bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fibrinogen supplementation for the trauma patient: Should you choose fibrinogen concentrate over cryoprecipitate?
Authors: Obaid Omar , Anand Tanya , Nelson Adam , Reina Raul , Ditillo Michael , Stewart Collin , Douglas Molly , Friese Randall , Gries Lynn , Joseph Bellal 
Published: July 2022

BACKGROUND
Trauma-induced coagulopathy is frequently associated with hypofibrinogenemia. Cryoprecipitate (Cryo), and fibrinogen concentrate (FC) are both potential means of fibrinogen supplementation. The aim of this study was to compare the outcomes of traumatic hemorrhagic patients who received fibrinogen supplementation using FC versus Cryo.

METHODS
We performed a 2-year (2016–2017) retrospective cohort analysis of the American College of Surgeons Trauma Quality Improvement Program database. All adult trauma patients (≥18 years) who received FC or Cryo as an adjunct to resuscitation were included. Patients with bleeding disorders, chronic liver disease, and those on preinjury anticoagulants were excluded. Patients were stratified into those who received FC, and those who received Cryo. Propensity score matching (1:2) was performed. Outcome measures were transfusion requirements, major complications, hospital, and intensive care unit lengths of stay, and mortality.

RESULTS
A matched cohort of 255 patients who received fibrinogen supplementation (85 in FC, 170 in Cryo) was analyzed. Overall, the mean age was 41 ± 19 years, 74% were male, 74% were white and median Injury Severity Score was 26 (22–30). Compared with the Cryo group, the FC group required less units of packed red blood cells, fresh frozen plasma, and platelets, and had shorter in-hospital and intensive care unit length of stay. There were no significant differences between the two groups in terms of major in-hospital complications and mortality.

CONCLUSION
Fibrinogen supplementation in the form of FC for the traumatic hemorrhagic patient is associated with improved outcomes and reduced transfusion requirements as compared with Cryo. Further studies are required to evaluate the optimal method of fibrinogen supplementation in the resuscitation of trauma patients.

LEVEL OF EVIDENCE
Therapeutic/Care Management; Level III.
Genome-wide methylation analysis of early-onset schizophrenia
Authors: Srivastava Anil , Chaudhary Zanib , Qian Jessica , Al Chalabi Nzaar , Burhan Amer M. , Fischer Corinne E. , Gerretsen Philip , Kolla Nathan J. , Graff Ariel , Remington Gary , De Luca Vincenzo 
Published: July 2022

Objective
Schizophrenia (SCZ) is a debilitating disease with a complex genetic cause in which age at onset may reflect genetic vulnerability. Though there has been some association between genetic polymorphisms and age of onset, there has been little exploration of the role of epigenetic processes. We sought to explore the influence of DNA methylation, a key epigenetic mechanism, and its association with the age of onset of illness.

Methods
One hundred thirty-eight participants aged 18–75 years and previously diagnosed with SCZ spectrum disorders by the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders (SCID DSM-5) were recruited. Venous blood was collected and genome-wide DNA methylation was quantified using the Illumina Infinium HumanMethylation450 BeadChip array. Individual CpG sites and regions of differential methylation were explored by the age of onset; covariates included age, sex, as well as white blood cell composition.

Results
Binary grouping (early vs. late onset) revealed four intergenic CpG sites on chromosome 2 that were above the expected P-value threshold, with hypermethylation of the CpG site cg10392614 most strongly associated with early-onset SCZ. The four most strongly associated CpG sites, including cg 10392614, were intergenic. Continuous analysis revealed the top CpG site to be cg11723066, which is linked to the JAM3 gene, with hypomethylation associated with earlier onset; however, results were below the expected P-value threshold.

