bluuebunny/crossref_metadata_2025_split huggingface dataset:
SSTR2-targeted theranostics in hepatocellular carcinoma
Authors: Momeny Majid , AghaAmiri Solmaz , Vargas Servando Hernandez , Acidi Belkacem , Ghosh Sukhen C. , Bateman Tyler , Adams Jack , Khalaj Vahid , Kaseb Ahmed O. , Cao Hop S. Tran , Azhdarinia Ali 
Published: October 2024

Abstract(1)BackgroundWhile the clinical use of radiolabeled somatostatin analogs is established in neuroendocrine tumors, there is significant interest in expanding their use for other somatostatin receptor 2 (SSTR2)-expressing cancers. This study investigates the utility of SSTR2-targeted theranostics in hepatocellular carcinoma (HCC);(2)MethodsWe measured SSTR2 expression in HCC cell lines and clinical samples using qRT-PCR, Western blot, and a public dataset. We evaluated [67Gallium]Ga-DOTATATE uptake, tested [177Lutetium]Lu-DOTATATE cytotoxicity, and assessed [68Gallium]Ga-DOTATATE tumor targeting in HCC animal models and a patient via PET/CT;(3)ResultsSSTR2 expression was confirmed in HCC cell lines and clinical samples. Radioligand uptake studies validated SSTR2-mediated [67Gallium]Ga-DOTATATE uptake, and [177Lutetium]Lu-DOTATATE treatment reduced cell proliferation. [68Gallium]Ga-DOTATATE PET/CT scans detected tumors in animal models and spinal metastases in a patient with HCC;(4)ConclusionThese findings suggest for the first time that SSTR2-based theranostics could have strong implications for detection and treatment of HCC.Simple SummaryThis study investigates the use of SSTR2-targeted theranostics, combining diagnostic and therapeutic approaches, in hepatocellular carcinoma (HCC). We confirmed significant SSTR2 expression in HCC cells and patient samples, showing that radiolabeled compounds such as [67Ga]Ga-DOTATATE and [177Lu]Lu-DOTATATE, commonly used in neuroendocrine tumors, could also target HCC. In preclinical models and a patient case, PET/CT imaging and treatments demonstrated effective tumor detection and shrinkage. These findings suggest that SSTR2-targeted theranostics could offer a novel, targeted method for diagnosing and treating HCC, potentially improving outcomes for patients with this challenging cancer.
Art’s Hidden Topology: A window into human perception
Authors: Dmitruk Emil , Bajno Beata , Dreszer Joanna , Bałaj Bibianna , Ratajczak Ewa , Hajnowski Marcin , Janik Romuald A. , Kuś Marek , Kadir Shabnam N. , Rogala Jacek 
Published: October 2024

AbstractGenerations of researchers have sought a link between features of an artistic image and the audience’s experience. However, a direct link between the properties of an image and the responses evoked has still not been established. Given the importance of shape to human perception and artistic creation, it can be assumed that one of the most important aspects of an artistic image is the use of different visual structures. We show that a method from the field of computational topology, persistent homology, can be used to analyse properties of image structures and composition at multiple scales. In order to determine the reliability of this method as a tool for analysing visual artworks, we analysed two different sets of abstract paintings that revealed significant discrepancies in the eye tracking and electroencephalography (EEG) activity of viewers. Our research showed that our newly developed method using persistent homology, not only clearly distinguished between two sets of images, which was not possible with common statistical image properties, but also allowed us to map topological features onto gaze fixation heat maps.
Rigor and Reproducibility of Digital Spatial Profiling on Clinically Sourced Human Tissues
Authors: Smith Kelly D. , MacDonald James W. , Li Xianwu , Beirne Emily , Stewart Galen , Bammler Theo K. , Akilesh Shreeram 
Published: October 2024

ABSTRACTSpatial transcriptomic profiling enables precise quantification of gene expression with simultaneous localization of expression profiles onto tissue structures. This new technology promises to improve our understanding of the disease mechanisms. Therefore, there is intense interest in applying these methods in clinical trials or as laboratory developed tests to aid in diagnosis of disease. Before these technologies can be more broadly deployed in clinical research and diagnostics, it is necessary to thoroughly understand their performance in real world conditions. In this study, we vet technical reproducibility, data normalization methods and assay sensitivity focusing predominantly on one widely used spatial transcriptomic methodology, digital spatial profiling. Using clinically sourced human tissue specimens, we find that digital spatial profiling exhibits high rigor and reproducibility. Our approach lays the foundation for incorporation of digital spatial profiling methods into clinical workflows.
WNT and TGF-Beta Pathway Alterations in Early-Onset Colorectal Cancer Among Hispanic/Latino Populations
Authors: Monge Cecilia , Waldrup Brigette , Carranza Francisco , Velazquez-Villarreal Enrique 
Published: October 2024

