bluuebunny/crossref_metadata_2025_split huggingface dataset:
Importance of external validation and subgroup analysis in artificial-intelligence detecting low ejection fraction from electrocardiograms
Authors: Yagi Ryuichiro , Goto Shinichi , Katsumata Yoshinori , MacRae Calum A , Deo Rahul C 
Published: July 2022

AbstractIntroductionAsymptomatic left ventricular dysfunction (ALVD) carries an increased risk for overt heart failure and mortality, yet treatable to mitigate disease progression. An artificial intelligence (AI)-enabled 12-lead electrocardiogram (ECG) model demonstrated promise in ALVD screening but an unexpected drop in performance was observed in external validation. We thus sought to train ade novomodel for ALVD detection and investigate its performance across multiple institutions and across a broader set of patient strata.MethodsECGs taken within 14 days of an echocardiogram were obtained from 4 academic hospitals from the United States (BWH, MGH and UCSF) and Japan (Keio). Four AI models were trained to detect patients with ejection fraction < 40% using ECG from each of the 4 institutions. All the models were then evaluated on the held-out test dataset from the same intuition and all data from the 3 external institutions. Subgroup analyses stratified by patient characteristics and common overt ECG abnormalities were performed.ResultsA total of 221,846 ECGs were identified from the 4 institutions. While the BWH-trained and Keio-trained model yielded similar accuracy on its internal test data (AUROC 0.913 and 0.914 respectively), external validity was worse for Keio-trained model (AUROC: 0.905-0.915 for BWH-trained and 0.849-0.877 for Keio-trained model). Although ECG abnormalities including atrial fibrillation, left bundle branch block and paced rhythm reduced detection, the models performed robustly across patient characteristics and other ECG features.ConclusionDifferent dataset produces models with different performance highlighting the importance of external validation and extensive stratification analysis.
Predictive models for starting antiseizure medication withdrawal following epilepsy surgery in adults
Authors: Ferreira-Atuesta Carolina , de Tisi Jane , McEvoy Andrew W. , Miserocchi Anna , Khoury Jean , Yardi Ruta , Vegh Deborah T. , Butler James , Lee Hamin J. , Deli-Peri Victoria , Yao Yi , Wang Feng-Peng , Zhang Xiao-Bin , Shakhatreh Lubna , Siriratnam Pakeeran , Neal Andrew , Sen Arjune , Tristram Maggie , Varghese Elizabeth , Biney Wendy , Gray William P , Peralta Ana Rita , Rainha-Campos Alexandre , Gonçalves-Ferreira António JC. , Pimentel José , Arias Juan Fernando , Terman M Samuel , Terziev Robert , Lamberink Herm J. , Braun Kees P.J. , Otte Willem M , Rugg-Gunn Fergus J. , Gonzalez Walter , Bentes Carla , Hamandi Khalid , O’ Brien Terence J. , Perucca Piero , Yao Chen , Burman Richard J. , Jehi Lara , Duncan John S. , Sander Josemir W , Koepp Matthias , Galovic Marian 
Published: July 2022

AbstractMore than half of adults with epilepsy undergoing resective epilepsy surgery achieve long-term seizure freedom and might consider withdrawing antiseizure medications (ASMs). We aimed to identify predictors of seizure recurrence after starting postoperative ASM withdrawal and develop and validate predictive models.We performed an international multicentre observational cohort study in nine tertiary epilepsy referral centres. We included 850 adults who started ASM withdrawal following resective epilepsy surgery and were free of seizures other than focal non-motor aware seizures (auras) before starting ASM withdrawal. We developed a model predicting recurrent seizures, other than auras, using Cox proportional hazards regression in a derivation cohort (n=231). Independent predictors of seizure recurrence, other than auras, following the start of ASM withdrawal were focal-aware seizures after surgery and before withdrawal (adjusted hazards ratio [aHR] 5.5, 95% confidence interval [CI] 2.7-11.1), history of focal to bilateral tonic-clonic seizures before surgery (aHR 1.6, 95% CI 0.9-2.8), time from surgery to the start of ASM withdrawal (aHR 0.9, 95% CI 0.8-0.9), and number of ASMs at time of surgery (aHR 1.2, 95% CI 0.9-1.6). Model discrimination showed a concordance statistic of 0.67 (95% CI 0.63-0.71) in the external validation cohorts (n=500). A secondary model predicting recurrence of any seizures (including auras) was developed and validated in a subgroup that did not have auras before withdrawal (n=639), showing a concordance statistic of 0.68 (95% CI 0.64-0.72). Calibration plots indicated high agreement of predicted and observed outcomes for both models.We show that simple algorithms, available as graphical nomograms and online tools (predictepilepsy.github.io), can provide probabilities of seizure outcomes after starting postoperative ASMs withdrawal. These multicentre-validated models may assist clinicians when discussing ASM withdrawal after surgery with their patients.
DNA methylation clock DNAmFitAge shows regular exercise is associated with slower aging and systemic adaptation
Authors: Jokai Matyas , Torma Ferenc , McGreevy Kristen M. , Koltai Erika , Bori Zoltan , Babszki Gergely , Bakonyi Peter , Gombos Zoltan , Gyorgy Bernadett , Aczel Dora , Toth Laszlo , Osvath Peter , Fridvalszky Marcell , Teglas Timea , Ligeti Balazs , Kalcsevszki Regina , Posa Aniko , Kujach Sylwester , Olek Robert , Kawamura Takuji , Seki Yasuhiro , Suzuki Katsuhiko , Tanisawa Kumpei , Goto Sataro , Boldogh Istvan , Ba Xueqing , Szabo Dora , Davies Kelvin J. A. , Horvath Steve , Radak Zsolt 
Published: July 2022

