bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of disease-specific TCRs maintaining pathogenic T helper cell responses in postinfectious Lyme Arthritis
Authors: Dirks Johannes , Fischer Jonas , Klaussner Julia , Hofmann Christine , Holl-Wieden Annette , Buck Viktoria , Klemann Christian , Girschick Hermann , Caruana Ignazio , Erhard Florian , Morbach Henner 
Published: January 2024

ABSTRACTBackgroundAntibiotic-Refractory Lyme Arthritis(ARLA) involves a complex interplay of T cell responses targetingBorrelia burgdorferiantigens succeeding towards autoantigens by epitope spreading. However, the precise molecular mechanisms driving the pathogenic T cell response in ARLA remain unclear. Our aim was to elucidate the molecular program of disease-specific Th cells.MethodsUsing flow cytometry, high-throughput T cell receptor (TCR) sequencing and scRNA-seq of CD4+Th cells isolated from the joints of European ARLA patients, we aimed at inferring antigen specificity through unbiased analysis of TCR repertoire patterns, identifying surrogate markers for disease-specific TCRs and connecting TCR specificity to transcriptional patterns.ResultsPD-1hiHLA-DR+CD4+effector T cells were clonally expanded within the inflamed joints and persisted throughout disease course. Among these cells, we identified a distinct TCRβ motive restricted to HLA-DRB1*11 or *13 alleles. These alleles, being underrepresented in North American ARLA patients, were unexpectedly prevalent in our European cohort. The identified TCRβ motive served as surrogate marker for a convergent TCR response specific to ARLA, distinguishing it from other rheumatic diseases. In the scRNA-seq dataset, the TCRβ motive particularly mapped to peripheral T helper (TPH) cells displaying signs of sustained proliferation, continuous TCR signaling, and expressing CXCL13 and IFN-γ.ConclusionBy inferring disease-specific TCRs from synovial T cells we identified a convergent TCR response in the joints of ARLA patients that continuously fueled the expansion of TPHcells expressing a pathogenic cytokine effector program. The identified TCRs will aid in uncovering the major antigen targets of the maladaptive immune response.FundingSupported by the German Research Foundation (DFG) MO 2160/4-1; the Federal Ministry of Education and Research (BMBF; Advanced Clinician Scientist-Program INTERACT; 01EO2108) embedded in the Interdisciplinary Center for Clinical Research (IZKF) of the University Hospital Würzburg; the German Center for Infection Research (DZIF; Clinical Leave Program; TI07.001_007) and the Interdisciplinary Center for Clinical Research (IZKF) Würzburg (Clinician Scientist Program, Z-2/CSP-30).
Deep Survival Analysis for Interpretable Time-Varying Prediction of Preeclampsia Risk
Authors: Eberhard Braden W , Gray Kathryn J , Bates David W , Kovacheva Vesela P 
Published: January 2024

AbstractObjectiveSurvival analysis is widely utilized in healthcare to predict the timing of disease onset. Traditional methods of survival analysis are usually based on Cox Proportional Hazards model and assume proportional risk for all subjects. However, this assumption is rarely true for most diseases, as the underlying factors have complex, non-linear, and time-varying relationships. This concern is especially relevant for pregnancy, where the risk for pregnancy-related complications, such as preeclampsia, varies across gestation. Recently, deep learning survival models have shown promise in addressing the limitations of classical models, as the novel models allow for non-proportional risk handling, capturing nonlinear relationships, and navigating complex temporal dynamics.MethodsWe present a methodology to model the temporal risk of preeclampsia during pregnancy and investigate the associated clinical risk factors. We utilized a retrospective dataset including 66,425 pregnant individuals who delivered in two tertiary care centers from 2015-2023. We modeled the preeclampsia risk by modifying DeepHit, a deep survival model, which leverages neural network architecture to capture time-varying relationships between covariates in pregnancy. We applied time series k-means clustering to DeepHit’s normalized output and investigated interpretability using Shapley values.ResultsWe demonstrate that DeepHit can effectively handle high-dimensional data and evolving risk hazards over time with performance similar to the Cox Proportional Hazards model, achieving an area under the curve (AUC) of 0.78 for both models. The deep survival model outperformed traditional methodology by identifying time-varied risk trajectories for preeclampsia, providing insights for early and individualized intervention. K-means clustering resulted in patients delineating into low-risk, early-onset, and late-onset preeclampsia groups— notably, each of those has distinct risk factors.ConclusionThis work demonstrates a novel application of deep survival analysis in time-varying prediction of preeclampsia risk. Our results highlight the advantage of deep survival models compared to Cox Proportional Hazards models in providing personalized risk trajectory and demonstrating the potential of deep survival models to generate interpretable and meaningful clinical applications in medicine.
Prevalence and National Patterns of Commonly Prescribed Antidepressants and other Psychotropic Medications to patients with treatment-resistant depression in France
Authors: Alexandre Vimont , Margot Biscond , Henri Leleu , Sanchez-Rico² Marina , Nicolas Hoertel , Pierre-Michel Llorca 
Published: January 2024