AbstractOne of the fastest-growing minority groups in the U.S. is the Hispanic/Latino population. Recent studies have shown how this population is being disproportionately affected by early-onset colorectal cancer (CRC). Compared to corresponding non-Hispanic White (NHW) patients, Hispanic/Latino patients have both higher incidence of disease and rates of mortality. Two well-established drivers of early-onset CRC in the general population are alterations in the WNT and TGF-Beta signaling pathways; however, the specific roles of these pathways in Hispanic/Latino are poorly understood. Here, we assessed CRC mutations in the WNT and TGF-Beta pathways by conducting a bioinformatics analysis using cBioPortal. Cases of CRC were stratified both by age and ethnicity: 1) early-onset was defined as <50 years vs. late-onset as ≥50 years; 2) we compared early-onset in Hispanics/Latinos to early-onset in NHWs. No significant differences were evident when we compared early-onset and late-onset CRC cases within the Hispanic/Latino cohort. These results are consistent with findings from large cohorts that do not specify ethnicity. However, we found significant differences when we compared early-onset CRC in Hispanic/Latino patients to early-onset CRC in NHW patients: specifically, alterations in the gene bone morphogenetic protein-7 (BMP7) were more frequent in early-onset CRC for the Hispanic/Latino patients. In addition to these findings, we observed that both NHW patients and Hispanic/Latino patients with early-onset disease had better clinical outcomes when there was evidence of WNT pathway alterations. Conversely, only the early-onset Hispanic/Latino population had improved outcomes when there was no evidence of TGF-Beta pathway alterations.In toto, these findings underscore how the WNT and TGF-Beta pathways may act differently in different ethnic groups who have early-onset CRC. These findings may set a stage for developing new therapies tailored for reducing cancer health disparities.
Humoral waning kinetics against SARS-CoV-2 is dictated by disease severity and vaccine platform
Authors: Tong Xin , Kellman Benjamin , Avendano Maria-Jose , Mendu Maanasa , Hsiao Jeff C. , Serrano Eileen , Garcia-Salum Tamara , Muena Nicolas , Pardo-Roa Catalina , Morales Mauricio , Levican Jorge , Salinas Erick , Cardenas-Cáceres Simone , Riquelme Arnoldo , Tischler Nicole D. , Lauffenburger Douglas A. , Alter Galit , McNamara Ryan P. , Medina Rafael A. 
Published: October 2024

AbstractSARS-CoV-2 vaccine-acquired immunity provides robust cross-variant recognition, while infection-acquired immunity can be heterogenous, with disease severity often modulating post-recovery responses. We assessed antibody waning dynamics between infection- and vaccination-acquired immunity across variants of concern (VOC). mRNA vaccination induced potent, cross-VOC Spike recognition and functional responses, but waned more rapidly for Omicron Spike. Hospitalized individuals developed more durable functional responses with lower peaks compared to mRNA vaccination, while outpatients exhibited slower decay than inactivated vaccine recipients. Humoral decay for the receptor binding domain tracked with neutralizing antibody titers, while S2-directed responses tracked with antibody-dependent myeloid cellular phagocytosis. Boosting the recovered patients with mRNA or inactivated vaccines expanded humoral breadth, durability, and restored functional responses, eliminating the severity- and platform-associated decay differences. Therefore, post-recovery hybrid immunization compensates for this distinction and broadens humoral breadth, highlighting the value of boosting immunity in previously infected individuals.One Sentence SummaryInfection- and vaccine-acquired immunity to COVID-19 exhibit different functional antibody profiles, each characterized by distinct kinetics of waning over time.
Transformers for rapid detection of airway stenosis and stridor
Authors: Anibal James , Doctor Rebecca , Boyer Micah , Newberry Karlee , De Santiago Iris , Awan Shaheen , Abdel-Aty Yassmeen , Dion Gregory , Daoud Veronica , Huth Hannah , Watts Stephanie , Wood Bradford J. , Clifton David , Gelbard Alexander , Powell Maria , Toghranegar Jamie , Bensoussan Yael ,   the Bridge2AI Voice Consortium
Published: October 2024

