bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk-benefit analysis of the AstraZeneca COVID-19 vaccine in Australia using a Bayesian network modelling framework
Authors: Lau Colleen L , Mayfield Helen J , Sinclair Jane E , Brown Samuel J , Waller Michael , Enjeti Anoop K , Baird Andrew , Short Kirsty , Mengersen Kerrie , Litt John 
Published: October 2021

ABSTRACTThrombosis and Thromobocytopenia Syndrome (TTS) has been associated with the AstraZencea (AZ) COVID-19 vaccine. Australia has reported low TTS incidence of <3/100,000 after the first dose, with case fatality rate (CFR) of 5-6%. Risk-benefit analysis of vaccination has been challenging because of rapidly evolving data, changing levels of transmission, and age-specific variation in rates of TTS, COVID-19, and CFR. We aim to optimise risk-benefit analysis by developing a model that enables inputs to be updated rapidly as evidence evolves. A Bayesian network was used to integrate local and international data, government reports, published literature and expert opinion. The model estimates probabilities of outcomes under different scenarios of age, sex, low/medium/high transmission (0.05%/0.45%/5.76% of population infected over 6 months), SARS-CoV-2 variant, vaccine doses, and vaccine effectiveness. We used the model to compare estimated deaths from vaccine-associated TTS with i) COVID-19 deaths prevented under different scenarios, and ii) deaths from COVID-19 related atypical severe blood clots (cerebral venous sinus thrombosis & portal vein thrombosis). For a million people aged ≥70 years where 70% received first dose and 35% received two doses, our model estimated <1 death from TTS, 25 deaths prevented under low transmission, and >3000 deaths prevented under high transmission. Risks versus benefits varied significantly between age groups and transmission levels. Under high transmission, deaths prevented by AZ vaccine far exceed deaths from TTS (by 8 to >4500 times depending on age). Probability of dying from COVID-related atypical severe blood clots was 58-126 times higher (depending on age and sex) than dying from TTS. To our knowledge, this is the first example of the use of Bayesian networks for risk-benefit analysis for a COVID-19 vaccine. The model can be rapidly updated to incorporate new data, adapted for other countries, extended to other outcomes (e.g., severe disease), or used for other vaccines.HIGHLIGHTSAZ vaccination risk-benefit analysis must consider age/community transmission levelAZ vaccine benefits far outweigh risks in older age groups and during high transmissionAZ vaccine-associated TTS lower fatality than COVID-related atypical blood clotsBayesian networks utility for risk-benefit analysis of rapidly evolving situationsBNs allow integrating multiple data sources when large datasets are not available
Non-Markovian modelling highlights the importance of age structure on Covid-19 epidemiological dynamics
Authors: Reyné Bastien , Richard Quentin , Noûs Camille , Selinger Christian , Sofonea Mircea T. , Djidjou-Demasse Ramsès , Alizon Samuel 
Published: October 2021

AbstractThe Covid-19 pandemic outbreak was followed by a huge amount of modelling studies in order to rapidly gain insights to implement the best public health policies. Most of these compartmental models involved ordinary differential equations (ODEs) systems. Such a formalism implicitly assumes that the time spent in each compartment does not depend on the time already spent in it, which is at odds with the clinical data. To overcome this “memoryless” issue, a widely used solution is to increase and chain the number of compartments of a unique reality (e.g. have infected individual move between several compartments). This allows for greater heterogeneity and thus be closer to the observed situation, but also tends to make the whole model more difficult to apprehend and parameterize. We develop a non-Markovian alternative formalism based on partial differential equations (PDEs) instead of ODEs, which, by construction, provides a memory structure for each compartment thereby allowing us to limit the number of compartments. We apply our model to the French 2021 SARS-CoV-2 epidemic and, while accounting for vaccine-induced and natural immunity, we analyse and determine the major components that contributed to the Covid-19 hospital admissions. The results indicate that the observed vaccination rate alone is not enough to control the epidemic, and a global sensitivity analysis highlights a huge uncertainty attributable to the age-structured contact matrix. Our study shows the flexibility and robustness of PDE formalism to capture national COVID-19 dynamics and opens perspectives to study medium or long-term scenarios involving immune waning or virus evolution.
Genomic diversity of SARS-CoV-2 in Pakistan during fourth wave of pandemic
Authors: Umair Massab , Ikram Aamer , Rehman Zaira , Haider Adnan , Badar Nazish , Ammar Muhammad , Ahad Abdul , Suleman Rana , Salman Muhammad 
Published: October 2021

