bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patient Clusters and Cost Trajectories in Atrial Fibrillation: Evidence from the Swiss Atrial Fibrillation Cohort
Authors: Helena Aebersold , Miquel Serra-Burriel , Fabienne Foster-Witassek , Giorgio Moschovitis , Stefanie Aeschbacher , Angelo Auricchio , Beer Jürg H. , Eva Blozik , Bonati Leo H. , David Conen , Stefan Felder , Huber Carola A. , Michael Kühne , Andreas Müller , Jolanda Oberle , Paladini Rebecca E. , Tobias Reichlin , Nicolas Rodondi , Anne Springer , Annina Stauber , Christian Sticherling , Thomas Szucs , Stefan Osswald , Matthias Schwenkglenks 
Published: June 2022

AbstractAimsEvidence on long-term costs of atrial fibrillation (AF) and associated factors is scarce. As part of the Swiss-AF prospective cohort study we aimed to characterise AF costs and their development over time, and to assess specific patient clusters and their cost trajectories.MethodsSwiss-AF enrolled 2,415 patients with variable duration of AF between 2014 and 2017. Patient clusters were identified using hierarchical cluster analysis of baseline characteristics. Ongoing yearly follow-ups include health insurance clinical and claims data. An algorithm was developed to adjudicate costs to AF and related complications.ResultsHierarchical analysis identified three patient clusters. “Cardiovascular-dominated” (CV-dominated) patients had the highest proportions of prior myocardial infarction and presence of diabetes. “Heart failure-dominated” (HF-dominated) patients had the highest occurrence of heart failure and permanent AF. “Isolated symptomatic” (IS) patients were younger and had the highest occurrence of paroxysmal AF. A subpopulation of 1,024 Swiss-AF patients with available claims data was followed up for a median [interquartile range] of 3.24 [1.09] years. Average yearly AF-adjudicated costs amounted to CHF 5,679, remaining stable across the observation period. CV-dominated (N = 253 with claims data) and HF-dominated patients (N = 185) depicted similarly high costs across all cost outcomes, the IS (N = 586) patients accrued the lowest costs.ConclusionOur results highlight three well-differentiated patient clusters with specific costs that could be used for stratification in both clinical and economic studies. Patient characteristics associated with adjudicated costs as well as cost trajectories may enable an early understanding of the magnitude of upcoming AF-related healthcare costs.What is already known on this topicAtrial fibrillation (AF) is a complex disease and constitutes a major economic and societal challenge due to its high prevalence worldwide.What this study addsThis study, based on a large prospective cohort study, provides evidence on real-world AF costs and their development over time. Data-derived patient clusters are linked to costs and their respective cost trajectories are assessed.How this study might affect research, practice or policyThe identified patient clusters and their characteristics may help clinicians and payers to gain an early insight and understanding of the magnitude of the expected AF-related healthcare costs.
Associations between prenatal alcohol and tobacco exposure and cortical and subcortical brain measures in South African children: a pilot study
Authors: Uban Kristina A. , Jonker Deborah , Donald Kirsten A. , Brooks Samantha J. , Bodison Stefanie C. , Kan Eric , Butler-Kruger Letitia , Roos Annerine , Steigelmann Babette , Melly Brigitte , Adise Shana , Marshall Andrew , Narr Katherine L. , Joshi Shantanu H. , Odendaal Hein J. , Sowell Elizabeth R. , Stein Dan J. 
Published: June 2022