Conclusion
Studies on DNA methylation in the first-episode psychosis population may help further our understanding of the role of epigenetics in the age of onset of SCZ.
Single-nucleus RNA-seq reveals disrupted cell maturation by chorioamnionitis in the preterm cerebellum of nonhuman primates
Authors: Newman Josef , Tong Xiaoying , Tan April , De Paiva Vanessa Nunes , Presicce Pietro , Kannan Paranthaman S , Williams Kevin , Damianos Andreas , Newsam Marione Tamase , Benny Merline , Wu Shu , Young Karen , Miller Lisa A. , Kallapur Suhas G , Chougnet Claire A , Jobe Alan H , Brambilla Roberta , Schmidt Augusto F. 
Published: July 2022

AbstractPreterm birth is often associated with chorioamnionitis and increased risk of neurodevelopmental disorders. Preterm birth also leads to cerebellar underdevelopment but the mechanisms of disrupted cerebellar development in preterm infants are little understood. Here, we leveraged single-nuclei RNA-sequencing of the cerebellum in a rhesus macaque model of chorioamnionitis and preterm birth, to show that chorioamnionitis leads to Purkinje cell loss and disrupted maturation of granule cells and oligodendrocytes in the fetal cerebellum at late gestation. Purkinje cell loss is accompanied by decreased sonic hedgehog signaling from Purkinje cells to granule cells, which show an accelerated maturation. Chorioamnionitis also accelerated pre-oligodendrocyte maturation into myelinating oligodendrocytes, confirmed by increased expression of myelin basic protein in the cerebellum of chorioamnionitis-exposed fetuses. These findings are consistent with reported histopathological findings in individuals with autism and suggest a novel mechanism through which perinatal inflammation contributes to neurodevelopmental disorders.
Bayesian Shrinkage Priors in Zero-Inflated and Negative Binomial Regression models with Real World Data Applications of COVID-19 Vaccine, and RNA-Seq
Authors: Bhattacharyya Arinjita , Mitra Riten , Rai Shesh , Pal Subhadip 
Published: July 2022

AbstractBackgroundCount data regression modeling has received much attention in several science fields in which the Poisson, Negative binomial, and Zero-Inflated models are some of the primary regression techniques. Negative binomial regression is applied to modeling count variables, usually when they are over-dispersed. A Poisson distribution is also utilized for counting data where the mean is equal to the variance. This situation is often unrealistic since the distribution of counts will usually have a variance that is not equal to its mean. Modeling it as Poisson distributed leads to ignoring under- or overdispersion, depending on if the variance is smaller or larger than the mean. Also, situations with outcomes having a larger number of zeros such as RNASeq data require Zero-inflated models. Variable selection through shrinkage priors has been a popular method to address the curse of dimensionality and achieve the identification of significant variables.MethodsWe present a unified Bayesian hierarchical framework that implements and compares shrinkage priors in negative-binomial and zero-inflated negative binomial regression models. The key feature is the representation of the likelihood by a Polya-Gamma data augmentation, which admits a natural integration with a family of shrinkage priors. We specifically focus on the Horseshoe, Dirichlet Laplace, and Double Pareto priors. Extensive simulation studies address the efficiency of the model and mean square errors are reported. Further, the models are applied to data sets such as the Covid-19 vaccine, and Covid-19 RNA-Seq data among others.ResultsThe models are robust enough to address variable selection, and MSE decreases as the sample size increases, having lower errors inp > ncases. The noteworthy results showed that the adverse events of Covid-19 vaccines were dependent on age, recovery, medical history, and prior vaccination with a remarkable reduction in MSE of the fitted values. No. of publications of Ph.D. students were dependent on the no. of children, and the no. of articles in the last three years.ConclusionsThe models are robust enough to conduct both variable selections and produce effective fit because of their high shrinkage property and applicability to a broad range of biometric and public health high dimensional problems.
Time-Dependent Maximum Entropy Model for Populations of Retinal Ganglion Cells†
Authors: Delamare Geoffroy , Ferrari Ulisse 
Published: July 2022

