigating a variety of previously unexplored forms of parity violation in particle physics. Data and software are shared at https://zenodo.org/record/6827724 .

Here the authors explore the effects of disasters on adaptation actions in 549 cities, finding that the effects of disaster frequency and severity are modest and depend on action type, population size, and adaptive capacity.

Summary: Background: Heart transplantation is an effective treatment offering the best recovery in both quality and quantity of life in those affected by refractory, severe heart failure. However, transplantation is limited by donor organ availability. The reintroduction of heart donation after the circulatory determination of death (DCD) in 2014 offered an uplift in transplant activity by 30%. Thoraco-abdominal normothermic regional perfusion (taNRP) enables in-situ reperfusion of the DCD heart. The objective of this paper is to assess the clinical outcomes of DCD donor hearts recovered and transplanted from donors undergoing taNRP. Method: This was a multicentre retrospective observational study. Outcomes included functional warm ischaemic time, use of mechanical support immediately following transplantation, perioperative and long-term actuarial survival and incidence of acute rejection requiring treatment. 157 taNRP DCD heart transplants, performed between February 2, 2015, and July 29, 2022, have been included from 15 major transplant centres worldwide including the UK, Spain, the USA and Belgium. 673 donations after the neurological determination of death (DBD) heart transplantations from the same centres were used as a comparison group for survival. Findings: taNRP resulted in a 23% increase in heart transplantation activity. Survival was similar in the taNRP group when compared to DBD. 30-day survival was 96.8% ([92.5%–98.6%] 95% CI, n = 156), 1-year survival was 93.2% ([87.7%–96.3%] 95% CI, n = 72) and 5-year survival was 84.3% ([69.6%–92.2%] 95% CI, n = 13). Interpretation: Our study suggests that taNRP provides a significant boost to heart transplantation activity. The survival rates of taNRP are comparable to those obtained for DBD transplantation in this study. The similar survival may in part be related to a short warm ischaemic time or through a possible selection bias of younger donors, this being an uncontrolled observational study. Therefore, our study suggests that taNRP offers an effective method of organ preservation and procurement. This early success of the technique warrants further investigation and use. Funding: None of the authors have a financial relationship with a commercial entity that has an interest in the subject.

The article presents the ongoing research, which aims to select suitable electrodes and mixtures of conductive inks, which will be used as a converter between the pressure and electrical quantities in the design of planar pressure transducers. In the described research, we continue our previous work and the work of other authors who have previously dealt with the properties of conductive inks and electrodes. Due to the only partial results in the given field, we decided to perform an extensive and original measurement of a total of 172 combinations of different electrode sizes, various conductive ink mixtures and ink layer thicknesses. Thanks to this, it will be possible, in the future, to select a suitable combination of electrodes and inks when designing pressure sensors for industrial and agricultural applications without the need to perform time-consuming preparatory measurements. The aim of the measurements is also to determine the usable working range of the pressures and the corresponding sensitivity for certain combinations of electrodes and inks, and to also exclude those variants which are unsuitable for the given purposes. This paper presents the introductory part of the measurements, which aims to verify the methodology of the measurements on a test plate at robotised workspace that is connected to a PC in real time via the program LabView. The described introductory measurements proved our methodology to be suitable to the given purpose; however, there minor problems emerged with the actual working pressure range of the transducer and the consequential necessary adjustments of the control program.

Purpose Advances in endovascular technology have expanded the treatment options for intracranial aneurysms. Intrasaccular flow diversion is a relatively new technique that aims to disrupt blood inflow at the neck of the aneurysm, hence promoting intrasaccular thrombosis. The Woven EndoBridge device (WEB; MicroVention, Aliso Viejo, CA, USA) is an US Food and Drug Administration approved intrasaccular flow diverter for wide-necked aneurysms. We report the early interim clinical and radiological outcomes of patients with both ruptured and unruptured intracranial aneurysms (IAs) treated using the WEB device in an Australian population. Materials and Methods A retrospective analysis was done of patients with ruptured or unruptured IAs who received treatment with WEB across 5 Australian neuroendovascular referral centers between May 2017 and November 2020. Angiographic occlusion was assessed with time-of-flight magnetic resonance angiography. Complications were recorded and clinical outcomes were assessed using the modified Rankin scale at follow-up. Results In total, 66 aneurysms were treated in 63 patients, with successful deployment of the WEB device in 98.5% (n=65). Eighteen (26.9%) ruptured aneurysms were included. Failure of deployment occurred in a single case. Adjunct coiling and/or stenting was performed in 20.9% (n=14) cases. Sixty-two patients with 65 aneurysms using a WEB device were followed up (mean=9.1 months), and 89.4% of these had complete aneurysm occlusion while 1.5% remained patent. Functional independence was achieved in 93.5% of cases. Conclusion Early results following the use of WEB devices in Australia demonstrate safety and adequate aneurysm occlusion comparable to international literature.

A central component of adolescents’ social and emotional learning (SEL) consists of their ability to foster positive relationship skills through connectedness with their school community. This study focuses on the assessment of student’s SEL competencies in relation to their socio-demographic characteristics, formal and informal socialization behaviors, and academic outcomes in both public and private schools. The research is based on the secondary analysis of large-scale nationally representative data from the High School Longitudinal Study of 2009 (HSLS:2009) and focuses on ninth graders experiencing the transition to secondary education. Guided by both SEL and school climate frameworks, we identified survey items that describe students’ feelings of acceptance, pride, and support in their grade nine learning environment as indicators of perceptions of school climate and builders of SEL skills and used multivariate statistical analysis to examine how SEL skills and behavioral socialization affect school achievement. Study findings should inform school practitioners in developing academic and socio-cultural programs that incorporate SEL skills development.