bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of Cerebral Microbleeds and Risk of Stroke and Mortality in Posterior Circulation Cerebral Infarction
Authors: Wang Yajuan , Sun Xiaoyan , Wu Shasha , Sun Jianxiu , Yang Yuyuan , Luan Moxin , Yu Fei , Zhou Jing , Chi Xiaosa , Zheng Xueping 
Published: July 2024

AbstractObjectiveThis study was investigated to determine whether CMBs were associated with the risk of recurrent stroke or all-cause death in patients with acute posterior circulation cerebral infarction.MethodsA retrospective analysis was conducted on 323 patients with acute posterior circulation cerebral infarction who aged ≥ 45 years and were hospitalized at Qingdao University Affiliated Hospital from January 1, 2016 to December 31, 2020. Patients were divided into different CMBs groups according to the presence, number and distribution of CMBs. Occurrence of stroke and death was recorded during follow-up. We drew Kaplan Meier survival curves and constructed Cox proportional hazards regression models based on different CMBs groups and clinical outcomes.ResultsA total of 323 patients were enrolled in our study, and 138 (42.72%) had CMBs. During a median follow-up of 1357 days, 87 (26.94%) experienced recurrent stroke or death. ≥5 CMBs (HR 1.723; 95% CI 1.021-2.907; P=0.041) and lobar CMBs (HR 2.312; 95% CI 1.204-4.441; P=0.012) were independent predictors associated with the composite risk of recurrent stroke and all-cause death. All CMBs statuses were not significantly correlated with the risk of recurrent stroke. The presence of CMBs (HR 3.358; 95% CI 1.259-8.954; P=0.015), ≥ 5 CMBs (HR 5.290; 95% CI 1.599-17.499; P=0.006) and deep CMBs (HR 3.265; 95% CI 1.003-10.628; P=0.049) were all independent factors associated with all-cause death.ConclusionsIn patients with acute posterior circulation cerebral infarction, ≥5 CMBs and lobar CMBs may increase the risk of poor clinical outcome (the composite of recurrent stroke and all-cause death). Furthermore, the presence CMBs, ≥ 5 CMBs and deep CMBs all independently may increase the risk of all-cause death.
Early prediction of ovarian cancer risk based on real world data
Authors: de la Oliva Víctor , Esteban-Medina Alberto , Alejos Laura , Muñoyerro-Muñiz Dolores , Villegas Román , Dopazo Joaquín , Loucera Carlos 
Published: July 2024

AbstractThis study presents the development of an early prediction model for high-grade serous ovarian cancer (HGSOC) using real-world data from the Andalusian Health Population Database (BPS), containing electronic health records (EHR) of over 15 million patients. Leveraging the extensive data availability, the model aims to identify individuals at high risk of HGSOC without the need for specific tumor markers or prior stratification into risk groups. Utilizing an Explainable Boosting Machine (EBM) algorithm, the model incorporates diverse clinical variables including demographics, chronic diseases, symptoms, blood test results, and healthcare utilization patterns. The model was trained and validated using a total of 3,088 HGSOC patients diagnosed between 2018 and 2022 along with 114,942 controls of similar characteristics, to emulate the prevalence of the disease, achieving a sensitivity of 0.65 and a specificity of 0.85. This study underscores the importance of using patient data from the general population, demonstrating that effective early detection models can be developed from routinely collected healthcare data. The approach addresses limitations of traditional screening methods by providing a cost-effective and broadly applicable tool for early cancer detection, potentially improving patient outcomes through timely interventions. The interpretability of the early prediction model also offers insights into the most significant predictors of cancer risk, further enhancing its utility in clinical settings.
CFO: Calibration-Free Odds Bayesian Designs for Dose Finding in Clinical Trials
Authors: Fang Jialu , Wang Wenliang , Yin Guosheng 
Published: July 2024