AbstractThe inverse Ising model is used in computational neuroscience to infer probability distributions of the synchronous activity of large neuronal populations. This method allows for finding the Boltzmann distribution with single neuron biases and pairwise interactions that maximizes the entropy and reproduces the empirical statistics of the recorded neuronal activity. Here we apply this strategy to large populations of retinal output neurons (ganglion cells) of different types, stimulated by multiple visual stimuli with their own statistics. The activity of retinal output neurons is driven by both the inputs from upstream neurons, which encode the visual information and reflect stimulus statistics, and the recurrent connections, which induce network effects. We first apply the standard inverse Ising model approach, and show that it accounts well for the system’s collective behavior when the input visual stimulus has short-ranged spatial correlations, but fails for long-ranged ones. This happens because stimuli with long-ranged spatial correlations synchronize the activity of neurons over long distances. This effect cannot be accounted for by pairwise interactions, and so by the pairwise Ising model. To solve this issue, we apply a previously proposed framework that includes a temporal dependence in the single neurons biases to model how neurons are driven in time by the stimulus. Thanks to this addition, the stimulus effects are taken into account by the biases, and the pairwise interactions allow for characterizing the network effect in the population activity and for reproducing the structure of the recurrent functional connections in the retinal architecture. In particular, the inferred interactions are strong and positive only for nearby neurons of the same type. Inter-type connections are instead small and slightly negative. Therefore, the retinal architecture splits into weakly interacting subpopulations composed of strongly interacting neurons. Overall, this temporal framework fixes the problems of the standard, static, inverse Ising model and accounts for the system’s collective behavior, for stimuli with either short or long-range correlations.
Brightness illusions evoke pupil constriction and a preceding primary visual cortex response in rats
Authors: Vasilev Dmitrii , Raposo Isabel , Totah Nelson K. 
Published: July 2022

AbstractThe mind affects the body via central nervous system (CNS) control of the autonomic nervous system (ANS). In humans, one striking illustration of the mind-body connection is that illusions, subjectively perceived as bright, drive constriction of the eye’s pupil by activating the sympathetic arm of the ANS. How the CNS is involved in this pupil response is unknown and requires an animal model for intracerebral investigation of potential regions, cell types, and neuronal projections. However, the physiological response to this illusion has long been thought to occur only in humans. Here, we report that the same brightness illusion that evokes pupil constriction in humans also does so in rats. Cortex-wide EEG recordings revealed that, compared to a luminance-matched control stimulus, the illusion (which appears subjectively brighter to humans) evoked a larger response only in primary visual cortex (V1). This cortical response preceded pupil constriction by ~335 msec suggesting a potential causal role for V1 on the pupil. Our results establish a new animal model of importance for studying how the CNS response involved in sensing a brightness illusion drives a physiological reaction in the body. We provide objective evidence that complex mind-body connections are not confined to humans and that V1 may be part of a shared, mammalian, neural network for bodily reactions to illusions.
Studying the age of onset and detection of Chronic Myeloid Leukemia using a three-stage stochastic model
Authors: Nag Suryadeepto , Bhat Ananda Shikhara , Chakrabarty Siddhartha P. 
Published: July 2022

AbstractChronic Myeloid Leukemia (CML) is a biphasic malignant clonal disorder that progresses, first with a chronic phase, where the cells have enhanced proliferation only, and then to a blast phase, where the cells have the ability of self-renewal. It is well-recognized that the Philadelphia chromosome (which contains the BCR-ABL fusion gene) is the “hallmark of CML”. However, empirical studies have shown that the mere presence of BCR-ABL may not be a sufficient condition for the development of CML, and further modifications related to tumor suppressors may be necessary. Accordingly, we develop a three-mutation stochastic model of CML progression, with the three stages corresponding to the non-malignant cells with BCR-ABL presence, the malignant cells in the chronic phase and the malignant cells in the blast phase. We demonstrate that the model predictions agree with age incidence data from the United States. Finally, we develop a framework for the retrospective estimation of the time of onset of malignancy, from the time of detection of the cancer.
Optimization of 4D Combined Angiography and Perfusion using Radial Imaging and Arterial Spin Labeling
Authors: Okell Thomas W. , Chiew Mark 
Published: July 2022

