bluuebunny/crossref_metadata_2025_split huggingface dataset:
Procollagen C-Proteinase Enhancer 1 (PCPE-1) is a marker of myocardial fibrosis and impaired cardiac function in a murine model of pressure overload
Authors: Lagoutte Priscillia , Oudot Alexandra , Dussoyer Mélissa , Goncalves Victor , Guillemin Mélanie , Bouchot Olivier , Vandroux David , Bellaye Pierre-Simon , Moali Catherine , Goff Sandrine Vadon-Le 
Published: March 2021

Abstract(1)AimsProcollagen C-proteinase enhancer 1 (PCPE-1) is an extracellular matrix protein and a major regulator of fibrillar collagen biosynthesis. Previous work has shown that its abundance is often increased in the context of tissue repair and fibrosis. The present study was designed to evaluate its potential as a biomarker of myocardial interstitial fibrosis (MIF), a well-established pathogenic pathway leading to heart failure.(2)Methods and ResultsCardiac fibrosis was induced in rats using an optimized model of chronic pressure overload triggered by angiotensin II and Nω-nitro-L-arginine methyl ester (L-NAME). All treated animals suffered from heart hypertrophy and the increase in heart collagen volume fraction (CVF), evidenced by histology and68Ga-Collagelin uptake, confirmed the development of cardiac fibrosis. Functional analysis by simultaneous PET-MRI further showed that our model closely reflected the pathological features seen in human MIF, including left ventricle thickening and diastolic dysfunction associated with decreased ejection fraction. PCPE-1 mRNA and protein levels were augmented by factors of 3.4 and 6.1 respectively in the heart tissue of treated rats. Moreover, protein abundance was well-correlated with CVF (r=0.92, p<0.0001) and PCPE-1 immuno-detection mainly localized the protein to fibrotic areas. Finally, PCPE-1 plasma levels measured by ELISA were increased in fibrotic rats compared to controls.(3)ConclusionTogether, our findings demonstrate that PCPE-1 levels in the heart and circulation tightly reflect the cardiac fibrosis status and heart function impairment in rats and suggest that it could be a very useful marker to monitor human heart diseases leading to fibrosis.
TCRβrearrangements without D-segment are common, abundant and public
Authors: de Greef Peter C. , de Boer Rob J. 
Published: March 2021

AbstractT cells play an important role in adaptive immunity. An enormous clonal diversity of T-cells with a different specificity, encoded by the T-cell receptor (TCR), protect the body against infection. Most TCRβchains are generated from a V-, D-, and J-segment during recombination in the thymus. Although complete absence of the D-segment is not easily detectable from sequencing data, we find convincing evidence for a substantial proportion of TCRβrearrangements lacking a D-segment. Additionally, sequences without a D-segment are more likely to be abundant within individuals and/or shared between individuals. We find that such sequences are preferentially generated during fetal development and persist within the elderly. Summarizing, TCRβrearrangements without a D-segment are not uncommon, and tend to allow for TCRβchains with a high abundance in the naive repertoire.
Interleukin-17A causes osteoarthritis-like transcriptional changes in human osteoarthritis-derived chondrocytes and synovial fibroblastsin vitro
Authors: Mimpen Jolet Y. , Baldwin Mathew J. , Cribbs Adam P. , Philpott Martin , Carr Andrew J. , Dakin Stephanie G. , Snelling Sarah J.B. 
Published: March 2021

AbstractIncreased interleukin (IL)-17A has been identified in joints affected by osteoarthritis (OA), but it is unclear how IL-17A, and its family members IL-17AF and IL-17F, can contribute to human OA pathophysiology. Therefore, we aimed to evaluate the gene expression and signalling pathway activation effects of the different IL-17 family members in fibroblasts derived from cartilage and synovium of patients with end-stage knee OA. Immunohistochemistry staining confirmed that IL-17 receptors A (IL-17RA) and IL-17RC are expressed in end-stage OA-derived cartilage and synovium. Chondrocytes and synovial fibroblasts derived from end-stage OA patients were treated with IL-17A, IL-17AF, or IL-17F, and gene expression was assessed with bulk RNA-Seq. Hallmark pathway analysis showed that IL-17 cytokines regulated several OA pathophysiology-related pathways including immune-, angiogenesis-, and complement-pathways in both chondrocytes and synovial fibroblasts derived from end-stage OA patients. While overall IL-17A induced the strongest transcriptional response, followed by IL-17AF and IL-17F, not all genes followed this pattern. Disease-Gene Network analysis revealed that IL-17A-related changes in gene expression in these cells are associated with experimental arthritis, knee arthritis, and musculoskeletal disease gene-sets. Western blot analysis confirmed that IL-17A significantly activates p38 and p65 NF-κB. Incubation of chondrocytes and synovial fibroblasts with IL-17A antibody secukinumab significantly inhibited IL-17A-induced gene expression. In conclusion, the association of IL-17-induced transcriptional changes with arthritic gene-sets supports a role for IL-17A in OA pathophysiology. Therefore, secukinumab could be investigated as a potential therapeutic option in OA patients.
Parallel inference of hierarchical latent dynamics in two-photon calcium imaging of neuronal populations
Authors: Prince Luke Y. , Bakhtiari Shahab , Gillon Colleen J. , Richards Blake A. 
Published: March 2021