AbstractThe calibration-free odds type (CFO-type) of designs, as data-driven decision-making Bayesian approaches, leverage historical cumulative data across various dose levels, primarily aiming at identifying the maximum tolerated dose (MTD). Inheriting the ideas from game theory or “tug-of-war”, CFO mimics the games of force: one pushes the dose down while the other pushes it up. Extensive simulations validate that CFO-type designs maintain an optimal balance between efficiency and safety in MTD identification, with performance metrics that are comparable to, or occasionally surpass the state-of-the-art methods. This article primarily introduces the R packageCFOfor implementing and assessing CFO-type designs in phase I clinical trials. Besides, we propose integrating the mechanism of exploration and exploitation from reinforcement learning into the CFO design, leading to a novel approach: the randomized CFO (rCFO) design. TheCFOpackage encompasses various variants tailored to accommodate different scenarios. Beyond the fundamental CFO design, these include the two-dimensional CFO (2dCFO) designed for drug-combination trials, accumulative CFO (aCFO) for accruing all dose information, time-to-event CFO (TITE-CFO), and fractional CFO (fCFO) which are developed to specifically address late-onset toxicity. Moreover, hybrid designs such as TITE-aCFO and f-aCFO, which integrate both late-onset toxicity and all dose information for decision making, are also included.CFOprovides a robust set of functions used for determining subsequent cohort doses, selecting the MTD, and conducting simulations to evaluate design operating characteristics. The properties and results are presented to trial investigators through simple textual and graphical outputs. The user-friendly interface, adaptability to various design considerations, and the comprehensive implementation of CFO-type designs positionCFOas a noteworthy tool for phase I clinical trials.
Causes of excess deaths in the US relative to other wealthy nations, 1999-2020: a population autopsy
Authors: Bor Jacob , Raquib Rafeya , Himmelstein David , Woolhandler Steffie , Stokes Andrew C. 
Published: July 2024

ABSTRACTImportanceThe US has higher mortality rates than other wealthy nations.ObjectiveTo determine causes of death responsible for excess mortality in the US compared to other wealthy nations and how the causes involved in this survival gap have changed over time.DesignRepeat cross-sectional study, 1999 to 2020.SettingUnited States and 12 other wealthy nations.ParticipantsAll residents.ExposuresResiding in the US versus other wealthy nations.Main outcome and measuresExcess US mortality in each year due to specific causes of death using data from the World Health Organization Mortality Database. Differences between the US and other wealthy nations were quantified for each cause of death as: (1) the number of excess US deaths (i.e., deaths that would have been averted if US death rates equaled the average rates of other wealthy nations); (2) years of life lost (YLL) resulting from excess US deaths; and (3) the ratio of observed deaths to expected deaths if US mortality rates equaled the average of other wealthy nations.Results10,856,851 excess US deaths occurred between 1999 and 2020. In 2019, prior to the COVID-19 pandemic, there were 637,682 excess US deaths, with leading causes including circulatory diseases (41% of total), mental and nervous system disorders (25%), diabetes, renal, and metabolic diseases (15%), drug poisonings, alcohol-related deaths, and suicide (13%), respiratory disease (12%), and transportation accidents (5%). Over two decades, excess US deaths due to drug poisonings, alcohol and suicide increased from -5,937 in 1999 to 109,015 in 2020. In 2019, deaths from drug poisonings were 6.7 times higher in the US than in peer countries. Circulatory mortality accounted for the largest absolute number of excess US deaths in nearly every year. In 2020, one in 5 excess US deaths were attributed to COVID-19.Conclusions and RelevanceThe US had substantially higher death rates than other wealthy nations between 1999 and 2020, despite having similar access to advanced medical technology. Many of these excess US deaths could likely be avoided by adopting health and social policies that have benefited peer countries.KEY POINTSQuestionWhat causes of death are responsible for the survival gap between the US and other wealthy nations?FindingsBetween 1999 and 2020, 10,856,851 US deaths would have been averted if the US had mortality rates equal to the average of peer countries. Circulatory diseases were the leading cause of excess deaths, although deaths due to drugs, alcohol, and suicide increased the most during the study period. Mental and nervous system disorders, diabetes, renal, and metabolic diseases, and transportation accidents were also major contributors.MeaningThe causes of death responsible for the US survival gap suggest areas for policy intervention.
Sex-modulated association between thyroid stimulating hormone and informant-perceived anxiety in non-depressed older adults: prediction models and relevant cutoff value
Authors: Hallab Asma ,   Alzheimer’s Disease Neuroimaging Initiative
Published: July 2024