AbstractUpper airway stenosis is a potentially life-threatening condition involving the narrowing of the airway. In more severe cases, airway stenosis may be accompanied by stridor, a type of disordered breathing caused by turbulent airflow. Patients with airway stenosis have a higher risk of airway failure and additional precautions must be taken before medical interventions like intubation. However, stenosis and stridor are often misdiagnosed as other respiratory conditions like asthma/wheezing, worsening outcomes. This report presents a unified dataset containing recorded breathing tasks from patients with stridor and airway stenosis. Customized transformer-based models were also trained to perform stenosis and stridor detection tasks using low-cost data from multiple acoustic prompts recorded on common devices. These methods achieved AUC scores of 0.875 for stenosis detection and 0.864 for stridor detection, demonstrating potential to add value as screening tools in real-world clinical workflows, particularly in high-volume settings like emergency departments.
TREM2Risk Variants with Alzheimer’s Disease Differ in Rate of Cognitive Decline
Authors: Dijkstra Janna I.R. , Vermunt Lisa , Venkatraghavan Vikram , Ozgehov Georgii , Coomans Emma M. , Ossenkoppele Rik , van de Giessen Elsmarieke , Hulsman Marc , de Geus Christa M. , van der Flier Wiesje M. , Sikkes Sietske A.M. , Barkhof Frederik , Tijms Betty , Gouw Alida A. , de Haan Willem , Vijverberg Everard G.B. , Pijnenburg Yolande A.L. , Holstege Henne , Teunissen Charlotte E. , van der Lee Sven J. 
Published: October 2024

ABSTRACTRare variants of the triggering receptor expressed on myeloid cell 2 (TREM2) gene are major risk factors for Alzheimer’s disease (AD), and drugs targeting the TREM2 protein are being developed. However, it is unknown whether carriers of aTREM2risk variant have a clinically distinct AD phenotype. Here we studied a full range of clinical measures in a large cohort ofTREM2variant carriers (n=123, 7.8%, i.e., R62Hn=66, R47Hn=26, T96Kn=16, otherTREM2variantsn=17) compared to confirmed non-carriers (n=1,459) with biomarker confirmed symptomatic AD from Amsterdam Dementia Cohort.TREM2variant carriers (mean age at diagnosis 64.4 years (SD ±7.1), 54% female) did not show distinct clinical measures of AD at presentation compared to AD patients not carrying aTREM2variant (mean age at diagnosis 64.4 ±7.0, 52% female). Specifically, we observed no differences in MMSE, most neuropsychological domains (except visuospatial functioning), MRI scores, CSF biomarkers, and EEG. Also, in an exploratory analysis of neuroimaging measures, including structural MRI (41 ROIs) and Tau-PET scans of four carriers (R62H, R47H, G58A, D87N),TREM2variant carriers showed similar atrophy patterns and similar abnormal tracer binding compared to non-carriers. Despite not being different at baseline, carriers did show faster cognitive decline in follow-up. Carriers declined 0.63 ±0.25 points on the MMSE more per year compared to non-carriers, but there was no difference in the hazard rate of death after diagnosis.Finally, we explored whether specificTREM2variants are associated with distinct clinical measures compared to the reference group, i.e. non-carriers, within the same cohort. Notably, both R47H and T96K carriers exhibited faster cognitive decline, and R47H carriers even showed an increased rate of death after diagnosis. In contrast to the shared cognitive decline, these variants showed different results for other measures at baseline.This study presents a detailed overview of the clinical measures in AD patients carrying aTREM2risk variant, and it shows that carriers ofTREM2risk variants cannot be distinguished based on clinical presentation at baseline. However, carriers exhibit a faster global cognitive decline compared to non-carriers. Variant-specific analyses suggest that especially R47H and T96K carriers drive the association ofTREM2variants with faster cognitive decline.
Predictive accuracy of diagnostic tests for excessive bleeding in cardiac surgery: the COPTIC-C study
Authors: Liao Weiqi , Grant Robert , Lai Florence Y , Aujla Hardeep , Wozniak Marcin , Patel Hasmukh R , Green Laura , Mumford Andrew , Murphy Gavin J 
Published: October 2024

