bluuebunny/crossref_metadata_2025_split huggingface dataset:
Emergence of transmissible SARS-CoV-2 variants with decreased sensitivity to antivirals in immunocompromised patients with persistent infections
Authors: Nooruzzaman Mohammed , Johnson Katherine E.E. , Rani Ruchi , Finkelsztein Eli J. , Caserta Leonardo C. , Kodiyanplakkal Rosy P. , Wang Wei , Hsu Jingmei , Salpietro Maria T. , Banakis Stephanie , Albert Joshua , Westblade Lars , Zanettini Claudio , Marchionni Luigi , Soave Rosemary , Ghedin Elodie , Diel Diego G. , Salvatore Mirella 
Published: June 2024

AbstractWe investigated the impact of antiviral treatment on the emergence of SARS-CoV-2 resistance during persistent infections in immunocompromised patients (n=15). All patients received remdesivir and some also received nirmatrelvir-ritonavir or monoclonal antibodies. Sequence analysis showed that nine patients carried viruses with mutations in the nsp12 (RNA dependent RNA polymerase), while four had viruses with nsp5 (3C protease) mutations. Infectious SARS-CoV-2 with a double mutation in nsp5 (T169I) and nsp12 (V792I) was recovered from respiratory secretions 77 days after initial COVID-19 diagnosis from a patient treated with remdesivir and nirmatrelvir-ritonavir.In vitrocharacterization confirmed its decreased sensitivity to remdesivir and nirmatrelvir, which was overcome by combined antiviral treatment. Studies in golden Syrian hamsters demonstrated efficient transmission to contact animals. This study documents the isolation of SARS-CoV-2 carrying resistance mutations to both nirmatrelvir and remdesivir from a patient and demonstrates its transmissibilityin vivo.
Anabolic sensitivity in healthy, lean, older men is associated with higher expression of amino acid sensors and mTORC1 activators
Authors: Horwath Oscar , Moberg Marcus , Hodson Nathan , Edman Sebastian , Johansson Mats , Andersson Eva , van Hall Gerrit , Rooyackers Olav , Philp Andrew , Apró William 
Published: June 2024

AbstractBackgroundSarcopenia is thought to be underlined by age-associated anabolic resistance and dysregulation of intracellular signalling pathways. However, it is unclear whether these phenomena are driven by ageingper seor other confounding factors.MethodsLean and healthy young (n=10, 22 ± 3 yrs, BMI; 23.4 ± 0.8 kg/m2) and old men (n=10, 70 ± 3 yrs, BMI; 22.7 ± 1.3 kg/m2) performed unilateral resistance exercise followed by intake of essential amino acids (EAA). Muscle biopsies were collected from the rested and the exercised leg before, immediately after, as well as 60 and 180 minutes after EAA intake. Muscle samples were analyzed for amino acid concentrations, muscle protein synthesis (MPS) and associated anabolic signaling.ResultsFollowing exercise, peak plasma levels of EAA and leucine were similar between groups, but the area under the curve was ∼11% and ∼28% lower in Young (p<0.01). Absolute levels of muscle EAA and leucine peaked 60 min after exercise, with ∼15 and ∼21 % higher concentrations in the exercising leg (p<0.01) but with no difference between groups. MPS increased in both the resting (∼ 0.035%·h-1to 0.056%·h-1, p<0.05) and exercising leg (∼ 0.035%·h-1to 0.083%·h-1, p<0.05) with no difference between groups. Phosphorylation of S6K1Thr389increased to a similar extent in the exercising leg in both groups but was 2.8-fold higher in the resting leg of Old at the 60 min timepoint (p<0.001). Phosphorylation of 4E-BP1Ser65increased following EAA intake and exercise, but differences between legs were statistically different only at 180 min (p<0.001). However, phosphorylation of this site was on average 78% greater across all timepoints in Old (p<0.01). Phosphorylation of eEF2Thr56was reduced (∼ 66 and 39%) in the exercising leg at both timepoints after EAA intake and exercise, with no group differences (p<0.05). However, phosphorylation at this site was reduced by ∼ 27% also in the resting leg at 60 min, an effect that was only seen in Old (p<0.01). Total levels of Rheb (∼ 45%), LAT1 (∼ 31%) and Rag B (∼ 31%) were higher in Old (p<0.001).ConclusionLean and healthy old men do not manifest AR as evidenced by potent increases in MPS and mTORC1 signalling following EAA intake and exercise. Maintained anabolic sensitivity with age appears to be a function of a compensatory increase in basal levels of proteins involved in anabolic signalling. Therefore, our results suggest that ageper sedoes not appear to cause AR in human skeletal muscle.
Is ChatGPT smarter than Otolaryngology trainees? A comparison study of board style exam questions
Authors: Patel J , Robinson PZ , Illing EA , Anthony BP 
Published: June 2024

