bluuebunny/crossref_metadata_2025_split huggingface dataset:
A genome‐wide association study of European advanced cancer patients treated with opioids identifies regulatory variants on chromosome 20 associated with pain intensity
Authors: Minnai Francesca , Shkodra Morena , Noci Sara , Esposito Martina , Brunelli Cinzia , Pigni Alessandra , Zecca Ernesto , Skorpen Frank , Klepstad Pål , Kaasa Stein , Corli Oscar , Pallotti Maria C. , Maltoni Marco C. , Caraceni Augusto T. , Colombo Francesca 
Published: December 2024

AbstractBackgroundOpioids in step III of the WHO analgesic ladder are the standard of care for treating cancer pain. However, a significant minority of patients do not benefit from therapy. Genetics might play a role in predisposing patients to a good or poor response to opioids. Here, we investigated this issue by conducting a genome‐wide association study (GWAS).MethodsWe genotyped 2057 European advanced cancer patients treated with morphine, buprenorphine, fentanyl and oxycodone. We carried out a whole‐genome regression model (using REGENIE software) between genotypes and the opioid response phenotype, defined as a numerical score measuring patient pain intensity.ResultsThe GWAS identified five non‐coding variants on chromosome 20 with a p‐value <5.0 × 10−8. For all of them, the minor allele was associated with lower pain intensity. These variants were intronic to the PCMTD2 gene and were 200 kbp downstream of OPRL1, the opioid related nociceptin receptor 1. Notably according to the eQTLGen database, these variants act as expression quantitative trait loci, modulating the expression mainly of PCMTD2 but also of OPRL1. Variants in the same chromosomal region were recently reported to be significantly associated with pain intensity in a GWAS conducted in subjects with different chronic pain conditions.ConclusionsOur results support the role of genetics in the opioid response in advanced cancer patients. Further functional analyses are needed to understand the biological mechanism underlying the observed association and lead to the development of individualized pain treatment plans, ultimately improving the quality of life for cancer patients.Significance StatementThis genome‐wide association study on European advanced cancer patients treated with opioids identifies novel regulatory variants on chromosome 20 (near PCMTD2 and OPRL1 genes) associated with pain intensity. These findings enhance our understanding of the genetic basis of opioid response, suggesting new potential markers for opioid efficacy. The study is a significant advancement in pharmacogenomics, providing a robust dataset and new insights into the genetic factors influencing pain intensity, which could lead to personalized cancer pain management.
Evaluation of the standard battery of in vitro genotoxicity tests to predict in vivo genotoxicity through mathematical modeling: A report from the 8th International Workshop on Genotoxicity Testing
Authors: Luijten Mirjam , van Benthem Jan , Morita Takeshi , Corvi Raffaella , Escobar Patricia A. , Fujita Yurika , Hemmerich Jennifer , Honarvar Naveed , Kirkland David , Koyama Naoki , Lovell David P. , Mathea Miriam , Williams Andrew , Dertinger Stephen , Pfuhler Stefan , Pennings Jeroen L. A. 
Published: December 2024