AbstractBackgroundPrevalence of Treatment-Resistant Depression (TRD) varied widely across studies due to heterogeneous definitions. Several treatment strategies exist to manage patients with TRD but evidence from real-world data is scarce. Investigating their use in real-life settings is important to understand national prescribing practices and to refine prevalence estimation.MethodAll adult patients (≥ 18 years) with a TRD episode for the year 2019 were identified in a sample of four French regions accounting for 27% of national individuals. After exclusion of patients with psychotic or bipolar disorders, Parkinson’s disease, and dementia, TRD was defined by i/ 3 successive sequences of different antidepressants (AD), or ii/ the dispensing of several different AD together, or iii/ an AD with a potentiator (lithium, antiepileptic drugs, or antipsychotic drugs) over the same treatment period. The prevalence rate was estimated for the year 2019 and treatment patterns were described by treatment class and molecule.ResultsFor the year 2019, 66,810 patients were identified with TRD, accounting for 23.9% of all patients treated for depression. The mean age was 56 years (±15.9) with 63.7% of women. Standardized prevalence of TRD was estimated at 35.1 per 10 000 patients, and 25.8 per 10,000 patients when excluding patients probably treated for another primary diagnosis than depression. Association of an AD with an antipsychotic was the most frequently used strategy, with SSRIs and second-generation antipsychotics being the most often prescribed.ConclusionThis study provides robust population-based estimates of the prevalence of TRD in the French population. Description of treatment patterns highlight the widespread use of second-generation antipsychotics as potentiator of antidepressants.
OpenMAP-T1: A Rapid Deep Learning Approach to Parcellate 280 Anatomical Regions to Cover the Whole Brain
Authors: Nishimaki Kei , Onda Kengo , Ikuta Kumpei , Uchida Yuto , Mori Susumu , Iyatomi Hitoshi , Oishi Kenichi ,   the Alzheimer’s Disease Neuroimaging Initiative,   the Australian Imaging Biomarkers and Lifestyle flagship study of aging
Published: January 2024

0.AbstractThis study introduces OpenMAP-T1, a deep-learning-based method for rapid and accurate whole-brain parcellation in T1-weighted brain MRI, which aims to overcome the limitations of conventional normalization-to-atlas-based approaches and multi-atlas label-fusion (MALF) techniques. Brain image parcellation is a fundamental process in neuroscientific and clinical research, enabling a detailed analysis of specific cerebral regions. Normalization-to-atlas-based methods have been employed for this task, but they face limitations due to variations in brain morphology, especially in pathological conditions. The MALF teqhniques improved the accuracy of the image parcellation and robustness to variations in brain morphology, but at the cost of high computational demand that requires a lengthy processing time. OpenMAP-T1 integrates several convolutional neural network models across six phases: preprocessing; cropping; skull-stripping; parcellation; hemisphere segmentation; and final merging. This process involves standardizing MRI images, isolating the brain tissue, and parcellating it into 280 anatomical structures that cover the whole brain, including detailed gray and white matter structures, while simplifying the parcellation processes and incorporating robust training to handle various scan types and conditions. The OpenMAP-T1 was tested on eight available open resources, including real-world clinical images, demonstrating robustness across different datasets with variations in scanner types, magnetic field strengths, and image processing techniques, such as defacing. Compared to existing methods, OpenMAP-T1 significantly reduced the processing time per image from several hours to less than 90 seconds without compromising accuracy. It was particularly effective in handling images with intensity inhomogeneity and varying head positions, conditions commonly seen in clinical settings. The adaptability of OpenMAP-T1 to a wide range of MRI datasets and its robustness to various scan conditions highlight its potential as a versatile tool in neuroimaging.
A Comparative Study: Diagnostic Performance of ChatGPT 3.5, Google Bard, Microsoft Bing, and Radiologists in Thoracic Radiology Cases
Authors: Gunes Yasin Celal , Cesur Turay 
Published: January 2024