AbstractObjectivesThis study compares the performance of the artificial intelligence (AI) platform Chat Generative Pre-Trained Transformer (ChatGPT) to Otolaryngology trainees on board style exam questions.MethodsWe administered a set of 30 Otolaryngology board style questions to medical students (MS) and Otolaryngology residents (OR). 31 MSs and 17 ORs completed the questionnaire. The same test was administered to ChatGPT version 3.5, five times. Comparisons of performance were achieved using a one-way ANOVA with Tukey Post Hoc test, along with a regression analysis to explore the relationship between education level and performance.ResultsThe average scores increased each year from MS1 to PGY5. A one-way ANOVA revealed that ChatGPT outperformed trainee years MS1, MS2, and MS3 (p = <0.001, 0.003, and 0.019, respectively). PGY4 and PGY5 otolaryngology residents outperformed ChatGPT (p = 0.033 and 0.002, respectively). For years MS4, PGY1, PGY2, and PGY3 there was no statistical difference between trainee scores and ChatGPT (p = .104, .996, and 1.000, respectively).ConclusionChatGPT can outperform lower-level medical trainees on Otolaryngology board-style exam but still lacks the ability to outperform higher-level trainees. These questions primarily test rote memorization of medical facts; in contrast, the art of practicing medicine is predicated on the synthesis of complex presentations of disease and multilayered application of knowledge of the healing process. Given that upper-level trainees outperform ChatGPT, it is unlikely that ChatGPT, in its current form will provide significant clinical utility over an Otolaryngologist.
Predicting different dimensions of fatigue from speech data: a longitudinal study in shift workers
Authors: Norbury Agnes , Georgescu Alexandra Livia , Molimpakis Emilia , Goria Stefano , Cummins Nicholas 
Published: June 2024

ABSTRACTBackgroundShift work, or working outside of normal circadian cycles, is associated with both experience of fatigue and poorer long-term physical and mental health. However, current methods for assessing fatigue present several barriers to building understanding of how these risks develop over time within individuals.ObjectiveHere, we explore the potential of momentary speech activity-based fatigue measurement in a large, multi-lingual cohort of shift workers, using an intensive longitudinal study design (twice-daily measurement over two weeks inN=1,197 individuals from six different countries).MethodsParalinguistic speech features were used to predict different aspects of acute and chronic fatigue at each study time-point, with performance assessed in unseen (held-out) data. Results are reported both across the dataset as a whole, and for user-specific prediction models.FindingsIn the cross-sectional analysis, good (close to or exceeding current state-of-the-art) performance was achieved for both current sleep deprivation and self-reported sleepiness levels. The within-user analysis revealed robust increases in performance, yielding the ability to detect more subjective aspects of fatigue such as pervasive physical and mental exhaustion.ConclusionsThese findings offer preliminary support for the utility of using brief momentary speech samples as a low-burden, acceptable, and reliable measure of different aspects of fatigue in high-risk populations such as shift workers.Clinical ImplicationsDeveloping brief, accessible measures of different dimensions of fatigue is an important step towards building understanding of how risks for poorer health outcomes develop over time within individuals exposed to significant circadian disruption.SummaryWhat is already known on this topicPrevious studies have indicated that speech data may be a promising source of information about fatigue: however to date these have primarily been carried out in small, unrepresentative samples and in non-naturalistic settings, making results hard to generalize.What this study addsHere, we present evidence from a large international study where participants both provided momentary speech activity data and reported levels of different aspects of fatigue, as they went about their usual working lives. Importantly, we use a modelling framework that explicitly takes into account potential influences of factors such as age, sex, and language on speech features and target fatigue measures, as well as assessing potential biases and reliability of model output.How this study might affect research, practice or policyIf individuals who are at heightened risk of fatigue-related health problems are able to monitor their fatigue levels regularly and in real-time, this may yield the opportunity to intervene prior to transitioning into less tractable states of poor physical and mental health.
Frontotemporal Dementia Subtyping using Machine Learning, Multivariate Statistics, and Neuroimaging
Authors: Metz Amelie , Zeighami Yashar , Ducharme Simon , Villeneuve Sylvia , Dadar Mahsa 
Published: June 2024