AbstractThe emergence of different variants of concern of SARS-CoV-2 has resulted in upsurges of COVID positive cases around the globe. Pakistan is also experiencing fourth wave of COVID-19 with increasing number of positive cases. In order to understand the genomic diversity of circulating SARS-CoV-2 strains during fourth wave of pandemic in Pakistan, the current study was designed. The samples from 89 COVID-19 positive patients were subjected to whole genome sequencing using GeneStudio S5. The results showed that 99% (n=88) of isolates belonged to delta variant and only one isolate belonged to alpha variant. Among delta variant cases 26.1% (n=23) isolates were showing B.1.617.2 while 74% of isolates showing AY.4 lineage. Islamabad was found to be the most affected city with 54% (n=48) of cases, followed by Karachi (28%, n=25), and Rawalpindi (10%, n=9). AY.4 has slight difference in mutation profile compared to B.1.617.2. E156del, G142D and V26I mutations in spike and T181I in NSP6 were present in B.1.617.2 but not in AY.4. Interestingly, A446V mutation in NSP4 has been only observed in AY.4. The current study highlights the circulation of primarily delta variant (B.1.617.2 and AY.4) during fourth wave of pandemic in Pakistan.
Longitudinal changes and key determinants of meeting WHO recommended levels of physical activity during the COVID-19 pandemic in a UK-based sample: Findings from the HEBECO Study
Authors: Mitchell JJ , Dicken SJ , Kale D , Herbec A , Beard E , Shahab L 
Published: October 2021

AbstractBackgroundThe COVID-19 pandemic has seen government enforced restrictions on movement, with ‘stay-at-home’ orders in place for a second and third time in many nations. Such restrictions have altered physical activity (PA) habits. This study aimed to evaluate longitudinal trends in PA in a self-selected UK-based sample and the key predictors of these trends.MethodsFrom 23 April 2020 to 30 January 2021, an online survey collected detailed measures of PA engagement in a sample of 1,947 UK-based adults. Generalised estimating equations (GEE) were fitted to explore trends in PA engagement over time, and how sociodemographic, health, lifestyle and contextual factors impacted participant’s attainment of Word Health Organisation (WHO) recommended levels of PA (constituting muscle strengthening activity (MSA), and moderate or vigorous PA (MVPA)).ResultsAttainment of WHO recommended levels of total PA showed a decline. While one in five achieved the recommended levels of total PA in the first UK lockdown in April-June 2020 (19.5%, 95%, CI 17.8-21.3%) and a similar proportion in June-July 2020 (17.7%, 95%CI 16.1-19.5%), this reduced significantly during the period of eased restrictions in August-September 2020 (15.2%, 95%CI 13.7-16.9%) and the second UK lockdown in November 2020-January 2021 (14.1%, 95%CI 12.6-15.9%). The same trends were observed for MSA and MVPA individually. Better quality of life, higher socioeconomic position and higher pre-COVID-19 PA levels were associated with meeting WHO recommended PA levels, while having overweight or obesity, a limiting chronic health condition, or being in strict isolation showed the inverse associations. Time-specific associations with MSA or MVPA were observed for gender, age, ethnicity, and other health behaviours.ConclusionAmong a self-selected sample of UK-based adults, there were reductions in PA levels throughout the first UK lockdown without reversal during the ensuing period. Based on observed associations of reduced PA with socioeconomic and health-related indices, such changes may point towards deepening health inequities during the pandemic.
Gamma Entrainment Improves Synchronization Deficits in Dementia Patients
Authors: Lahijanian Mojtaba , Aghajan Hamid , Vahabi Zahra , Afzal Arshia 
Published: October 2021