AbstractDNAmPhenoAge, DNAmGrimAge, and the newly developed DNAmFitAge are DNA methylation (DNAm) based biomarkers that reflect the individual aging process. Furthermore, physical fitness is known to relate to the aging process, but its relationship to the gut microbiome has not yet been studied. Here, we examine the relationship among physical fitness, DNAm based biomarkers, and the microbiome in adults aged 33-88 with a wide range of physical fitness (including athletes with long-term training history). Higher levels of VO2max (ρ=0.2, p=6.4E-4, r=0.19, p=1.2E-3), Jumpmax p=0.11, p=5.5E-2, r=0.13 p= 2.8E-2), Gripmax (=ρ=0.17, p=3.5E-3, r=0.16, p=5.6E-3), and HDL levels (ρ=0.18, p=1.95E-3, r=0.19, p=1.1E-3) are associated with better verbal short term memory. In addition, verbal short term memory is associated with decelerated aging assessed with the new DNAm biomarker FitAgeAcceleration (ρ: −0.18, p=0.0017). DNAmFitAge is able to distinguish high fitness individuals from low/medium fitness individuals better than existing DNAm biomarkers and estimates a younger biological age in the high fit males and females (1.5 and 2.0 years younger, respectively). The microbiomal pathways are associated with VO2max, redox balance, and DNAmPhenoAge. PhenoAge Acceleration is influenced by pyruvate producing microbiomal pathways, where higher activity of these pathways lead to suppressed PhenoAge acceleration. Our research shows that regular physical exercise contributes to observable physiological, methylation, and microbiota differences which are beneficial to the aging process. DNAmFitAge emerged as a biological marker of the quality of life.
Part-time or full-time teleworking? A systematic review of the psychosocial risk factors of telework from home
Authors: Antunes Evelise Dias , Bridi Leonardo Rodrigues Thomaz , Santos Marta , Fischer Frida Marina 
Published: July 2022