AbstractObjectiveThe aim of this pilot study was to assess associations of prenatal alcohol exposure (PAE), prenatal tobacco exposure (PTE), and their interaction and quantity on subsequent cortical and subcortical measures at age 6 years.MethodsMothers with varying levels of alcohol and tobacco exposure at different trimesters during pregnancy were approached when their children (born participating in the Safe Passage Study) were approximately 6 years old. 72 mothers agreed to participate, and 51 children completed brain magnetic resonance imaging (MRI). Brain regions of interest (ROIs) that were significantly associated prior to multiple comparison testing, were examined for associations related to exposure quantity, frequency, and timing (QFT), to explore how patterns of PAE and PTE influence brain outcomes in children. Linear regression was used to identify associations between PAE, PTE, and their interaction with cortical (n = 68 ROIs) and subcortical (n = 40 ROIs) measures.ResultsPrior to correction for multiple comparison testing, both PAE and PTE, as well as their interaction, were associated with a range of cortical and subcortical measures. However, none of these findings survived correction for multiple comparisons. Nevertheless, when exploring quantity of PAE, the total amount of standard drinks consumed during pregnancy and the average number of drinks per drinking day were positively associated with cortical volume in the right fusiform gyrus.ConclusionThese trend results in this pilot study provide preliminary evidence that PAE impacts brain development in unique ways from PTE, and their interactive co-exposure is not a straight forward synergistic or additive effect on the brain.
Measures of Implicit and Explicit Adaptation Do Not Linearly Add
Authors: ’t Hart Bernard Marius , Taqvi Urooj , Gastrock Raphael Q. , Ruttle Jennifer E. , Modchalingam Shanaathanan , Henriques Denise Y.P. 
Published: June 2022

AbstractMoving effectively is essential for any animal. Thus, many different kinds of brain processes likely contribute to learning and adapting movement. How these contributions are combined is unknown. Nevertheless, the field of motor adaptation has been working under the assumption that measures of explicit and implicit motor adaptation can simply be added in total adaptation. While this has been tested, we show that these tests were insufficient. We put this additivity assumption to the test in various ways, and find that measures of implicit and explicit adaptation are not additive. This means that future studies should measure both implicit and explicit adaptation directly. It also challenges us to disentangle how various motor adaptation processes do combine when producing movements, and may have implications for our understanding of other kinds of learning as well. (data and code:https://osf.io/dh86e)
Conscientiousness associated with efficiency of the salience/ventral attention network: Replication in three samples using individualized parcellation
Authors: Sassenberg Tyler A. , Burton Philip C. , Mwilambwe-Tshilobo Laetitia , Jung Rex E. , Rustichini Aldo , Spreng R. Nathan , DeYoung Colin G. 
Published: June 2022

AbstractPrevious research in the field of personality neuroscience has identified associations of conscientiousness and related constructs like impulsivity and self-control with structural and functional properties of particular regions in the prefrontal cortex (PFC) and insula. Network- based conceptions of brain function suggest that these regions probably belong to a single large- scale network, labeled the salience/ventral attention network (SVAN). The current study tested associations between conscientiousness and resting-state functional connectivity in this network using two community samples (N = 244 and 239) and data from the Human Connectome Project (N = 1000). Individualized parcellation was used to improve the accuracy of functional localization and to facilitate replication. Functional connectivity was measured using an index of network efficiency, a graph theoretical measure quantifying the capacity for parallel information transfer within a network. Efficiency of a set of parcels in the SVAN was significantly associated with conscientiousness in all samples. Findings are consistent with a theory of conscientiousness as a function of variation in neural networks underlying effective prioritization of goals.
Age-related learning and working memory impairment in the common marmoset
Authors: Glavis-Bloom Courtney , Vanderlip Casey R , Reynolds John H 
Published: June 2022