AbstractDynamic latent variable modelling has provided a powerful tool for understanding how populations of neurons compute. For spiking data, such latent variable modelling can treat the data as a set of point-processes, due to the fact that spiking dynamics occur on a much faster timescale than the computational dynamics being inferred. In contrast, for other experimental techniques, the slow dynamics governing the observed data are similar in timescale to the computational dynamics that researchers want to infer. An example of this is in calcium imaging data, where calcium dynamics can have timescales on the order of hundreds of milliseconds. As such, the successful application of dynamic latent variable modelling to modalities like calcium imaging data will rest on the ability to disentangle the deeper- and shallower-level dynamical systems’ contributions to the data. To-date, no techniques have been developed to directly achieve this. Here we solve this problem by extending recent advances using sequential variational autoencoders for dynamic latent variable modelling of neural data. Our system VaLPACa (Variational Ladders for Parallel Autoencoding of Calcium imaging data) solves the problem of disentangling deeper- and shallower-level dynamics by incorporating a ladder architecture that can infer a hierarchy of dynamical systems. Using some built-in inductive biases for calcium dynamics, we show that we can disentangle calcium flux from the underlying dynamics of neural computation. First, we demonstrate with synthetic calcium data that we can correctly disentangle an underlying Lorenz attractor from calcium dynamics. Next, we show that we can infer appropriate rotational dynamics in spiking data from macaque motor cortex after it has been converted into calcium fluorescence data via a calcium dynamics model. Finally, we show that our method applied to real calcium imaging data from primary visual cortex in mice allows us to infer latent factors that carry salient sensory information about unexpected stimuli. These results demonstrate that variational ladder autoencoders are a promising approach for inferring hierarchical dynamics in experimental settings where the measured variable has its own slow dynamics, such as calcium imaging data. Our new, open-source tool thereby provides the neuroscience community with the ability to apply dynamic latent variable modelling to a wider array of data modalities.
Moral Hazard Heterogeneity: Genes and Health Insurance Influence Smoking after a Health Shock
Authors: Biroli Pietro , Zwyssig Laura 
Published: March 2021

AbstractDecision-making in the realm of health behaviors, such as smoking or drinking, is influenced both by biological factors, such as genetic predispositions, as well as environmental factors, such as financial liquidity and health insurance status. We show how the choice of smoking after a cardio-vascular health shock is jointly determined by the interaction between these biological and environmental constraints. Individuals who suffer a health shock when uninsured are 25.6 percentage points more likely to reduce smoking, but this is true only for those who have a low index of genetic predisposition to smoking. Individuals with a low index of genetic predisposition are more strategic and flexible in their behavioral response to an external shock. This differential elasticity of response depending on your genetic variants is evidence of individual-level heterogeneity in moral hazard. These results suggest that genetic heterogeneity is a factor that should be considered when evaluating the importance and fairness of health insurance policies.JEL CODESI12, I13, D63, D91
A Rapid Method to Evaluate Pre-Travel Programs for COVID-19: A Study in Hawaii
Authors: Hou Amy T. , Pang Genevieve C. , Mills Kristin M. , Bayudan Krizhna L. , Moore Dayna M. , Medina Luz P. , Pang Lorrin W. 
Published: March 2021