ABSTRACTPurposeTo investigate and compare the diagnostic performance of ChatGPT 3.5, Google Bard, Microsoft Bing, and two board-certified radiologists in thoracic radiology cases published by The Society of Thoracic Radiology.Materials and MethodsWe collected 124 “Case of the Month” from the Society of Thoracic Radiology website between March 2012 and December 2023. Medical history and imaging findings were input into ChatGPT 3.5, Google Bard, and Microsoft Bing for diagnosis and differential diagnosis. Two board-certified radiologists provided their diagnoses. Cases were categorized anatomically (parenchyma, airways, mediastinum-pleura-chest wall, and vascular) and further classified as specific or non-specific for radiological diagnosis. Diagnostic accuracy and differential diagnosis scores were analyzed using chi-square, Kruskal-Wallis and Mann-Whitney U tests.ResultsAmong 124 cases, ChatGPT demonstrated the highest diagnostic accuracy (53.2%), outperforming radiologists (52.4% and 41.1%), Bard (33.1%), and Bing (29.8%). Specific cases revealed varying diagnostic accuracies, with Radiologist I achieving (65.6%), surpassing ChatGPT (63.5%), Radiologist II (52.0%), Bard (39.5%), and Bing (35.4%). ChatGPT 3.5 and Bing had higher differential scores in specific cases (P<0.05), whereas Bard did not (P=0.114). All three had a higher diagnostic accuracy in specific cases (P<0.05). No differences were found in the diagnostic accuracy or differential diagnosis scores of the four anatomical location (P>0.05).ConclusionChatGPT 3.5 demonstrated higher diagnostic accuracy than Bing, Bard and radiologists in text-based thoracic radiology cases. Large language models hold great promise in this field under proper medical supervision.
Intravenous iron therapy with ferric carboxymaltose results in a rapid and sustained rise in myocardial iron content through a non-canonical pathway: a translational study
Authors: Vera-Aviles M , Kabir S , Shah A , Polzella P , Lim Y , Buckley P , Ball C , Swinkels D , Matlung H , Blans C , Holdship P , Nugent J , Andreson E , Desborough M , Piechnik S , Ferreira V , Lakhal-Littleton S 
Published: January 2024