AbstractHighlightsLower TSH levels predicted higher odds of anxiety in non-depressed older adults.The association between TSH and anxiety was significant in older males but not in older females.TSH level corresponding to 2.4 µIU/mL was a significant cutoff value in this association, under which thyroid function predicted significantly higher odds of anxiety in older males.Only in older males, but not older females, TSH levels were significantly lower in those with anxiety than in those without.IntroductionThe aim of this study was to assess the association between thyroid function and perceived anxiety in non-depressed older adults.MethodsNon-depressed Alzheimer’s Disease Neuroimaging Initiative participants with complete Thyroid Stimulating Hormone (TSH) and neuropsychiatric inventory (NPI/NPI-Q) were included. The association between anxiety and thyroid function was assessed by logistic regression and sex stratification. Restricted cubic splines were applied to evaluate non-linearity in the association.ResultsThe median age of 2,114 eligible participants was 73 years (68-78), 1,117 (52.84%) were males, and the median TSH was 1.69µIU/mL. There was a significant association between TSH and informant-perceived anxiety in the total study population (ORModel1=0.86, 95%CI 0.76-0.97, p=0.011), even after adjusting for bio-demographical (adj.ORModel2=0.85, 95%CI 0.75-0.96, p=0.007), and socio-cognitive confounders (adj.ORModel3=0.84, 95%CI 0.73-0.96, p=0.009). Sex-stratification showed similar significant results in all models only in males (ORModel1-male=0.71, 95%CI: 0.58-0.85,pModel1-male<0.001). In the general population and males, a TSH value of 2.4µIU/dL was a significant cutoff under which anxiety odds were significantly high, even after adjusting for confounders.ConclusionsThe sex-dependent association between TSH levels and perceived anxiety in non-depressed older adults is a novel finding that has to be further explored for a better understanding of the underlying neurobehavioral biology.Abstract Figure
Patterns of Immune Dysregulation in Bipolar Disorder
Authors: Argue Benney M.R. , Casten Lucas G. , McCool Shaylah , Alrfooh Aysheh , Gringer Richards Jenny , Wemmie John A. , Magnotta Vincent A. , Williams Aislinn J. , Michaelson Jacob , Fiedorowicz Jess G. , Scroggins Sabrina M. , Gaine Marie E. 
Published: July 2024

AbstractBackgroundBipolar disorder is a debilitating mood disorder associated with a high risk of suicide and characterized by immune dysregulation. In this study, we used a multi-faceted approach to better distinguish the pattern of dysregulation of immune profiles in individuals with BD.MethodsWe analyzed peripheral blood mononuclear cells (bipolar disorder N=39, control N=30), serum cytokines (bipolar disorder N=86, control N=58), whole blood RNA (bipolar disorder N=25, control N=25), and whole blood DNA (bipolar disorder N=104, control N=66) to identify immune-related differences in participants diagnosed with bipolar disorder compared to controls.ResultsFlow cytometry revealed a higher proportion of monocytes in participants with bipolar disorder together with a lower proportion of T helper cells. Additionally, the levels of 18 cytokines were significantly elevated, while two were reduced in participants with bipolar disorder. Most of the cytokines altered in individuals with bipolar disorder were proinflammatory. Forty-nine genes were differentially expressed in our bipolar disorder cohort and further analyses uncovered several immune-related pathways altered in these individuals. Genetic analysis indicated variants associated with inflammatory bowel disease also influences bipolar disorder risk.DiscussionOur findings indicate a significant immune component to bipolar disorder pathophysiology and genetic overlap with inflammatory bowel disease. This comprehensive study supports existing literature, whilst also highlighting novel immune targets altered in individuals with bipolar disorder. Specifically, multiple lines of evidence indicate differences in the peripheral representation of monocytes and T cells are hallmarks of bipolar disorder.
Genome-Wide Association Study of Metabolic Traits in the DuckweedSpirodela polyrhiza
Authors: Höfer Martin , Schäfer Martin , Wang Yangzi , Wink Samuel , Xu Shuqing 
Published: July 2024