ABSTRACTSince the start of the Coronavirus pandemic thousands of people have experienced teleworking and this practice is becoming increasingly commonplace. Systematic reviews can yield evidence and information to help inform the development of policies and regulations, the aim of this study was to highlight the differences in exposure to psychosocial risk factors for health between part-time and full-time teleworking from home. The protocol of the systematic review of the literature was registered on PROSPERO 2020 platform - International Prospective Register of Systematic Reviews (number CRD42020191455), according to the PRISMA statement guidelines. The key words “telework” and frequency (“part-time” or “full-time”), together with their synonyms and variations, were searched. Independent researchers conducted the systematic search of 7 databases: Scopus, SciELO, PePSIC; PsycInfo, PubMed, Applied Social Sciences Index and Abstracts (ASSIA) and Web of Science. Of the 638 articles identified from 2010 to June 2021, 32 were selected for data extraction. The authors evaluated the risk of bias and quality of evidence of the studies included using the Mixed Methods Appraisal Tool. The results were categorized into 7 dimensions of psychosocial risk factors: work intensity and working hours; emotional demands; autonomy; social relationships at work; conflict of values, work insecurity and home/work interface. The results revealed scant practice of full-time teleworking prior to the pandemic. Regarding the psychosocial risk factors found, differences were evident before and during the COVID-19 pandemic. For part-time and full-time telework prior to the pandemic, the dimensions of intensification of work and working hours, social relationships at work, and the home-work interface were the most prominent factors. However, in studies performed during the COVID-19 pandemic where teleworking was mostly performed full-time, there was an increase in focus on emotional demands and the home-work interface, and a reduction in the other dimensions.
High titre neutralizing antibodies in response to SARS-CoV-2 infection require RBD-specific CD4 T cells that include proliferative memory cells
Authors: Phetsouphanh Chansavath , Khoo Weng Hua , Jackson Katherine , Klemm Vera , Howe Annett , Aggarwal Anupriya , Akerman Anouschka , Milogiannakis Vanessa , Stella Alberto Ospina , Rouet Romain , Schofield Peter , Faulks Megan L. , Law Hannah , Danwilai Thidarat , Starr Mitchell , Munier C. Mee Ling , Christ Daniel , Singh Mandeep , Croucher Peter I , Brilot-Turville Fabienne , Turville Stuart , Phan Tri Giang , Dore Gregory J , Darley David , Cunningham Philip , Matthews Gail V , Kelleher Anthony D , Zaunders John J 
Published: July 2022

ABSTRACTLong-term immunity to SARS-CoV-2 infection, including neutralizing antibodies and T cell-mediated immunity, is required in a very large majority of the population in order to reduce ongoing disease burden. We have investigated the association between memory CD4 and CD8 T cells and levels of neutralizing antibodies in convalescent COVID-19 subjects. Higher titres of convalescent neutralizing antibodies were associated with significantly higher levels of RBD-specific CD4 T cells, including specific memory cells that proliferated vigorously in vitro. Conversely, up to half of convalescent individuals had low neutralizing antibody titres together with a lack of receptor binding domain (RBD)- specific memory CD4 T cells. These low antibody subjects had other, non-RBD, spike-specific CD4 T cells, but with more of an inhibitory Foxp3+ and CTLA-4+ cell phenotype, rather than the effector T- bet+, cytotoxic granzymes+ and perforin+ cells seen in high antibody subjects. Single cell transcriptomics of antigen-specific CD4+ T cells from high antibody subjects revealed heterogenous RBD-specific CD4+ T cells that comprised central memory, transitional memory and Tregs, as well as cytotoxic clusters containing diverse TCR repertoires, that were absent in individuals with low antibody levels. However, vaccination in low antibody convalescent individuals led to a slight but significant improvement in RBD-specific memory CD4 T cells and increased neutralizing antibody titres. Our results suggest that targeting CD4 T cell epitopes proximal to and within the RBD- region should be prioritized in booster vaccines.One Sentence SummaryIndividuals with low neutralising antibody titres may be at risk of SARS-CoV-2 re-infection due to a failure to generate a high quality CD4 T cell response specific for receptor binding domain (RBD), including memory CD4 T cells that proliferate in vitro in response to RBD, and which are also therefore an important target for vaccine design.
Decreased ventral tegmental area CB1R signaling reduces sign-tracking and shifts cue-outcome dynamics in rat nucleus accumbens
Authors: Bacharach Sam Z. , Martin David A. , Stapf Cassie A. , Sun Fangmiao , Li Yulong , Cheer Joseph F. , Calu Donna J. 
Published: July 2022