AbstractPurposeWe tested the hypothesis that addition of biomarkers of multimorbidity and biological ageing would improve the predictive accuracy of point-of-care viscoelastometry or laboratory tests of coagulation for clinically important bleeding following cardiac surgery.MethodsThe analyses included 2437 participants in the Coagulation and Platelet laboratory Testing in Cardiac surgery (COPTIC study) with complete clinical, TEG®5000 Thromboelastography, ROTEM®, Multiplate® aggregometry, full blood count, laboratory reference tests of coagulopathy, and biomarkers of biological ageing and multimorbidity. Models with different biomarkers to predict the composite primary outcome, Clinically Important Bleeding, was developed using logistic regression and internally validated using 10-fold cross-validation. Discrimination, calibration, and clinical utility of the models were assessed comprehensively.ResultsFor the primary outcome, the AUROC for the best predictive model using TEG/ROTEM with other biomarkers was 0.694 (0.612–0.775). The best predictive model included laboratory reference tests of coagulation, full blood count results, and biomarkers of multimorbidity and ageing, AUROC=0.701 (0.620–0.781), although clinical utility was not superior to using laboratory reference tests alone. Discrimination was higher for components of the primary outcome; large volume (≥4 units) red cell transfusion 0.754 (0.602–0.903), and large volume procoagulant transfusion 0.723 (0.590–0.857), but not for excess loss in drains/re-sternotomy 0.701 (0.613–0.788). Calibration was generally good among the models.ConclusionDiagnostic tests for bleeding following cardiac surgery demonstrate moderate discrimination, although this was influenced by the definition of bleeding. Small improvements in discrimination with inclusion of additional disease biomarkers, with similar calibration and clinical utility.Take-home message1. Current diagnostic tests demonstrate moderate predictive accuracy for excessive bleeding following cardiac surgery. In this study, addition of biomarkers of multimorbidity and biological ageing improved discrimination but not clinical utility.2. Existing clinical definitions of bleeding represent heterogeneous phenotypes, presenting a barrier to research investigating the disease processes.Important abbreviations used in this paper:CIB – Clinically Important BleedingCCB – Clinical Concern about BleedingAUROC – Area Under the Receiver Operating Characteristic Curve
Factors Influencing Health Insurance Enrollment and Its Impact on Outpatient Service Utilization in Saudi Arabia: Insights from the National Saudi Family Health Survey
Authors: Althabaiti Khaled Shaeel , Hunsberger Monica , Khan Jahangir , Ahmed Sayem 
Published: October 2024

ABSTRACTThe Kingdom of Saudi Arabia (KSA) recently launched a reform plan for its health care system in 2021 driven by its Vision 2030 initiative. This vision aims to reduce dependence on government resources by transitioning to the national health insurance model and the Cooperative Health Insurance program, especially for the immigrant population. This reform may impact the utilization of health services by citizenship and insurance status. The current study aims to identify factors influencing health insurance enrollment and its impact on outpatient service utilization in the Kingdom of Saudi Arabia. This study used data from the 2018 Saudi Family Health Survey (FHS). The survey covers a nationally representative sample from KSA (n=8,274), which contains questions that obtain information about the health insurance enrollment, health care utilization, chronic disease condition, and health status of the respondents. We conducted a bivariate analysis using a chi-square test and an independent-sample t-test to examine the significance of differences between groups (by nationality and insurance status). We employed multiple binary logistic regression models to measure the association between health insurance enrollment and the demographic and socioeconomic characteristics of the respondents. Further, the multiple Poisson regression model was used to estimate the effect of health insurance status on the utilization of outpatient care. Most of the respondents were Saudis (76.8%), and the number of males (54.9%) respondents were higher than the females. Around 26.2% of the total respondents were insured and the proportion of insured was significantly higher among non-Saudis (72.8%) compared to Saudis (12.1%). The logistic regression showed that individuals with a high monthly income, non-Saudi, males, being married, high level of education, and perceived good health were associated with health insurance enrollment. We found health insurance enrollment was associated with lower utilization of outpatient services (co-efficient -0.107; P<0.001). Other factors increasing utilization of outpatient services were being female, having a high monthly income, being never married, having chronic diseases, and the perception of bad health. Significant determinants of health insurance enrollment were being non-Saudi, males, having a high income, higher education level, and perceived good health status. However, health insurance was associated with lower utilization of outpatient services. The results of the current study should be taken into consideration when planning for the implementation and monitoring reform of the health system in Saudi Arabia.
Deep Learning-Based Detection of Carotid Plaques Informs Cardiovascular Risk Prediction and Reveals Genetic Drivers of Atherosclerosis
Authors: Omarov Murad , Zhang Lanyue , Doroodgar Jorshery Saman , Malik Rainer , Das Barnali , Bellomo Tiffany R. , Mansmann Ulrich , Menten Martin J. , Natarajan Pradeep , Dichgans Martin , Raghu Vineet K. , Anderson Christopher D. , Georgakis Marios K. 
Published: October 2024