AbstractIn human health risk assessment of chemicals and pharmaceuticals, identification of genotoxicity hazard usually starts with a standard battery of in vitro genotoxicity tests, which is needed to cover all genotoxicity endpoints. The individual tests included in the battery are not designed to pick up all endpoints. This explains why resulting data can appear contradictory, thereby complicating accurate interpretation of the findings. Such interpretation could be improved through application of mathematical modeling. One of the advantages of mathematical modeling is that the strengths and weaknesses of each test are taken into account. Furthermore, the generated predictions are objective and convey the associated uncertainties. This approach was explored by the working group “Predictivity of In Vitro Genotoxicity Testing,” convened in the context of the 8th International Workshop on Genotoxicity Testing (IWGT). Specifically, we applied mathematical modeling to a database with publicly available in vitro and in vivo data for genotoxicity. The results indicate that a mammalian in vitro clastogenicity test and a mammalian cell gene mutation test together provide strong predictive weight‐of‐evidence for evaluating genotoxic hazard of a substance, although they are better in predicting absence of genotoxic potential than in predicting presence of genotoxic potential. Remarkably, the bacterial reverse mutation (Ames) test did not significantly change these predictions when used in combination with in vitro mutagenicity and clastogenicity tests using cells of mammalian origin. However, in case only data from a bacterial reverse mutation test are available for the assessment of genotoxic potential, these do bear weight of evidence and thus can be used. Genotoxicity assays are generally executed in tiers, in which the bacterial reverse mutation test often is the starting point. Thus, it is reasonable to suspect that early in development test results from the bacterial reverse mutation test have influenced the composition of the database studied here. We performed several tests on the robustness of the database used for the analyses presented here, and the forthcoming results do not indicate a strong bias. Further research comparing in vitro genotoxicity data with in vivo data for additional compounds will provide more insights whether it is indeed time to reconsider the composition of the standard in vitro genotoxicity battery.
Money Growth and Inflation—How to Account for the Differences in Empirical Results
Authors: Mandler Martin , Scharnagl Michael 
Published: December 2024

ABSTRACTEmpirical analyses have presented different results on the long‐run relationship between money growth and inflation with some pointing to a stable relationship with a slope coefficient of close to one and others suggesting instability or a weakening of the relationship over time. Using the example case of the United States and nearly 150 years of data, we provide a systematic investigation into and comparison of the results from time series‐based empirical evidence on the relationship between money growth and inflation. We use the results from a wavelet analysis as a benchmark as it offers a flexible framework that provides information on the relationship both across different frequencies and different points in time. We relate these results to those in the literature obtained from other empirical approaches and investigate the underlying causes of differences in the results. We argue that it is possible to arrive at a consistent conclusion of a stable correlation between money growth and inflation in the United States at cycles of 30 to 60 years with a declining trend in the slope relationship even though the empirical results in the literature appear to be at odds. We show that in some analyses, the evidence on the “long‐run” relationship is distorted by unintentionally including higher frequencies or that results are dominated by outliers at very low frequencies for which the data do not contain much information. Furthermore, the way in which different analyses account for time variation also can influence the results.
Scenario‐based water balance analysis of estuary reservoir for multipurpose water supply
Authors: Bang Jehong , Choi Jin‐Yong , Lee Sang‐Hyun , Hwang Soonho , Kang Moon‐Seong 
Published: December 2024

AbstractIn the circumstance of increasing industrial and municipal water demand, estuary reservoirs are one of the critical water resources that can be a solution. Therefore, we simulated the water balance model of an estuary agricultural reservoir to evaluate the impact of additional industrial water release on its performance. We considered runoff and treated water as water inflow and irrigation requirement in paddy fields and water use in the hydrogen plant as water release. Runoff and irrigation water requirements were estimated using the Tank model and the FAO modified Penman method, respectively. Industrial water demand was surveyed at 32,000 m3 day−1 throughout the year. The results show that the reservoir's reliability increases as the water loss and irrigation area decrease with reusing the return flow, which is hardly affected by the industrial water supply. The trend of resiliency resembles reliability; however, the industrial release has the most significant impact when lower water loss is applied and the paddy area is decreased. Vulnerability gets worse when additional purpose water is released. In other words, the more water the reservoir releases, the more severe the drought gets. Therefore, the engineer and operator should consider the expected risks presented as reliability, resiliency and vulnerability in the design and management of the reservoir.
Skull Ossification in the Andean Toad Rhinella spinulosa (Bufonidae) and the Genetic Model Organism Xenopus tropicalis (Pipidae) Reveals Heterochrony Phenomena and Frontoparietal Suture Modifications
Authors: Mundaca Marco , Rojas Japhet , Cumilaf Lefney , Jara Federico , Muñoz David , Pastenes Luis , Méndez Marco , Tovar Lina M. , Torrejón Marcela , Montoya‐Sanhueza Germán , Marcellini Sylvain 
Published: December 2024