AbstractFrontotemporal Dementia (FTD) is a prevalent form of early-onset dementia characterized by progressive neurodegeneration. It encompasses a group of heterogeneous disorders, including behavioral variant frontotemporal dementia (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), and semantic variant primary progressive aphasia (svPPA). Due to disease heterogeneity and overlapping symptoms, diagnosis of FTD and its subtypes still poses a challenge. Magnetic-resonance imaging (MRI) is commonly used to support the diagnosis of FTD. Using machine learning and multivariate statistics, we tested whether brain atrophy patterns are associated with severity of cognitive impairment, whether this relationship differs between the phenotypic subtypes, and whether we could use these brain patterns to classify patients according to their FTD variant.A total of 136 patients (70 bvFTD, 36 svPPA, 30 nfvPPA) from the frontotemporal lobar degeneration neuroimaging initiative (FTLDNI) database underwent brain MRI and clinical and neuropsychological examination. Deformation-based morphometry (DBM), which offers increased sensitivity to subtle local differences in structural image contrasts was used to estimate regional cortical and subcortical atrophy. Atlas-based associations between DBM values and performance across different cognitive tests were assessed using partial least squares (PLS). We then applied linear regression models to discern the group differences regarding the relationship between atrophy and cognitive decline in the three FTD phenotypes. Lastly, we assessed whether the combination of neural and behavioral patterns in the latent variables identified in the PLS analysis could be used as features in a machine-learning model to predict FTD subtypes in patients.Results revealed four significant latent variables that combined accounted for 86% of the shared covariance between cognitive and brain atrophy measures. PLS-based atrophy and behavioral patterns predicted the FTD phenotypes with a cross-validated accuracy of 89.12%, with high specificity (91.46-97.15%) and sensitivity (84.19-93.56%). When using only MRI measures and two behavioral tests in the PLS and classification algorithm, ensuring clinical feasibility, our model was similarly precise (83.62%, specificity 86.38-93.51%, sensitivity 76.17-87.50%). Here, including only atrophy or behavior patterns in the analysis led to prediction accuracies of 69.76% and 76.38%, respectively, highlighting the increased value of combining MRI and clinical measures in subtype classification.We demonstrate that the combination of brain atrophy and clinical characteristics, and multivariate statistical methods can serve as an imaging biomarker for early disease phenotyping in FTD, whereby inclusion of DBM measures adds to the classification precision in the absence of extensive clinical testing.
Spatial Clustering Analysis with Spectral Imaging-based Single-Step Multiplex Immunofluorescence (SISS-mIF)
Authors: Nakamura Tomohiko , Kaneko Noe , Taguchi Towako , Ikeda Kenji , Sakata Moe , Inoue Miori , Kuwayama Tetsuro , Tatsuta Hirokazu , Onishi Iichiroh , Kurata Morito , Nakagawa Kazuhiro 
Published: June 2024

AbstractPrecision medicine, anchored in spatial biology, is essential for the accurate diagnosis of cancer and prediction of drug responses. We have introduced the Spectral Imaging-based Single-Step Multiplex Immunofluorescence (SISS-mIF) technique, which leverages hyperspectral imaging to simultaneously capture fluorescence spectra. This approach automatically optimizes tissue autofluorescence spectra for each image, facilitating the use of fluorescent direct-labeled antibodies for multicolor staining in a single step. Unlike conventional methods, images are outputted as antibody counts rather than fluorescence intensity, allowing for consistent comparisons under different imaging conditions. We demonstrate that this technique allows for identical cell detection of CD3, CD5, and CD7 in T-cell lymphoma on a single slide. The utilization of fluorescent direct-labeled antibodies enables the triple staining of CD3, CD5, and CD7 without cross-reactivity, maintaining the same intensity as single stains. Moreover, we developed a joint Non-Negative Matrix Factorization-based Spatial Clustering Analysis (jNMF-SCA) with a modified spectral unmixing system, highlighting its potential as a supportive diagnostic tool for T-cell lymphoma.
TRIM7 ubiquitinates SARS-CoV-2 membrane protein to limit apoptosis and viral replication
Authors: Gonzalez-Orozco Maria , Tseng Hsiang-chi , Hage Adam , Xia Hongjie , Behera Padmanava , Afreen Kazi , Peñaflor-Tellez Yoatzin , Giraldo Maria I. , Huante Matthew , Puebla-Clark Lucinda , van Tol Sarah , Odle Abby , Crown Matthew , Teruel Natalia , Shelite Thomas R , Menachery Vineet , Endsley Mark , Endsley Janice J. , Najmanovich Rafael J. , Bashton Matthew , Stephens Robin , Shi Pei-Yong , Xie Xuping , Freiberg Alexander N. , Rajsbaum Ricardo 
Published: June 2024