AbstractAging is the greatest risk factor for the development of neurodegenerative diseases, yet we still do not understand how the aging process leads to pathological vulnerability. The research community has relied heavily on mouse models, but the considerable anatomical, physiological, and cognitive differences between mice and humans limit their translational relevance. Ultimately, these barriers necessitate the development of novel aging models. As a non-human primate, the common marmoset (Callithrix jacchus) shares many features in common with humans and yet has a significantly shorter lifespan (10 years) than other primates, making it ideally suited to longitudinal studies of aging. Our objective was to evaluate the marmoset as a model of age-related cognitive impairment. To do this, we utilized the Delayed Recognition Span Task (DRST) to characterize age-related changes in working memory capacity in a cohort of sixteen marmosets varying in age from young adult to geriatric. These monkeys performed thousands of trials over periods of time ranging up to 50 percent of their adult lifespan. To our knowledge, this represents the most thorough cognitive profiling of any marmoset aging study conducted to-date. By analyzing individual learning curves, we found that aged animals exhibited delayed onset of learning, slowed learning rate after onset, and decreased asymptotic working memory performance. These findings are not accounted for by age-related impairments in motor speed and motivation. This work firmly establishes the marmoset as a model of age-related cognitive impairment.Significance StatementUnderstanding the normal aging process is fundamental to identifying therapeutics for neurodegenerative diseases for which aging is the biggest risk factor. Historically, the aging field has relied on animal models that differ markedly from humans, constraining translatability. Here, we firmly establish a short-lived non-human primate, the common marmoset, as a key model of age-related cognitive impairment. We demonstrate, through continuous testing over a substantial portion of the adult marmoset lifespan, that aging is associated with both impaired learning and working memory capacity, unaccounted for by age-related changes in motor speed and motivation. Characterizing individual cognitive aging trajectories reveals inherent heterogeneity, which could lead to earlier identification of the onset of impairment, and extended timelines during which therapeutics are effective.
Prediction of cancer treatment response from histopathology images through imputed transcriptomics
Authors: Hoang Danh-Tai , Dinstag Gal , Hermida Leandro C. , Ben-Zvi Doreen S. , Elis Efrat , Caley Katherine , Sammut Stephen-John , Sinha Sanju , Sinha Neelam , Dampier Christopher H. , Stossel Chani , Patil Tejas , Rajan Arun , Lassoued Wiem , Strauss Julius , Bailey Shania , Allen Clint , Redman Jason , Beker Tuvik , Jiang Peng , Golan Talia , Wilkinson Scott , Sowalsky Adam G. , Pine Sharon R. , Caldas Carlos , Gulley James L. , Aldape Kenneth , Aharonov Ranit , Stone Eric A. , Ruppin Eytan 
Published: June 2022

ABSTRACTAdvances in artificial intelligence have paved the way for leveraging hematoxylin and eosin (H&E)-stained tumor slides for precision oncology. We present ENLIGHT-DeepPT, an approach for predicting response to multiple targeted and immunotherapies from H&E-slides. In difference from existing approaches that aim to predict treatment response directly from the slides, ENLIGHT-DeepPT is an indirect two-step approach consisting of (1) DeepPT, a new deep-learning framework that predicts genome-wide tumor mRNA expression from slides, and (2) ENLIGHT, which predicts response based on the DeepPT inferred expression values. DeepPT successfully predicts transcriptomics in all 16 TCGA cohorts tested and generalizes well to two independent datasets. Importantly, ENLIGHT-DeepPT successfully predicts true responders in five independent patients’ cohorts involving four different treatments spanning six cancer types with an overall odds ratio of 2.44, increasing the baseline response rate by 43.47% among predicted responders, without the need for any treatment data for training. Furthermore, its prediction accuracy on these datasets is comparable to a supervised approach predicting the response directly from the images, trained and tested on the same cohort in cross validation. Its future application could provide clinicians with rapid treatment recommendations to an array of different therapies and importantly, may contribute to advancing precision oncology in developing countries.Statement of SignificanceENLIGHT-DeepPT is the first approach shown to successfully predict response tomultipletargeted and immune cancer therapies from H&E slides. In distinction from all previous H&E slides prediction approaches, it does not require supervised training on a specific cohort for each drug/indication treatment but is trained to predict expression on the TCGA cohort and then can predict response to an array of treatments without any further training. ENLIGHT-DeepPT can provide rapid treatment recommendations to oncologists and help advance precision oncology in underserved regions and low-income countries.
Discovery of synapse-specific RNA N6-methyladenosine readers associated with the consolidation of fear extinction memory
Authors: Madugalle Sachithrani U. , Liau Wei-Siang , Zhao Qiongyi , Li Xiang , Gong Hao , Marshall Paul R. , Periyakaruppiah Ambika , Zajackowski Esmi L. , Leighton Laura J. , Ren Haobin , Musgrove Mason , Davies Joshua , Rauch Simone , He Chuan , Dickinson Bryan C. , Fletcher Lee , Fulopova Barbora , Williams Stephen R. , Spitale Robert C. , Bredy Timothy W. 
Published: June 2022