AbstractPurposeTo extend and optimize a non-contrast MRI technique to obtain whole head 4D (time-resolved 3D) angiographic and perfusion images from a single scan.Methods4D combined angiography and perfusion using radial imaging and arterial spin labeling (CAPRIA) uses pseudocontinuous labeling with a 3D golden ratio (“koosh ball”) readout to continuously image the blood water as it travels through the arterial system and exchanges into the tissue. High spatial/temporal resolution angiograms and low spatial/temporal resolution perfusion images can be flexibly reconstructed from the same raw k-space data at any timepoint within the readout. A constant flip angle (CFA) and a quadratic variable flip angle (VFA) excitation schedule were optimized through simulations and tested in healthy volunteers. A conventional sensitivity encoding (SENSE) reconstruction was compared against a locally low rank (LLR) reconstruction, which leverages spatiotemporal correlations to improve reconstruction quality. Differences in image quality were assessed through split-scan repeatability.ResultsThe optimized VFA schedule (2-9°) reduced initial signal attenuation whilst boosting the signal at later timepoints, resulting in a significant (p < 0.001) improvement in image quality (up to 84%), particularly for the lower SNR perfusion images. The LLR reconstruction provided effective denoising without biasing the signal timecourses, significantly improving angiographic and perfusion imaging repeatability (up to 143%, p < 0.001) and enabling the clear depiction of small distal vessels and late tissue perfusion.Conclusion4D CAPRIA can be optimized using a VFA schedule and LLR reconstruction to yield whole head 4D angiograms and perfusion images from a single scan.
Analysis of Chromatin Data Supports a Role For CD14+ Monocytes/Macrophages in Mediating Genetic Risk for Juvenile Idiopathic Arthritis
Authors: Crinzi Elizabeth A. , Haley Emma K. , Poppenberg Kerry E. , Jiang Kaiyu , Tutino Vincent M. , Jarvis James N. 
Published: July 2022

AbstractIntroductionGenome wide association studies (GWAS) have identified multiple regions that confer genetic risk for the polyarticular/oligoarticular forms of juvenile idiopathic arthritis (JIA). However, genome-wide scans do not identify the cells impacted by genetic polymorphisms on the risk haplotypes or the genes impacted by those variants. We have shown that genetic variants driving JIA risk are likely to affect both innate and adaptive immune functions. We provide additional evidence that JIA risk variants impact innate immunity.Materials and MethodsWe queried publicly available H3K4me1/H3K27ac ChIP-seq data in CD14+ monocytes to determine whether the linkage disequilibrium (LD) blocks incorporating the SNPs that tag JIA risk loci showed enrichment for these epigenetic marks. We also queried monocyte/macrophage GROseq data, a functional readout of active enhancers. We defined the topologically associated domains (TADs) encompassing enhancers on the risk haplotypes and identified genes within those TADs expressed in monocytes. We performed ontology analyses of these genes to identify cellular processes that may be impacted by these variants. We also used whole blood RNAseq data from the Genotype-Tissue Expression (GTEx) data base to determine whether SNPs lying within monocyte GROseq peaks influence plausible target genes within the TADs encompassing the JIA risk haplotypes.ResultsThe LD blocks encompassing the JIA genetic risk regions were enriched for H3K4me1/H3K27ac ChIPseq peaks (p=0.00021 and p=0.022) when compared to genome background. Eleven and sixteen JIA were enriched for resting and activated macrophage GROseq peaks, respectively risk regions (p=0.04385 and p=0.00004). We identified 321 expressed genes within the TADs encompassing the JIA haplotypes in human monocytes. Ontological analysis of these genes showed enrichment for multiple immune functions. Finally, we found that SNPs lying within the GROseq peaks are strongly associated with expression levels of plausible target genes in human whole blood.ConclusionsThese findings support the idea that both innate and adaptive immunity are impacted by JIA genetic risk variants.
Long read single cell RNA sequencing reveals the isoform diversity of Plasmodium vivax transcripts
Authors: Hazzard Brittany , Sá Juliana M. , Ellis Angela C. , Pascini Tales V. , Amin Shuchi , Wellems Thomas E. , Serre David 
Published: July 2022