ABSTRACTAnurans are famous for having evolved a highly simplified skull through bone loss and fusion events. Nevertheless, their skeleton displays a rich morphological diversity associated with adaptations to diverse lifestyles and ecological niches. Here, we report larval skull ossification in the Andean toad Rhinella spinulosa (Bufonidae), and compare it to the phylogenetically distant genetic model organism Xenopus tropicalis (Pipidae). We find that the ossification timing of most skull bones is conserved between both species, except for the prootic and the angulosplenial that ossify at much later stages in R. spinulosa than X. tropicalis. We propose that a delayed lower jaw ossification in R. spinulosa is tightly related to the more extensive metamorphosis process observed in this species where the ventrally oriented mouth opening shifts anteriorly. We also report two conspicuous notches in the R. spinulosa frontoparietal bone mineralization front which are absent in X. tropicalis, and presumably represent evolutionary remnants of the coronal suture that separates the frontal and parietal bones in most vertebrates. As such notches have not been overtly reported in the literature, we examined the X. tropicalis sibling species Xenopus laevis, and were able to identify similar, albeit transient, indentations in the forming frontoparietal bone, suggesting that vestigial coronal sutures might exist in more frog species than anticipated. Taken together, we show that R. spinulosa represents an ideal organism to study heterochronic shifts and the mechanisms underlying cranial suture loss which drove anuran skull simplification.
Prevalence of a delayed diagnosis of caffeine poisoning in the emergency department of a Japanese hospital
Authors: Komagamine Junpei , Kurihara Tomohiro 
Published: December 2024

AbstractBackgroundMost cases of acute caffeine poisoning are easily diagnosed at initial hospital visits. Nonetheless, accurate diagnosis is sometimes delayed in some patients with this condition. Therefore, our aim was to determine the prevalence of delayed diagnosis of acute caffeine poisoning in the emergency department (ED).MethodsA single‐center retrospective observational study was conducted. All consecutive patients with acute caffeine poisoning who were admitted to our hospital from January 2016 to March 2024 were included. The primary outcome was the proportion of patients who did not receive a correct diagnosis initially in the ED.ResultsA total of 30 patients were included. The median age was 23 years (IQR 19–27), 24 (80%) were women, and 18 (60%) had psychiatric disorders. The diagnosis of acute caffeine poisoning was delayed in three patients (10%, 95% CI 0%–21%), among whom the initial diagnoses were encephalitis (n = 1), epileptic seizures (n = 1), and altered consciousness for unknown reasons (n = 1). Patients with delayed diagnoses experienced seizures more frequently during their ED stay than patients without delayed diagnoses did (p < 0.001).ConclusionThe initial diagnosis is missed in 1 of every 10 patients with acute caffeine poisoning. The presence of seizure as the initial sign was associated with delayed diagnosis of acute caffeine poisoning.
Disease modifying osteoarthritis drug discovery using a temporal phenotypic reporter in 3D aggregates of primary human chondrocytes
Authors: Cruz Maria A. , Gronowicz Scott , Karimzadeh Makan , Martyniak Kari , Medam Ramapaada , Kean Thomas J. 
Published: December 2024