ABSTRACTSign-tracking rats show enhanced cue sensitivity before drug experience that predicts greater discrete cue-induced drug-seeking compared to goal-tracking or intermediate-rats. Cue-evoked dopamine in the nucleus Accumbens (NAc) is a neurobiological signature of sign-tracking behaviors. Here, we examine a critical regulator of the dopamine system; endocannabinoids, which bind the cannabinoid receptor-1 (CB1R) in the Ventral Tegmental Area (VTA) to control cue-evoked striatal dopamine levels. We use cell-type specific optogenetics, intra-VTA pharmacology and fiber photometry to test the hypothesis that VTA CB1R receptor signaling regulates NAc dopamine levels to control sign-tracking. We trained rats in a Pavlovian lever autoshaping task (PLA) to determine their tracking groups before testing the effect of VTA→NAc dopamine inhibition. We found this circuit is critical for mediating the vigor of the ST response. Upstream of this circuit, intra-VTA infusions of rimonabant, a CB1R inverse agonist, during PLA decrease lever and increase foodcup approach in sign-trackers. Using fiber photometry to measure fluorescent signals from dopamine sensor, GRABDA, we tested the effects of intra-VTA rimonabant on NAc dopamine dynamics during autoshaping. We found that intra-VTA rimonabant decreased sign-tracking behaviors, which was associated with increases NAc shell, but not core, dopamine levels during reward delivery (US). We also observed a relationship between cue (CS)-evoked NAc dopamine activity and rigidity of behavior between rimonabant treatment sessions. Our results suggest that CB1R signaling in the VTA influences the balance between the CS- and US-evoked dopamine responses in the NAc and biases behavioral responding to cues in sign-tracking rats.SIGNIFICANCE STATEMENTSubstance Use Disorder is a chronically relapsing neurobiological disorder that affects a subset of individuals that engage in drug use. Recent research suggests that there are individual behavioral and neurobiological differences prior to drug experience that predict addiction and relapse vulnerabilities. Here, we investigate how midbrain endocannabinoids regulate a brain pathway that is exclusively involved in driving cue-motivated behaviors of sign-tracking rats. This work contributes to our mechanistic understanding of individual vulnerabilities to cue-triggered natural reward seeking that have relevance for drug motivated behaviors.
Brain-based Lifespan Trajectories of Social Cognition: From Resting-state fMRI Perspective
Authors: Fan Wei , Yan Zhi-Xiong 
Published: July 2022

AbstractBrain lifespan trajectories of intrinsic functional connectivity (iFC) in social cognition (SC) provide comprehensive insight and effective reference for normal development and clinical intervention. Unfortunately, for a lack of lifespan samples, the neural mechanism underlying SC in a lifespan developmental perspective is largely unknown, though relative behavior evidence has been investigated well. We, based on common functional networks, aim to map out voxel-wise iFC features between the SC networks and the entire cerebral cortex and further chart its corresponding trajectory patterns across the lifespan. Three networks, namely moral cognition, theory of mind (ToM), and empathy, are chosen as representatives of core SC networks. NKI-RS Enhanced (N = 316, ages 8-83 years old) dataset is selected as a lifespan resting-state fMRI dataset to delineate iFC characteristics and construct developmental trajectories. The result shows that the SC networks represent dissociable and network-specific connectivity profiles. Empathy network, as the most age-related susceptible network, shows a linear up trend with dorsal attention network, a linear decrease with ventral attention network, and a quadric-concave with somatomotor and dorsal attention networks. In addition, the sex effect is also discovered in empathy network, which exhibits linear and quadric gender differences with frontoparietal and vision networks respectively. ToM network follows a pronounced quadric-convex (inverted U-shape) trajectory with ventral attention network. No linear and quadric trajectory is found in moral cognition network. These findings indicate that SC networks display a wide range of iFC both with the fundamental networks (e.g., somatomotor, vision) and advanced networks (e.g., attention and control) in specific developmental trajectories, which will provide a better understanding of SC neural mechanism and life-span developmental trajectories also give valuable references for SC abnormal detection and effective therapy.
Plasticity manifolds and ion-channel degeneracy govern circadian oscillations of neuronal intrinsic properties in the suprachiasmatic nucleus
Authors: Nagaraj Harshith , Narayanan Rishikesh 
Published: July 2022