AbstractSARS-CoV-2 is a highly transmissible virus that causes COVID-19 disease. Mechanisms of viral pathogenesis include excessive inflammation and viral-induced cell death, resulting in tissue damage. We identified the host E3-ubiquitin ligase TRIM7 as an inhibitor of apoptosis and SARS-CoV-2 replication via ubiquitination of the viral membrane (M) protein.Trim7-/-mice exhibited increased pathology and virus titers associated with epithelial apoptosis and dysregulated immune responses. Mechanistically, TRIM7 ubiquitinates M on K14, which protects cells from cell death. Longitudinal SARS-CoV-2 sequence analysis from infected patients revealed that mutations on M-K14 appeared in circulating variants during the pandemic. The relevance of these mutations was tested in a mouse model. A recombinant M- K14/K15R virus showed reduced viral replication, consistent with the role of K15 in virus assembly, and increased levels of apoptosis associated with the loss of ubiquitination on K14. TRIM7 antiviral activity requires caspase-6 inhibition, linking apoptosis with viral replication and pathology.
Structural robustness and temporal vulnerability of the starvation-responsive metabolic network in liver of healthy and obese mice
Authors: Morita Keigo , Hatano Atsushi , Kokaji Toshiya , Sugimoto Hikaru , Tsuchiya Takaho , Ozaki Haruka , Egami Riku , Li Dongzi , Terakawa Akira , Ohno Satoshi , Inoue Hiroshi , Inaba Yuka , Suzuki Yutaka , Matsumoto Masaki , Takahashi Masatomo , Izumi Yoshihiro , Bamba Takeshi , Hirayama Akiyoshi , Soga Tomoyoshi , Kuroda Shinya 
Published: June 2024

AbstractAdaptation to starvation is a multi-molecular and temporally ordered process, that could be impaired in obesity. To elucidate how the healthy liver regulates various molecules in a temporally ordered manner during starvation and how obesity disrupts this process, we measured time course multiomic data in the liver of wild-type (WT) and leptin-deficient obese (ob/ob) mice during starvation. Using the measured data, we constructed a starvation-responsive metabolic network, that is a transomic network including responsive molecules and their regulatory relationships during starvation, and analyzed the structure of the network. In WT mice, ATP and AMP, the energy indicators, regulated various metabolic reactions in the network as the hub molecules, both of which were not responsive inob/obmice. However, the structural properties of the network were maintained inob/obmice. In WT mice, the molecules in the network were temporally ordered through metabolic process coordinated by the hub molecules including ATP and AMP and were positively or negatively co-regulated. By contrast, both temporal order and co-regulation were disrupted inob/obmice. Taken together, the starvation-responsive metabolic network is structurally robust, but temporally vulnerable by the loss of responsiveness of the hub molecules in obesity. In addition, we proposed a potential therapeutic target to treat the negative effects of obesity on intermittent fasting to extend lifespan.One Sentence SummaryHub molecules activate or inhibit various molecules in a temporally ordered manner in healthy liver, and the regulatory network is structurally robust but temporally vulnerable to obesity.
Exploring the functional, protective, and transcriptomic effects of GIP on cytokine-exposed human pancreatic islets and EndoC-βH5 cells
Authors: Henriksen Kristine , Jørgensen Anne , Kaur Simranjeet , Gerwig Rebekka , Svane Cecilie Amalie Brøgger , Knop Filip K. , Størling Joachim 
Published: June 2024