AbstractAtherosclerotic cardiovascular disease, the leading cause of global mortality, is driven by lipid accumulation and plaque formation within arterial walls. Carotid plaques, detectable via ultrasound, are a well-established marker of subclinical atherosclerosis. In this study, we trained a deep learning model to detect plaques in 177,757 carotid ultrasound images from 19,499 UK Biobank (UKB) participants (aged 47-83 years) to assess the prevalence, risk factors, prognostic significance, and genetic architecture of carotid atherosclerosis in a large population-based cohort. The model demonstrated high performance metrics with accuracy, sensitivity, specificity, and positive predictive value of 89.3%, 89.5%, 89.2%, and 82.9%, respectively, identifying carotid plaques in 45% of the population. Plaque presence and count were significantly associated with future cardiovascular events over a median follow-up period of up to 7 years, leading to improved risk reclassification beyond established clinical prediction models. A genome-wide association study (GWAS) meta-analysis of carotid plaques (29,790 cases, 36,847 controls) uncovered two novel genomic loci (p < 5×10−8) with downstream analyses implicating lipoprotein(a) and interleukin-6 signaling, both targets of investigational drugs in advanced clinical development. Observational and Mendelian randomization analyses showed associations between smoking, low-density-lipoprotein (LDL) cholesterol, and high blood pressure and the odds of carotid plaque presence. Our study underscores the potential of carotid plaque assessment for improving cardiovascular risk prediction, provides novel insights into the genetic basis of subclinical atherosclerosis, and offers a valuable resource for advancing atherosclerosis research at the population scale.
Expansion of clinical genetic testing since the completion of the human genome project
Authors: Bastarache Lisa , Tinker Rory J. , Schuler Bryce A. , Richter Lucas , Phillips John A. , Stead William W. , Hooker Gillian , Peterson Josh F. , Ruderfer Douglas M. 
Published: October 2024

AbstractThe sequencing of the first human genome led to expectations of the widespread use of genetics in medicine. However, assessing the true impact of genetic testing on clinical practice is challenging due to the lack of integration in the electronic health record (EHR). We extracted clinical genetic tests from the EHRs of over 1.8 million patients seen at Vanderbilt University Medical Center from 2002 to 2022, using both automated and manual methods. Using these data, we quantified the extent of clinical genetic testing in healthcare and described how testing patterns have changed over time, including utilization rate, test comprehensiveness, diagnoses made, and the number of variants of uncertain significance (VUS) returned.We also assessed genetic testing rates across medical specialties and introduce a measure – the genetic attributed fraction (GAF) – to compute the proportion of observed phenotypes attributable to a genetic diagnosis. We identified 104,392 tests, 32% of which were only reported in unstructured text, and 19,032 molecularly confirmed diagnoses or risk factors. The proportion of patients genetic testing recorded in their EHRs from 1.0% in 2002 to 6.1% in 2022, and testing became more comprehensive with the growing use of multigene panels. This corresponded with a substantial increase in the variety of diseases diagnosed with genetic testing, from 51 unique diseases in 2002 to 509 in 2022, alongside a growing number of VUS.The phenome-wide GAF for 6,505,620 diagnoses made in 2022 was 0.46%, with 74 phenotypes having a GAF greater than 5%, including pancreatic insufficiency (67%), chorea (64%), atrial septal defect (24%), Microcephaly (17%), paraganglioma (17%), and ovarian cancer (6.8%). Our study provides a comprehensive quantification of the increasing role of genetic testing at a major academic medical institution. These results demonstrate the now pervasive use of genetic testing across diverse medical contexts and its growing utility in explaining observed medical phenome.