ABSTRACTBackground and AimsIntravenous iron therapies contain iron-carbohydrate complexes, designed to ensure iron becomes bioavailable via the intermediary of spleen and liver reticuloendothelial macrophages. How other tissues obtain and handle this iron remains unknown. This study addresses this question in the context of the heart.MethodsA prospective observational study was conducted in 12 patients receiving ferric carboxymaltose (FCM) for iron deficiency. Myocardial, spleen and liver magnetic resonance relaxation times, and plasma iron markers were collected longitudinally. To examine the handling of iron taken up by the myocardium, intracellular labile iron pool (LIP) was imaged in FCM-treated mice and cells.ResultsIn patients, myocardial relaxation time T1 dropped maximally 3hrs post FCM, remaining low 42 days later, while splenic T1 dropped maximally at 14 days, recovering by 42 days. In plasma, non-transferrin bound iron (NTBI) peaked at 3hrs, while ferritin peaked at 14 days. Changes in liver T1 diverged amongst patients. In mice, myocardial LIP rose 1h and remained elevated 42 days after FCM. In cardiomyocytes, FCM exposure raised LIP rapidly. This was prevented by inhibitors of NTBI transporters T-type and L-Type calcium channels and divalent metal transporter 1.ConclusionsIntravenous iron therapy with FCM delivers iron to the myocardium rapidly through NTBI transporters, independently of reticuloendothelial macrophages. This iron remains labile for weeks, reflecting the myocardium’s limited iron storage capacity. These findings challenge current notions of how the heart obtains iron from these therapies and highlight the potential for long-term dosing to cause cumulative iron build-up in the heart.TRANSLATIONAL PERSPECTIVEMany patients now receive long-term IV iron therapy. The finding that a single standard dose of IV iron causes a sustained rise in myocardial iron underscores the risk for cumulative build-up to occur with multiple doses. Magnetic resonance monitoring of myocardial iron may be required to safeguard against progression towards pathological myocardial iron overload in these patients.Plasma ferritin levels reflect the iron content of reticuloendothelial macrophages. The finding that myocardial iron elevation following IV iron therapy is independent from reticuloendothelial macrophages highlights the limitations of using plasma ferritin cut-offs to safeguard against the risk of tissue iron overload.GRAPHICAL ABSTRACT
Sildenafil’s Effectiveness in the Primary Coronary Slow Flow Phenomenon: A Randomized Controlled Clinical Trial
Authors: Andishmand Abbas , Seyedhossaini Seyedmostafa , Namayandeh Seyedeh Mahdieh , Mirjalili Seyed Reza , Adelzadeh Elnaz , Entezari Amin 
Published: January 2024

AbstractBackgroundOn the one hand, the coronary slow flow phenomenon (CSFP) may cause recurrence of chest pain, prompting medical examinations and further healthcare expenses, and on the other side, it can result in myocardial infarction, ventricular arrhythmia, and sudden cardiac death.ObjectivesDue to the lack of agreement on the optimal treatment for CSFP, we decided to examine the effectiveness of sildenafil in this context.MethodsWe assessed the eligibility of 196 CSFP patients to participate in a 12-week, triple-blind, randomized, placebo-controlled study for receiving either 50 mg daily oral sildenafil or placebo. We evaluated the efficacy of sildenafil based on exercise tolerance test parameters, severity of angina, adverse effects, and major adverse cardiovascular events.ResultsTwenty eligible patients were randomly allocated in a 1:1 ratio to two groups. Sildenafil demonstrated significant efficacy in improving angina severity, with all recipients achieving a Class I angina severity, contrasting with a 40% attainment in the placebo group (P=0.011). Notably, Sildenafil induced statistically significant reductions in systolic and diastolic blood pressure, unlike the placebo group. Although a reduction in the QT interval favored Sildenafil (−21 millisecond vs +3 milliseconds), statistical significance was not reached (P=0.09 vs. P=0.67). Moreover, Sildenafil markedly improved Duke Treadmill Score (DTS) (P=0.005), while the placebo group showed non-significant improvement. Concurrently, the Sildenafil group exhibited significant enhancements in functional capacity (METs) and maximum heart rate during exercise testing compared to the placebo group.ConclusionsWe suggest that a daily low dose of sildenafil could be a valuable therapeutic option for CSFP.Graphical abstract
The Paradigm Shift: Reclassification of SARS-CoV-2 and Longitudinal Immune Responses in Japanese Healthcare Workers
Authors: Chano Tokuhiro , Kita Hiroko , Yamashita Tomoko , Fujimura Hirokazu , Ikemoto Toshiyuki 
Published: January 2024