AbstractPlasmodium infections often consist of heterogenous populations of parasites at different developmental stages and with distinct transcriptional profiles, which complicates gene expression analyses. The advent of single cell RNA sequencing (scRNA-seq) enabled disentangling this complexity and has provided robust and stage-specific characterization of Plasmodium gene expression. However, scRNA-seq information is typically derived from the end of each mRNA molecule (usually the 3’-end) and therefore fails to capture the diversity in transcript isoforms documented in bulk RNA-seq data. Here, we describe the sequencing of scRNA-seq libraries using Pacific Biosciences (PacBio) chemistry to characterize full-length Plasmodium vivax transcripts from single cell parasites. Our results show that many P. vivax genes are transcribed into multiple isoforms, primarily through variations in untranslated region (UTR) length or splicing, and that the expression of these isoforms is often developmentally regulated. Our findings demonstrate that long read sequencing can be used to characterize mRNA molecules at the single cell level and provides an additional resource to better understand the regulation of gene expression throughout the Plasmodium life cycle.Author SummarySingle cell RNA-sequencing is a valuable tool for identifying cell specific differences in heterogenous populations. However, scRNA-seq has limitations in assigning reads to genes of organisims with poorly annotated UTRs, due to the poly-A caputre utilized by some scRNA-seq technologies, this technical limitation also makes identifying transcript specific differences, like alternative splicing, difficult. Despite its importance in human disease the P. vivax genome annotation is still relatively sparce, especially in the UTRs, and very little is known about transcript differece in the different life stages of the parasite life cycle. Here, we utilize a modified version of 10X scRNA-seq technology to capture full length transcripts via PacBio sequencing from both sporozoite and blood stages of P. vivax. This allowed us to predict full length stage specific transcripts for P. vivax as well as identify important variation in the previously poorly annotated UTRs. These findings will aide in futhering our understanding of P. vivax transcript regulation across the life cycle stages.
Regulation of sleep quantity and intensity by long and short isoforms of SLEEPY kinase
Authors: Xu Junjie , Zhou Rui , Wang Guodong , Guo Ying , Gao Xue , Zhou Shuang , Ma Chengyuan , Chen Lin , Shi Bihan , Wang Haiyan , Wang Fengchao , Liu Qinghua 
Published: July 2022

AbstractIn Sleepy (Sik3Slp) or Sik3S551A mice, deletion or mutation of inhibitory phosphorylation site serine551 (S551) from salt-inducible kinase 3 (SIK3) markedly increases daily non-rapid eye movement sleep (NREMS) amount, accompanied with constitutively elevated NREMS delta power density–a measure of sleep intensity or quality. Multiple SLP/SIK3 isoforms are expressed in mouse brain neurons, however, their respective roles in sleep regulation remain to be elucidated. Here, we identified a new and most abundant short isoform of SLP/SIK3 and examined sleep phenotypes resulted from isoform-specific expression of SLP-short (S) and long (L) isoforms. Adeno-associated virus-mediated adult brain chimeric (ABC)-expression of SLP-S in neurons, but not in astrocytes, significantly and constitutively elevates NREMS delta power, whereas slightly increases NREMS amount. The ability of SLP-S to regulate sleep quantity/intensity is abrogated by kinase-inactivating mutations, suggesting that the sleep-promoting activity of SLP-S is dependent on its kinase activity. In Sik3S551A-L knock-in mice, isoform-specific expression of SIK3S551A-L (or SLP-L) significantly increases NREMS amount with a modest effect on NREMS delta power. ABC-expression of SLP-S complements the sleep phenotypes of heterozygous Sik3S551A-L mice by further increasing NREMS amount and NREMS delta power to levels of Sik3Slp or Sik3S551A mice. Taken together, these results indicate that both SLP-L and SLP-S isoforms contribute critically to the increases of sleep quantity and intensity in Sik3Slp or Sik3S551A mice.Statement of SignificancePrevious studies have identified SIK3 as a key sleep regulatory kinase, of which gain-of-function mutations markedly increase sleep quantity and intensity in Sleepy mice. Multiple SLEEPY isoforms are expressed in mouse brain neurons, but their respective contributions to the hypersomnia phenotypes of Sleepy mice remain unclear. Here, we identified a new short isoform of SLP/SIK3 and examined sleep phenotypes resulted from specific expression of SLEEPY-short or long isoform. Our results indicate that both long and short isoforms of SLEEPY kinase contribute critically to increases of sleep quantity and intensity in Sleepy mice. Future studies are needed to identify downstream substrates of SLEEPY kinase that mediate regulation of sleep quantity/intensity, which should facilitate development of new treatments for human sleep disorders.