AbstractOur aim was to develop a novel approach to identify disease‐modifying drugs for osteoarthritis (OA), focusing on stimulating type II collagen anabolism in chondrocytes. As ELISA or western blot are destructive, laborious and time consuming, primary human chondrocytes expressing Gaussia luciferase under the control of the type II collagen promoter were developed and used. We cultured them in 3D cartilage aggregates under physioxia, to temporally screen a natural product library over 3‐weeks. Hit compounds were analyzed for their potential targets in silico, first by structure, then by RNA‐Seq. Two hit compounds were then further analyzed using biochemical assays, dose‐response curves, and histological analyses to confirm their effects on type II collagen expression and chondrogenesis. Aromoline shows promise as a potential disease modifying compound, demonstrating an increase in type II collagen expression within cartilage sourced from chondrocytes of three distinct donors. Aromoline is a bisbenzylisoquinoline alkaloid that has been studied for its antiproliferative, anti‐inflammatory, and antimicrobial properties, and we are the first to explore its effects on chondrocytes and chondrogenesis. In silico analysis revealed the dopamine receptor D4 (DRD4) as a potential target, confirmed by type II collagen upregulation after aromoline treatment and with DRD4‐specific agonist ABT‐724. This novel approach combining in silico and in vitro methods provides a platform for drug discovery in a challenging and under‐researched area. In conclusion, a novel drug (aromoline) and target receptor (DRD4) were identified as stimulating type II collagen, with the future goal of treating or preventing OA.
Chronology of Late Pleistocene glacial advances in a Mount Mercedario catchment, Subtropical Andes of Argentina (32° S)
Authors: Jeanneret Pilar , Moreiras Stella Maris , Merchel Silke , Preusser Frank , May Jan‐Hendrik , Gärtner Andreas , Orgeira María Julia 
Published: December 2024

ABSTRACTGlacial fluctuations leave distinct imprints on the landscapes of mountain environments, such as moraines and outwash terraces, that allow the reconstruction of past environmental changes. Unraveling the environmental history of the valleys of the Subtropical Andes of Argentina poses challenges due to the complex interplay of various surficial processes driven by both climatic and tectonic forces, which affects the preservation of glacial deposits. Consequently, there are few studies on past glaciations in this region compared to the rest of the Andes. This study focused on the lower section of the Blanco River Basin and the piedmont of the Frontal Cordillera in the south of San Juan Province, Argentina. A comprehensive geomorphological map of glacial landforms was created, along with sedimentological studies of outwash terraces. Additionally, numerical ages were obtained for both landforms using terrestrial cosmogenic nuclides for moraine boulders and luminescence dating for sandy layers in the outwash terraces. Our findings reveal at least two glacial advances since the Last Glacial Maximum (LGM), each associated with distinct outwash levels. The Río Blanco Advance occurred during the LGM, and the Laguna Advance is assigned to the late stages of the LGM, both with their corresponding outwash terraces. Additionally, the Amarillo Advance is believed to have occurred during the Holocene period and an older Marine Istope Stage 5 d named Guanaquito Advance. The provided data add valuable numerical information about glacial fluctuations since the LGM and also reveal the impact of glacial downwasting on piedmont landforms.
Assessing the sustainability of Pacific walrus harvest in a changing environment
Authors: Johnson Devin L. , Eisaguirre Joseph M. , Taylor Rebecca L. , Andersen Erik M. , Garlich‐Miller Joel L. 
Published: December 2024

AbstractHarvest sustainability is a primary goal of wildlife management and conservation, and in a changing world, it is increasingly important to consider environmental drivers of population dynamics alongside harvest in cohesive management plans. This is particularly pertinent for harvested species that acutely experience effects of climate change. The Pacific walrus (Odobenus rosmarus divergens), a crucial subsistence resource for Indigenous communities, is simultaneously subject to rapid habitat loss associated with diminishing sea ice and an increasing anthropogenic footprint in the Arctic. We developed a theta‐logistic population modeling‐management framework to evaluate various harvest scenarios combined with 4 potential climate and disturbance scenarios (ranging from optimistic to pessimistic, based largely on sea ice projections from general circulation models) to simulate Pacific walrus population dynamics to the end of the twenty‐first century, focusing on the independent‐aged female subset of the population. We considered 2 types of harvest strategies: 1) state‐dependent harvest scenarios wherein we calculated harvest as a percentage of the population and updated annual harvests at set intervals as the population was reassessed, and 2) annually consistent harvest scenarios wherein annual harvest levels remain consistent into the future. All climate and disturbance scenarios indicated declines of varying severity in Pacific walrus abundance to the end of the twenty‐first century, even in the absence of harvest. However, we found that a state‐dependent annual harvest of 1.23% of the independent‐aged female subset of the population (e.g., 1,280 independent‐aged females harvested in 2020, similar to contemporary harvest levels) met our criterion for sustainability under all climate and disturbance scenarios, considering a medium risk tolerance level of 25%. This indicates that the present rate of Pacific walrus harvest is sustainable and will continue to be—provided the population is assessed at regular intervals and harvest is adapted to match changes in population dynamics. Our simulations indicate that a sustainable annually‐consistent harvest is also possible but only at low levels if the population declines as expected. Applying a constant annual harvest of 1,280 independent‐aged females failed to meet our criterion for sustainability under 3 of the 4 climate and disturbance scenarios we evaluated and had a higher probability of quasi‐extinction than an equivalent state‐dependent harvest scenario (1.23%). We highlight the importance of state‐dependent management strategies and suggest our modeling framework is useful for managing harvest sustainability in a changing climate.
Predictive analysis of economic and clinical outcomes in total knee arthroplasty: Identifying high‐risk patients for increased costs and length of stay
Authors: Maman David , Liba Guy , Hirschmann Michael Tobias , Ben Zvi Lior , Fournier Linor , Steinfeld Yaniv , Berkovich Yaron 
Published: December 2024