AbstractImmune-mediated beta-cell destruction and lack of alpha-cell responsiveness to hypoglycaemia are hallmarks of type 1 diabetes pathology. The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) may hold therapeutic potential for type 1 diabetes due to its insulinotropic and glucagonotropic effects, as well as its beta-cell protective effects shown in rodent islets. Here, we examined the functional, protective, and transcriptomic effects of GIP treatment upon diabetogenic cytokine exposure to interleukin (IL)-1β ± interferon (IFN)-γ in human EndoC-βH5 beta cells and isolated human islets, respectively.GIP dose-dependently augmented glucose-stimulated insulin secretion from EndoC-βH5 cells and increased insulin and glucagon secretion from human islets during high and low glucose concentrations, respectively. The insulinotropic effect of GIP in EndoC-βH5 cells was abrogated by KN-93, an inhibitor of calcium/calmodulin-dependent protein kinase 2 (CaMK2). GIP did not prevent cytokine-induced apoptosis or cytokine-induced functional impairment of human EndoC-βH5 cells. GIP also did not prevent cytokine-induced apoptosis in human islets. GIP treatment of human islets with or without cytokines for 24 hours did not significantly impact the transcriptome. GIP potentiated cytokine-induced secretion of IL-10 and c-c motif chemokine ligand (CCL)-2 from human islets while decreasing the secretion of c-x-c motif chemokine ligand (CXCL)-8. In EndoC-βH5 cells, GIP reduced IFN-γ-induced secretion of tumor necrosis factor (TNF)-α, IL-2, IL-6, and IL-10 but increased the secretion of CXCL8, CCL2, CCL4, and CCL11.In conclusion, our results suggest that the insulinotropic effect of GIP is CaMK2-dependent. Furthermore, our results indicate that GIP does not provide substantial cytoprotective effects against diabetogenic cytokine challenge or significantly modulate the transcriptome of human islets when applied at a supraphysiological level. GIP may, however, still exert selective inflammation-modulatory effects upon diabetogenic cytokine exposure.
Stability of four carbapenem antibiotics in discs used for antimicrobial susceptibility testing
Authors: Shahab Selvi N. , Bexkens Michiel L. , Kempenaars Nikita , Rijfkogel Amber , Karuniawati Anis , Vos Margreet C. , Goessens Wil H.F. , Severin Juliëtte A. 
Published: June 2024

ABSTRACTIn low-to middle-income countries, microbiological laboratories often use disc diffusion for antimicrobial susceptibility testing (AST). Reliable AST of carbapenem antibiotics is crucial for treatment decisions and surveillance purposes. Transport and storage conditions of materials used for AST are critical and may be challenging in some settings, where temperature cannot always be controlled. This study aimed to test the stability of four carbapenems in discs for AST under unfavourable conditions,i.e., at room temperature and 35°C for up to 72 hours. Imipenem, meropenem, ertapenem, and doripenem discs from three brands, Oxoid, Becton Dickinson, and HiMedia, containing 10 μg of antibiotic were included. Discs were exposed to six unfavourable conditions and the recommended storage-condition as control. Subsequently, disc diffusion testing following the EUCAST guidelines was performed with four well-defined strains ofEscherichia coliwith different susceptibility profiles to carbapenems. The inhibition zone diameters were measured after 16-18 hours of incubation at 35±2°C. All experiments were executed in triplicate. In parallel, the carbapenems’ degradation was observed using a spectrophotometric method. Our study revealed that carbapenem discs were generally stable for AST although the concentration of most carbapenem antibiotics in discs decreased over time. Overall, imipenem (Oxoid and Becton Dickinson) discs were the most stable. Meropenem discs were less stable when exposed to 35°C than at room temperature. Concentrations of carbapenems in HiMedia discs were higher than those in Oxoid and Becton Dickinson. For carbapenem AST using disc diffusion in a rural area, we recommend using imipenem discs from Oxoid or Becton Dickinson.GRAPHICAL ABSTRACTHIGHLIGHTSIn remote areas, transportation conditions of AST discs may be challengingDiscs with four carbapenems from three brands were tested using six conditionsCarbapenem discs were generally stable for ASTIn unfavourable conditions, concentrations in the discs degraded over timeImipenem (Oxoid and Becton Dickinson) discs were the most stable