AbstractBackgroundPre-travel testing programs are being implemented around the world to curb COVID-19 and its variants from incoming travelers. A common approach is a single pre-travel test, 72 hours before departure, such as in Hawaii; however this raises concerns for those who are incubating or those infected after pre-travel testing or during transit. We need a rapid method to assess the effectiveness of pre-travel testing programs, and we use Hawaii as our case study.MethodsWe invited travelers departing from Kahului main airport at the end of their visit to Maui (major tourist destination among the Hawaiian islands) and performed COVID-19 PCR testing. Eligible participants needed a negative pre-travel test and a Hawaiian stay ≤ 14 days. We designed for anonymous testing at the end of travel so that travel plans would be unaffected, and we aimed for ≥ 70% study participation.ResultsAmong consecutive eligible travelers, 282 consented and 111 declined to participate, leading to a 72% (67-76%, 95% confidence interval) participation rate. Among 281 tested participants, two were positive with COVID-19, with an estimated positivity rate of 7 cases per 1,000 travelers. The top states of residence are California (58%) and Washington (21%). The mean length of stay was 7.7 ± 0.2 days. Regarding pre-travel testing, 87% had non-nasopharyngeal tests and 66% had self-administered tests.ConclusionsThis positivity rate leads to an estimated 17-30 infected travelers arriving daily to Maui in November-December 2020, and an estimated 52-70 infected travelers arriving daily to Hawaii during the same period. These counts surpass the Maui District Health Office’s projected ability to accommodate 10 infected visitors daily in Maui; therefore, an additional mitigation layer for travelers is recommended. This rapid field study can be replicated widely in airports to assess effectiveness of pre-travel programs and can be expanded to evaluate COVID-19 importation and its variants.
Robust methylation-based classification of brain tumors using nanopore sequencing
Authors: Kuschel Luis P. , Hench Jürgen , Frank Stephan , Hench Ivana Bratic , Girard Elodie , Blanluet Maud , Masliah-Planchon Julien , Misch Martin , Onken Julia , Czabanka Marcus , Karau Philipp , Ishaque Naveed , Hain Elisabeth G. , Heppner Frank , Idbaih Ahmed , Behr Nikolaus , Harms Christoph , Capper David , Euskirchen Philipp 
Published: March 2021

AbstractDNA methylation-based classification of cancer provides a comprehensive molecular approach to diagnose tumors. In fact, DNA methylation profiling of human brain tumors already profoundly impacts clinical neuro-oncology. However, current implementations using hybridization microarrays are time-consuming and costly. We recently reported on shallow nanopore whole-genome sequencing for rapid and cost-effective generation of genome-wide 5-methylcytosine profiles as input to supervised classification using random forests complemented by a medium-resolution copy number profile derived from the same raw data. Here, we demonstrate that this approach allows to discriminate a wide spectrum of primary brain tumors using public reference data of 82 distinct tumor entities. We developed a pseudo-probability score as a confidence score for interpretation in a clinical context. Using bootstrap sampling in a discovery cohort of N = 56 cases, we find that a minimum set of 1,000 random CpG features is sufficient for high-confidence classification by ad hoc random forests for most cases and demonstrate robustness across laboratories with matching results in 13/13 cases. When applying the confidence score threshold to an independent validation series (N = 111), the method demonstrated 100% specificity for the remaining 93 cases. In a prospective benchmarking (N = 15), median time to results was 21.1 hours. In conclusion, nanopore sequencing allows robust and rapid methylation-based classification across the full spectrum of brain tumors. The integrated confidence score facilitates possible clinical implementation, while requiring further prospective evaluation.
Estimating the impact of reopening schools on the reproduction number of SARS-CoV-2 in England, using weekly contact survey data
Authors: Munday James D , I Jarvis Christopher , Gimma Amy , Wong Kerry LM , Zandvoort Kevin van ,   CMMID COVID-19 Working Group, Funk Sebastian , Edmunds W. John 
Published: March 2021

AbstractBackgroundSchools have been closed in England since the 4th of January 2021 as part of the national restrictions to curb transmission of SARS-CoV-2. The UK Government plans to reopen schools on the 8th of March. Although there is evidence of lower individual-level transmission risk amongst children compared to adults, the combined effects of this with increased contact rates in school settings are not clear.MethodsWe measured social contacts when schools were both open or closed, amongst other restrictions. We combined these data with estimates of the susceptibility and infectiousness of children compared with adults to estimate the impact of reopening schools on the reproduction number.ResultsOur results suggest that reopening all schools could increase R from an assumed baseline of 0.8 to between 1.0 and 1.5, or to between 0.9 and 1.2 reopening primary or secondary schools alone.ConclusionOur results suggest that reopening schools is likely to halt the fall in cases observed in recent months and risks returning to rising infections, but these estimates rely heavily on the current estimates or reproduction number and the current validity of the susceptibility and infectiousness profiles we use.
Risk and mitigation of aerosolisation from lung function testing: results from the AERATOR study
Authors: Sheikh S , Hamilton F , Nava GW , Gregson F , Arnold D , Riley C , Brown J ,   AERATOR group, Bzdek B , Reid J , Maskell N , Dodd JW 
Published: March 2021