AbstractPurposeThe purpose of this study was to predict high‐risk patients who experience significant increases in hospital charges and length of stay (LOS) following specific postoperative complications.MethodsThis study analyzed over two million patients from the Nationwide Inpatient Sample database undergoing elective total knee arthroplasty (TKA) for primary osteoarthritis. Baseline demographics, clinical characteristics and incidence of postoperative complications were examined. A neural network model was utilized to predict high‐risk patients who fall into the top 25% for both LOS and total hospital charges after complications such as sepsis or surgical site infection (SSI).ResultsThe most common complications were blood loss anaemia (14.6%), acute kidney injury (1.6%) and urinary tract infection (0.9%). Patients with complications incurred significantly higher total charges (mean $66,804) and longer LOS (mean 2.9 days) compared to those without complications (mean $58,545 and 2.1 days, respectively). The neural network model demonstrated strong predictive performance, with an area under the curve of 0.83 for the training set and 0.78 for the testing set. Key complications like sepsis and SSIs significantly impacted hospital charges and LOS. For example, a 57‐year‐old patient with diabetes and sepsis had a 100% probability of being in the top 25% for both total charges and LOS.ConclusionPostoperative complications in TKA patients significantly increase hospital charges and LOS. The neural network model effectively predicted high‐risk patients after specific complications occurred, offering a potential tool for improving patient management and resource allocation.Levels of EvidenceLevel III.
Learning sites for health systems research: Reflections on five programs in Africa, Asia, and Central America
Authors: Witter Sophie , Regmi Shophika , Raven Joanna , Nzinga Jacinta , van der Merwe Maria , Flores Walter , D'Ambruoso Lucia 
Published: December 2024

AbstractIntroductionLearning sites have supported intervention development and testing in health care, but studies reflecting on lessons relating to their deployment for health policy and system research (HPSR) in low‐ and middle‐income settings are limited.MethodsThis experience report draws from learning over three continents and five research and community engagement programs—the oldest starting in 2010—to reflect on the challenges and benefits of doing embedded HPSR in learning sites, and how those have been managed. Its objective is to generate better understanding of their potential and constraints. The report draws from team members' experiential insights and program publications.ResultsChallenges relating to initial engagement in the sites included building and maintaining trust, managing partner expectations, and negotiating priority topics and stakeholders. Once the embedded research was underway, sustaining engagement, and managing power dynamics within the group, supporting all participants in developing new skills and managing rapidly changing settings were important. Finally, the complexity of reflecting on action and assessing impact are outlined, along with potential approaches to managing all of these challenges and the variety of gains that have been noted across the programs.ConclusionsWe highlight the potential of learning sites to develop relationships, capacities, and local innovations which can strengthen health systems in the long term and some lessons in relation to how to do that, including the importance of stable, long‐term funding as well as developing and recognizing facilitation skills among researchers. Supporting spaces for learning is particularly important when health systems face resource constraints and everyday or acute stressors and shocks.