ABSTRACTMotivation and methodsThe suprachiasmatic nucleus (SCN) is the master circadian clock of the mammalian brain that sustains a neural code for circadian time through oscillations in the firing rate of constituent neurons. These cell-autonomous oscillations in intrinsic properties are mediated by plasticity in a subset of ion-channels expressed in SCN neurons and are maintained despite widespread neuron-to-neuron variability in ion channel expression profiles. How do SCN neurons undergo stable transitions and maintain precision in intrinsic properties spanning the day-night cycle if several ion channels change concomitantly in a heterogeneous neuronal population? Here, we address this important question using unbiased stochastic searches on the parametric and the plasticity spaces using populations of SCN models, each explored for multiple valid transitions spanning one complete circadian cycle (day-to-night followed by night-to-day transitions).ResultsOur analyses provided three fundamental insights about the impact of heterogeneities on the circadian oscillations of SCN intrinsic properties. First, SCN neurons could achieve signature electrophysiological characteristics (day-like or night-like) despite pronounced heterogeneity in ion channel conductances, with weak pairwise correlations between their conductance values. This ion-channel degeneracy precluded the need to maintain precise ionchannel expression profiles for achieving characteristic electrophysiological signatures of SCN neurons, thus allowing for parametric heterogeneities despite functional precision. Second, it was not essential that specific conductances had to change by precise values for obtaining valid day-to-night or night-to-day transitions. This plasticity degeneracy, the ability of disparate combinations of ion-channel plasticity to yield the same functional transition, confers flexibility on individual neurons to take one of several routes to achieve valid transitions. Finally, we performed nonlinear dimensionality reduction analyses on the valid plasticity spaces and found the manifestation of a low-dimensional plasticity manifold in day-to-night transitions, but not in night-to-day transitions. These observations demonstrated that the concomitant changes in multiple ion channels are not arbitrary, but follow a structured plasticity manifold that provides a substrate for stability in achieving stable circadian oscillations.ImplicationsOur analyses unveil an elegant substrate, involving a synthesis of the degeneracy and the plasticity manifold frameworks, to effectuate stable circadian oscillations in a heterogeneous population of SCN neurons. Within this framework, the ability of multiple ion channels to change concomitantly provides robustness and flexibility to effectively achieve precise transitions despite widespread heterogeneities in ion-channel expression and plasticity.
Extracellular matrix sensing via modulation of orientational order of integrins and F-actin in focal adhesions
Authors: Grudtsyna Valeriia , Packirisamy Swathi , Bidone Tamara , Swaminathan Vinay 
Published: July 2022

AbstractSpecificity of cellular responses to distinct cues from the extracellular matrix (ECM) requires precise and sensitive decoding of information from the cell surface. However, how known mechanisms of mechanosensing such as force dependent catch bonds and conformational changes in focal adhesion (FA) proteins can confer this sensitivity is not known. Using a combination of polarization microscopy and computational modeling, here we identify regulation of orientational order or molecular co-alignment of FA proteins as a mechanism able to precisely tune cell sensitivity to the ECM. We find that αV integrins and F-actin in FAs show changes in orientational order in an ECM-mediated integrin activation dependent manner. This magnitude of orientational order is sensitive to changes in ECM density but independent of myosin-II activity though actomyosin contractility can further fine-tune it. A molecular clutch model for integrin binding ECM ligands demonstrates that orientational order of integrin-ECM binding and catch bonds tune cellular sensitivity to ECM density. This mechanism is also able to decouple ECM density changes from changes in ECM stiffness thus also contributing to specificity. Taken together, our results suggest relative geometric organization of FA components as an important regulator of mechanotransduction.
Morphological evaluation of rat cerebellum following administration of nitrogen monoxide precursor and inhibitor
Authors: Chegini Hamidreza , Chegini Azin , Gholamzad Amir , Sadeghi Hadis , Noori Mougahi Seyed Mohammad Hossein 
Published: July 2022

AbstractIn this study, the quantitative and qualitative effects of nitrogen monoxide on cerebellar histopathology, by increasing or decreasing in vivo production of this substance, were investigated. In this study, forty Wistar female rats (RAT) with a weight of about 200 to 250 grams and an average age of eight weeks were used. Rats were divided into five groups of eight, including control groups, normal saline, L-NAME, L-Arginine, L-NAME + L-Arginine. On the third, fourth and fifth days, the injection was performed intraperitoneally and on the eighteenth day, after anesthesia with ether and then craniotomy, the brain and cerebellum of the animals were removed and After quantitative measurements including weight and volume, organs were fixed in 10% formalin and after tissue preparation steps, to prepare the slide, sections with a thickness of 5 to 6 microns were prepared from the samples and by general method such as Hematoxylin-eosin and special techniques like Mason trichrome and toluidine blue were stained and evaluated. The results of this study show that in the case of cerebellum, there is no significant difference in the quantitative weight parameter between the control groups, normal saline, L-Arg, L-NAME and L-NAME + L-Arg groups. Regarding the volume parameter, a significant increase (P <0.01) was observed in L-Arg group compared to L-NAME, L-Arg + L-NAME and normal saline groups. In microscopic qualitative parameters, the most changes in the L-Arg group were seen as follows: The granular and molecular layers of the cerebellum became slightly thickened, some of the nuclei in the granular and molecular layers became severely hyperchromatized, and Purkinje cell accumulation was seen with lymphocytic invasion. In the other groups, there were no significant changes. It is inferred from this study that L-Arginine can cause histopathological changes in cerebellar tissue by increasing NO levels in cerebellum. However, in this study, unlike other similar studies, L-NAME injection did not cause significant histopathological change.