SummaryThe RNA modification N6-methyladenosine (m6A) is critically involved in the regulation of gene activity underlying experience-dependent plasticity, and is necessary for the functional interplay between RNA and RNA binding proteins (RBPs) in the nucleus. However, the complete repertoire of m6A-modified RNA interacting RBPs in the synaptic compartment, and whether they are involved in fear extinction, have yet to be revealed. Using RNA immunoprecipitation followed by mass spectrometry, we discovered 12 novel, synapsespecific, learning-induced m6A readers in the medial prefrontal cortex of male C57/B6 mice. m6A RNA-sequencing also revealed a unique population of learning-related m6A-modified RNAs at the synapse, which includes a variant of the long non-coding RNA (lncRNA) metastasis associated lung adenocarcinoma transcript 1 (Malat1). m6A-modified Malat1 binds to a subset of novel m6A readers, including cytoplasmic FMR1 interacting protein 2 (CYFIP2) and dihydropyrimidase-related protein 2 (DPYSL2) and a cell-type-specific, state-dependent, and synapse-specific reduction in m6A-modified Malat1 disrupts the interaction between Malat1 and DPYSL2 and impairs fear extinction. The consolidation of fear-extinction memory therefore relies on an interaction between m6A-modified Malat1 and select RBPs in the synaptic compartment.
A model of coevolution and local adaptation between hosts and parasites in continuous space
Authors: Week Bob , Bradburd Gideon 
Published: June 2022

AbstractPrevious host-parasite coevolutionary theory has focused on understanding the determinants of local adaptation using spatially discrete models. However, these studies fall short of describing patterns of host-parasite local adaptation across spatial scales. In contrast, empirical work demonstrates patterns of adaptation depend on the scale at which they are measured. Here, we propose a model of host-parasite coevolution in continuous space that naturally leads to a scale-dependent definition of local adaptation and a formal definition for the spatial scale of coevolution. In agreement with empirical findings, our model implies patterns of adaptation vary across spatial scales. When measured on spatial scales shorter than the scale of coevolution, we find the farther dispersing species is locally adapted. However, when measured at longer spatial scales, the opposite pattern is observed. We discuss our results in relation to those found using spatially discrete models and to conclusions drawn from empirical studies, and provide an example of our how our results can be used to inform the design of empirical studies.
Neurometabolic timecourse of healthy aging
Authors: Gong Tao , Hui Steve C.N. , Zöllner Helge J. , Britton Mark , Song Yulu , Chen Yufan , Gudmundson Aaron T. , Hupfeld Kathleen E. , Murali-Manohar Saipavitra , Porges Eric C. , Oeltzschner Georg , Chen Weibo , Wang Guangbin , Edden Richard A. E. 
Published: June 2022

AbstractPurposeThe neurometabolic timecourse of healthy aging is not well-established, in part due to diversity of quantification methodology. In this study, a large structured cross-sectional cohort of male and female subjects throughout adulthood was recruited to investigate neurometabolic changes as a function of age, using consensus-recommended magnetic resonance spectroscopy quantification methods.Methods102 healthy volunteers, with approximately equal numbers of male and female participants in each decade of age from the 20s, 30s, 40s, 50s, and 60s, were recruited with IRB approval. MR spectroscopic data were acquired on a 3T MRI scanner. Metabolite spectra were acquired using PRESS localization (TE = 30 ms; 96 transients) in the centrum semiovale (CSO) and posterior cingulate cortex (PCC). Water-suppressed spectra were modeled using the Osprey algorithm, employing a basis set of 18 simulated metabolite basis functions and a cohort-mean measured macromolecular spectrum. Pearson correlations were conducted to assess relationships between metabolite concentrations and age for each voxel; paired t-tests were run to determine whether metabolite concentrations differed between the PCC and CSO.ResultsTwo datasets were excluded (1 ethanol; 1 unacceptably large lipid signal). Statistically significant age-by-metabolite correlations were seen for tCr (R2=0.36; p<0.001), tCho (R2=0.11; p<0.001), sI (R2=0.11; p=0.004), and mI (R2=0.10; p<0.001) in the CSO, and tCr (R2=0.15; p<0.001), tCho (R2=0.11; p<0.001), and GABA (R2=0.11; p=0.003) in the PCC. No significant correlations were seen between tNAA, NAA, GSH, Glx or Glu and age in either region (all p>0.25). Levels of sI were significantly higher in the PCC in female subjects (p<0.001) than in male subjects. There was a significant positive correlation between linewidth and age.ConclusionThe results indicated age correlations for tCho, tCr, sI, and mI in CSO and for tCr, tCho and GABA in PCC, while no age-related changes were found for NAA, tNAA, GSH, Glu or Glx. Our results provide a normative foundation for future work investigating the neurometabolic time course of healthy aging using MRS.HighlightsA large structured cross-sectional cohort of neurometabolic aging dataset is presented;Age correlations were observed for tCho, tCr, sI, and mI in CSO and for tCr, tCho and GABA in PCC;No age correlations were found for NAA, tNAA, GSH, Glu or Glx in either region.
Better together against genetic effect heterogeneity: a sex-combined interaction analysis of testosterone levels in the UK Biobank data
Authors: Lin Boxi , Sun Lei 
Published: June 2022