AbstractThe exceptionally high growth rate and high contents of flavonoids make the giant duckweedSpirodela polyrhiza(L.) Schleid. (Arales: Lemnaceae) an ideal organism for food production and metabolic engineering. To facilitate this, identification of the genetic basis underlying growth and metabolic traits is essential. Here, we characterized the genetics underpinning the growth and contents of 42 metabolites inS. polyrhizausing a genome-wide association (GWA) approach. We found that biomass positively correlates with contents of many free amino acids, including L-Glutamine, L-Tryptophane and L-Serine, but negatively correlates with many specialized metabolites, such as flavonoids. GWA analysis showed that several candidate genes were simultaneously associated with several metabolic traits, qualifying them as targets for growth manipulation and metabolic engineering. Together, this study provides insights into the metabolic diversity ofS. polyrhizaand its underlying genetic architecture, paving the way for industrial applications of this plant via targeted breeding or genetic engineering.
FZD2 inhibits YAP and prevents cell cycle reentry in adult murine cardiomyocytes
Authors: Bisson Joseph A. , Quijada Pearl J. , Wang Yves T. , Lighthouse Janet K. , Helt Jay Christian , Kim Eugene , Morrisey Edward E. , Brookes Paul S. , Small Eric M. , Cohen Ethan D. 
Published: July 2024

ABSTRACTRationaleFully differentiated cardiomyocytes (CMs) are post-mitotic and cannot repopulate damaged tissue after myocardial infarction (MI). Understanding the mechanisms preventing CM proliferation or promoting their survival after injury may lead to treatment strategies for MI. While the effects of canonical WNT/β-catenin signaling in adult CMs have been examined, roles for non-canonical WNT signaling in cardiac homeostasis and repair remain unexplored.ObjectiveTo determine the function of the non-canonical WNT receptor frizzled 2 (FZD2) in adult cardiac homeostasis and injury.Methods and ResultsFZD2 was deleted from the CMs of adult mice to investigate its role in myocardial homeostasis.Fzd2conditional knockout (CKO) mice had cardiomegaly but not hypertrophy. FZD2-deficient CMs expressed proliferation and cytokinesis markers, suggesting that they have increased proliferation potential. FZD2-deletion caused the accumulation of β-catenin. However, β-catenin localized to the membranes of FZD2-deficient CMs and did not activate target gene expression. Instead, the YES-associated protein (YAP) regulated genesv-myc avian myelocytomatosis viral oncogene 1 (Mycl), andB cell leukemia/lymphoma 2 (Bcl2l1)were upregulated inFzd2CKO CMs relative to controls. Knockdown of FZD2 increased YAP activity in neonatal ventricular CMs (NVCMs), while overexpressing FZD2 inhibited YAP. Neither β-catenin knockdown nor mutating the large tumor suppressor 1 and 2 (LATS1/2) target site on YAP blocked the effects of FZD2 on YAP in NVCMs, suggesting that FZD2 utilizes different effectors than canonical WNT and Hippo signaling.Fzd2CKO and control mice were subjected to MI to determine if FZD2-deletion affects cardiac repair. While ischemia and necrosis were similar 24 hours post MI,Fzd2CKO mice had better cardiac function and less scarring than controls.ConclusionsFZD2 reduces YAP activity and prevents adult murine CMs from reentering the cell cycle. FZD2-deletion improves heart function and reduces scarring in mice after MI, implicating FZD2 as a target for pharmacological intervention.
Equine piroplasmosis in different geographical areas in France: prevalence heterogeneity of asymptomatic carriers and low genetic diversity ofTheileria equiandBabesia caballi
Authors: Jouglin M , Bonsergent C , de la Cotte N , Mège M , Bizon C , Couroucé A , Lallemand E , Lemonnier L.C. , Leblond A , Leroux A , Marano I , Muzard A , Quéré E , Toussaint M , Agoulon A , Malandrin L 
Published: July 2024