IntroductionLung function tests are fundamental diagnostic and monitoring tools for patients with respiratory symptoms. There is significant uncertainty around whether potentially infectious aerosol is produced during different lung function testing modalities; and limited data on possible mitigation strategies to reduce risk to staff and limit fallow time.MethodsHealthy volunteers were recruited in an ultraclean, laminar flow theatre and had standardised spirometry as per ERS/ATS guidance, as well as peak flow measurement and FENO assessment of airway inflammation. Aerosol emission was sampled minimum once each second using both an Aerodynamic Particle Sizer (APS) and Optical Particle Sizer (OPS), and compared to breathing, speaking and coughing. Mitigation strategies such as a peak flow viral filter and a CPET facemask (to mitigate induced coughing) were tested.Results33 healthy volunteers were recruited. Aerosol emission was highest in cough (1.61 particles/cm3/sample), followed by unfiltered peak flow (0.76 particles/cm3/sample). Filtered spirometry produced lower peak aerosol emission (0.11 particles/ cm3/sample) than that of a voluntary cough, and addition of a viral filter to the mouthpiece reduced peak flow aerosol emission to similar levels. The filter made little difference to recorded FEV peak flow values. Peak aerosol FENO measurement produced negligible aerosol. Reusable CPET masks with filter reduced aerosol emission when breathing, speaking, and coughing significantly.ConclusionsCompared to voluntary coughing, all lung function testing produced fewer aerosol particles. Filtered spirometry produces lower peak aerosol emission than peak voluntary coughing, and should not be deemed an aerosol generating procedure. The use of viral filters reduces aerosol emission in peak flow by > 10 times, and has little impact on recorded peak flow values. CPET masks are a useful option to reduce aerosol emission from induced coughing while performing spirometry.
Value-based pricing of a COVID-19 vaccine
Authors: Gandjour Afschin 
Published: March 2021

AbstractAimThe purpose of this study is to determine the value-based price of a COVID-19 vaccine from a societal perspective in Germany.MethodsA decision model was constructed using, e.g., information on age-specific fatality rates, intensive care unit (ICU) costs and outcomes, and herd protection threshold. Three strategies were analysed: vaccination (with 95% and 50% efficacy), a mitigation strategy, and no intervention. The base-case time horizon was 5 years. The value of a vaccine included savings from avoiding COVID-19 mitigation measures and health benefits from avoiding COVID-19 related mortality. The value of an additional life year was borrowed from new, innovative oncological drugs, as cancer reflects a condition with a similar morbidity and mortality burden in the general population in the short term as COVID-19.ResultsA vaccine with a 95% efficacy dominates the mitigation strategy strictly. The value-based price (€1494) is thus determined by the comparison between vaccination and no intervention. This price is particularly sensitive to the probability of ICU admission and the herd protection threshold. In contrast, the value of a vaccine with 50% efficacy is more ambiguous.ConclusionThis study yields a value-based price for a COVID-19 vaccine with 95% efficacy, which is more than 50 times greater than the purchasing price.
An AI-assisted Online Tool for Cognitive Impairment Detection Using Images from the Clock Drawing Test
Authors: Amini Samad , Zhang Lifu , Hao Boran , Gupta Aman , Song Mengting , Karjadi Cody , Lin Honghuang , Kolachalama Vijaya B. , Au Rhoda , Paschalidis Ioannis Ch. 
Published: March 2021