ABSTRACTThe effect of a genetic variant on a complex trait may differ between female and male, and in the presence of such genetic effect heterogeneity, sex-stratified analysis is often used. For example, genetic effects are sex-specific for testosterone levels, and sex-stratified analysis of testosterone in literature provided easy-to-interpret, sex-specific effect size estimates. However, from the perspective of association testing power, sex-stratified analysis may not be the best approach. As sex-specific genetic effect implies SNP×Sex interaction effect, jointly testing SNP main and SNP×Sex interaction effects may be more powerful than sex-stratified analysis or the standard main-effect testing approach. Moreover, since individual data may be unavailable, it is then of interest to study if the interaction analysis can be derived from sex-stratified summary statistics. We considered several different sex-combined methods and evaluated them through extensive simulation studies. We observed that a) the joint SNP main and SNP×Sex interaction analysis is most robust to a wide range of genetic models, and b) this joint interaction testing result can be obtained by quadratically combining sex-stratified summary statistics (i.e. squared sum of the sex-stratified summary statistics). We then reanalysed the testosterone levels of the UK Biobank data using sex-combined interaction analysis, which identified 27 new loci that were missed by the sex-stratified approach and the standard sex-combined analysis. Finally, we provide supporting association evidence for nine new loci, uniquely identified by the sex-combined interaction analysis, from earlier association studies of either testosterone level or steroid biosynthesis pathway where testosterone is synthesized. We thus recommend sex-combined interaction analysis, particularly for traits with known sex differences, for most powerful association testing, then followed by sex-stratified analysis for effect size estimation and interpretation.
Endogenous GDF15 and FGF21 additively alleviate hepatic steatosis and insulin resistance in obese mice
Authors: Patel Satish , Haider Afreen , Alvarez-Guaita Anna , Bidault Guillaume , El-sayed Moustafa Julia Sarah , Guiu-Jurado Esther , Tadross John A. , Warner James , Harrison James , Virtue Samuel , Scurria Fabio , Zvetkova Ilona , Blüher Matthias , Small Kerrin S. , O’Rahilly Stephen , Savage David B. 
Published: June 2022

SummaryObesity in mice and humans is associated with elevated levels of at least two hormones responsive to cellular stress, namely GDF15 and FGF21. Over-expression of each of these is associated with weight loss and beneficial metabolic changes but where they are secreted from and what they are required for physiologically in the context of overfeeding remains unclear. Here we used tissue selective knockout mouse models to establish that, like FGF21, circulating GDF15 is primarily derived from the liver, rather than adipose tissue, muscle or macrophages in high fat fed mice. Combined whole body deletion of FGF21 and GDF15 does not result in any additional weight gain in high fat fed mice but is associated with significantly greater hepatic steatosis and insulin resistance. Collectively the data suggest that activation of the integrated stress response in hepatocytes is a major driver for GDF15 and FGF21 secretion in the context of overfeeding, and that they both act to alleviate this metabolic stress.