AbstractEquine piroplasmosis is a worldwide tick-borne disease caused by the protozoan parasitesTheileria equiandBabesia caballi, with significant economic and sanitary consequences. It can also limit the export of infected horses to piroplasmosis-free countries. These two parasites are genetically variable, with greater diversity observed inT. equi. This variability can potentially impact diagnostic accuracy.Our study aimed to evaluate the frequency of asymptomatic carriers of these parasites in France and describe the circulating genotypes. We used a species-specific nested PCR protocol targeting the 18S small subunit (SSU) rRNA gene and subsequent amplicon sequencing on blood samples collected from 566 asymptomatic horses across four National Veterinary Schools.The carrier frequency varied considerably, ranging from 18.7% around Paris (central-north) to 56.1% around Lyon (southeast), with an overall prevalence of 38.3%.T. equicarriers were ten times more frequent (91.7%, 209/228 isolates) compared toB. caballicarriers (8.8%, 19/228 isolates). Notably,T. equicarrier frequency was significantly lower in the northern region (Ile de France) compared to the southeastern regions. Interestingly, a strong correlation was observed between the frequencies of asymptomatic carriers and reported cases of acute piroplasmosis across all four geographic areas. Neither gender (female, gelding, or stallion) nor horse age showed a significant effect on the frequency of asymptomatic carriers. In areas with the highest carrier frequency, a substantial proportion of horses (22.2% to 37.5%) carriedT. equibefore the age of three, indicating high infection pressure.Genotyping of 201T. equiisolates revealed a predominance of genotype E (98%), with only a few isolates belonging to genotype A (2%). Notably, two of the four genotype A isolates were detected in horses originating from Spain. All 19B. caballiisolates belonged to the most common genotype A of this species.The discussion section explores the link between these results, the tick distribution and abundance, and the frequency of detection ofT. equiandB. caballiin febrile cases attributed to piroplasmosis.
A multicellular actin star network underpins epithelial organization and connectivity
Authors: Amlan Barai , Matis Soleilhac , Wang Xi , Shao-Zhen Lin , Marc Karnat , Elsa Bazellières , Sylvie Richelme , Dominique Berrebi , Frank Rümmele , Manuel Théry , Jean-François Rupprecht , Delphine Delacour 
Published: July 2024

SUMMARYEpithelial tissues serve as physical barriers against various external pressures yet remarkably maintain structural stability. Various cellular apparatus including bicellular junction and actomyosin network contribute to the epithelial integrity, packing and remodelling. Although their role in morphogenetic and mechanical processes have been extensively studied during embryogenesis and disease development, their synergistic effects in maintaining tissue organization and connection remain poorly understood. In this study, we discovered a tissue-scale actomyosin network connected through bicellular junctions and manifested in the villi of adult murine intestinal tissue. Later we reproduced such supracellular structure in the differentiated compartment ofex vivo intestinal epithelium model. The self-organized actomyosin networks comprised individual actin nodes in each hexagonal cell at the epithelial base with six radial actin branches, presenting an ‘actin star’ unit. The repeated units were connected through the bicellular junctions, forming a large, multicellular array covering the differentiated domains. Functionally, actin stars contribute to epithelial morphological stability by maintaining cell hexagonality and packing, thereby preserving the solid-like order of the epithelium. Laser ablation experiments validate a modified vertex theoretical model that connects the emergence of such solid-like order to the onset of tension along the actin star branches. Actin stars also acted as locks at the basal side minimizing protrusive activity in the epithelial layer, hindering cell migration and disorganization of the epithelial tissue. The large actomyosin array also enhanced the long-range connectivity that ensure overall tissue integrity. Altogether, the supracellular actin star network constitutes a basal biomechanical apparatus coordinating epithelial tissue stability and organization.