AbstractBackgroundWidespread early dementia detection could drastically increase clinical trial candidates and enable early interventions. Since the Clock Drawing Test (CDT) can be potentially used for diagnosing dementia related diseases, it can be leveraged to devise a computer-aided screening tool.ObjectiveThis work aims to develop an online screening tool by leveraging Artificial Intelligence and the CDT.MethodsImages of an analog clock drawn by 3, 263 cognitively intact and 160 impaired subjects were used. First, we processed the images from the CDT by a deep learning algorithm to obtain dementia scores. Then, individuals were classified as belonging to either category by combining CDT image scores with the participant’s age.ResultsWe have evaluated the performance of the developed models by applying 5-fold cross validation on 20% of the dataset. The deep learning model generates dementia scores for the CDT images with an Area Under the ROC Curve (AUC) of 81.3% ± 4.3%. A composite logistic regression model using age and the generated dementia scores, yielded an average AUC and average weighted F1 score of 92% ± 0.8% and 94.4% ± 0.7%, respectively.DiscussionCDT images were subjected to distortion consistent with an image drawn on paper and photographed by a cell phone. The model offers a cost-effective and easily deployable mechanism for detecting cognitive impairment online, without the need to visit a clinic.
A 1 to 1000 SARS-CoV-2 reinfection proportion in members of a large healthcare provider in Israel: a preliminary report
Authors: Perez Galit , Banon Tamar , Gazit Sivan , Moshe Shay Ben , Wortsman Joshua , Grupel Daniel , Peretz Asaf , Tov Amir Ben , Chodick Gabriel , Mizrahi-Reuveni Miri , Patalon Tal 
Published: March 2021

AbstractWith more than 100 million confirmed COVID-19 cases as of March 2021, reinfection is still considered to be rare. In light of increasing reports of reinfected COVID-19 patients, the need to better understand the real risk for reinfection is critical, with potential effects on public health policies aimed at containing the spread of SARS-CoV-2. In this descriptive preliminary report, we conducted a large-scale assessment on the country level of the possible occurrence of COVID-19 reinfection within the members of a large healthcare provider in Israel. Out of 149,735 individuals with a documented positive PCR test between March 2020 and January 2021, 154 had two positive PCR tests at least 100 days apart, reflecting a reinfection proportion of 1 per 1000. Given our strict inclusion criteria, we believe these numbers represent true reinfection incidence in MHS and should be clinically regarded as such.
Low Dose Regimens of BNT162b2 mRNA Vaccine Exceed SARS-Cov-2 Correlate of Protection Estimates for Symptomatic Infection, in those 19-55 Years of Age
Authors: Jurgens Graham 
Published: March 2021

AbstractBackgroundAn exact correlate of protection (CoP) is not yet known for symptomatic COVID-19. However, it is still possible to show a new vaccine regimen exceeds an unknown CoP, provided the regimen shows an equivalent or greater immunological response in all measured indicators relative to the immunological response elicited by a clinically proven vaccine regimen. The principle of comparing immunogenicity between regimens is what the FDA, EMA, and Access Consortium use to authorize modifications to the vaccines for VOC, without requiring clinical efficacy studies before implementation. It is logical to apply the same principle to modifying vaccine doses if the data is available to do so. A two dose 30ug regimen of BNT162b2 has strong clinical evidence of efficacy, as does a single dose 30 ug regimen. The immunological markers for these regimens have been profiled in detail in Phase 1 and 2 trial data.MethodsThe immunological profile (including binding antibodies, viral neutralization, cytokine profiles, and CD4 and 8 expansion) of the 2 dose 30ug BNT162b2 vaccine is examined, referred to as a highly conservative CoP estimate. The single dose 30 ug BNT162b2 immunological profile is also examined, a tenable CoP estimate. Data from the phase 1 and 2 trials are examined to see if alternate regimens meet or exceed the level of each immune marker measured, relative to the regimens listed above that have proven clinical efficacy.ResultsFor adults aged 19-55, a 2 dose 10ug BNT162b2 regimen elicits a comparable response to the standard 30 ug dose for each immune indicator, with viral neutralization nearly an order of magnitude greater than the tenable CoP estimate. Similarly, a single dose 10ug BNT 162b2 regimen or a two dose 1ug BNT 162b2 regimen equals or exceeds the immunogenicity of a single 30 ug dose.ConclusionIf it is reasonable for the FDA, EMA, and Access Consortium to approve vaccine modifications without a clinical trial based on immunogenicity data, three alternate low dose regimens were identified that meet the requirements of having comparable immunogenicity relative to a protocol that has proven clinical efficacy. Immediate implementation of these lower dose regimens should be considered as they have major implications in alleviating vaccine supply, as well as improving vaccine side effect profile, and lowering total cost of vaccination.