AbstractUnder the aegis of the National Infectious Diseases Act, the virus transitioned from a Category 2 menace to Category 5, analogous to seasonal influenza. The current study has investigated the protracted immune responses of healthcare workers (HCWs) towards SARS-CoV-2 in Japan. One year subsequent to the systematically implemented SARS-CoV-2 vaccination campaign among HCWs, humoral and cellular immune responses were sustained at levels as high as or higher than those immediately following the 3rd booster vaccination. Persisting immunity has highlighted the resilience and lasting memory exhibited in HCW defense against the virus.
Discordant effects ofex-vivoJAK inhibition on inflammatory responses in colonic compared to ileal mucosa
Authors: Kaboub Kawsar , Abu-Taha Hanan , Arrouasse Jessica , Shaham-Barda Efrat , Wasserberg Nir , Hayman-Manzur Lucille , Friedenberg Adi , Levy-Barda Adva , Goren Idan , Yanai Henit , Levi Zohar , Banai-Eran Hagar , Avni-Biron Irit , Ollech Jacob E , Cohen-Kedar Sarit , Dotan Iris , Rabinowitz Keren M 
Published: January 2024

AbstractBackground & aimsJanus kinase (JAK) inhibitors modulating JAK-STAT (signal transducers and activators of transcription) signaling pathway, are used for the treatment of patients with inflammatory bowel diseases (IBD). We aimed to identify the molecular effects of JAK inhibition in the human intestinal mucosa, considering the IBD location and phenotype.MethodsColonic and ileal explants from patients with ulcerative colitis (UC), Crohn’s disease (CD), or non-IBD controls (NC) were treatedex-vivowith the JAK inhibitor, tofacitinib. Phosphorylated STAT (p-STAT) levels were assessed by Western blot and Immunofluorescence. Inflammatory genes expression was assessed with Nanostring nCounter system. Human intestinal organoids were used to assess JAK inhibitors’ effects on p-STATs and iNOS expression.ResultsExplants were collected from 68 patients (NC=28; UC=20; CD=20). JAK inhibition reduced p-STAT1/3/5 expression in all explants. While p-STAT inhibition rates varied among patients (10%-88%), higher inhibition rates were observed in colonic compared to ileal explants. Significant alterations in 120 of 255 inflammatory genes were observed in colonic explants, while only 30 were observed in ileal NC explants. In colonic explants from UC, significant alterations were observed in 5 genes, includingSTAT1andNOS2. Various JAK inhibitors reduced IFN-γ-induced increase in p-STAT1 and iNOS expression in organoids.ConclusionsA site-specific anti-inflammatory effect of JAK inhibition by tofacitinib was noticed, whereby the colon was more robustly affected than the ileum.Ex-vivoresponse to tofacitinib is individual. JAK inhibition may attenuate inflammation by decreasing iNOS expression.Ex-vivomucosal platforms may be a valuable resource for studying drug impact and evaluating personalized treatment effects.
Heat Shock Proteins Function as Signaling Molecules to Mediate Neuron-Glia Communication During Aging
Authors: Wu Jieyu , Yang Olivia Jiaming , Soderblom Erik J. , Yan Dong 
Published: January 2024

AbstractThe nervous system is primarily composed of neurons and glia, and the communication between them plays profound roles in regulating the development and function of the brain. Neuron-glia signal transduction is known to be mediated by secreted or juxtacrine signals through ligand-receptor interactions on the cell membrane. Here, we report a novel mechanism for neuron-glia signal transduction, wherein neurons transmit proteins to glia through extracellular vesicles, activating glial signaling pathways. We find that in the amphid sensory organ ofCaenorhabditis elegans, different sensory neurons exhibit varying aging rates. This discrepancy in aging is governed by the crosstalk between neurons and glia. We demonstrate that early-aged neurons can transmit heat shock proteins (HSP) to glia via extracellular vesicles. These neuronal HSPs activate the IRE1-XBP1 pathway, further increasing their expression in glia, forming a positive feedback loop. Ultimately, the activation of the IRE1-XBP-1 pathway leads to the transcriptional regulation of chondroitin synthases to protect glia-embedded neurons from aging-associated functional decline. Therefore, our studies unveil a novel mechanism for neuron-glia communication in the nervous system and provide new insights into our understanding of brain aging.