AbstractNon-invasive gamma entrainment has shown promising results in alleviating cognitive symptoms of Alzheimer’s disease in mice and humans. In this study, we examine improvements in the synchronization characteristics of the brain’s oscillations induced by 40Hz auditory stimulation based on electroencephalography data recorded from a group of dementia patients. We observed that when the quality of entrainment surpasses a certain level, several indicators of brain synchronization significantly improve. Specifically, the entrained oscillatory activity maintains temporal phase stability in the frontal, parietal, and occipital regions, and persistent spatial phase coupling between them. In addition, notable theta-gamma phase-amplitude coupling is observed in these areas. Interestingly, a high theta power at rest predicts the quality of entrainment. We identify differentiating attributes of temporal/spatial synchronization and cross-frequency coupling in the data of two groups with entrained and non-entrained responses which point to enhanced network synchronization caused by entrainment and can explain its potential therapeutic effects.
SomaticSiMu: A mutational signature simulator
Authors: Chen David , Randhawa Gurjit S. , Soltysiak Maximillian P.M. , de Souza Camila P.E. , Kari Lila , Singh Shiva M. , Hill Kathleen A. 
Published: October 2021

AbstractSummarySomaticSiMu is an in silico simulator of single and double base substitutions, and single base insertions and deletions in an input genomic sequence to mimic mutational signatures. SomaticSiMu outputs simulated DNA sequences and mutational catalogues with imposed mutational signatures. The tool is the first mutational signature simulator featuring a graphical user interface, control of mutation rates, and built-in visualization tools of the simulated mutations. Simulated datasets are useful as a ground truth to test the accuracy and sensitivity of DNA sequence classification tools and mutational signature extraction tools under different experimental scenarios. The reliability of SomaticSiMu was affirmed by 1) supervised machine learning classification of simulated sequences with different mutation types and burdens, and 2) mutational signature extraction from simulated mutational catalogs.
Availability and ImplementationSomaticSiMu is written in Python 3.8.3. The open-source code, documentation, and tutorials are available at https://github.com/HillLab/SomaticSiMu under the terms of the Creative Commons Attribution 4.0 International License.Contactkhill22@uwo.caSupplementary informationSupplementary data are available at Bioinformatics online.
Transcriptomic analysis of DNA damage response in zebrafish embryos under simulated microgravity
Authors: Barua Subhrajit , Komissarov Aleksey , Kaur Harpreet , Brodsky Elia 
Published: October 2021

AbstractSpace is an extremely hostile environment. Traveling to space has numerous effects on the body of the astronauts at a molecular level. As space agencies prepare for long-term missions, it becomes important to investigate these problems and address them. Thus, in the current study, we assessed the impact of simulated microgravity on the basic pathways especially DNA damage response. We identified a total of 7542 significantly differentially expressed genes. Out of these genes, 4504 were found to be up-regulated while 3038 were down-regulated in the simulated microgravity group in comparison to controls. Pathway enrichment analysis revealed that simulated microgravity has an effect on vital basic biological processes like DNA damage repair, peptide transport, and metabolism. To explore if the same pathways were also altered in humans, we explored the NASA twin study data and found that DDR was also significantly affected in the astronaut but due to ionizing radiation. Upon further investigation, we found that 62 genes belonging to the DDR pathway were mutually differentially expressed in Scott Kelly and the zebrafish embryos. However, there were 29 significantly differentially expressed genes belonging to the DDR pathway in zebrafish embryos that were not found to be differentially expressed in Scott Kelly. Out of these 29 genes, 14 were specific to zebrafish. Upon further investigation, we found that the DDR pathway is affected differently in simulated microgravity as compared to ionizing radiation. These observations provide a preliminary look into the difference in DDR induced by the different factors of spaceflight.
Normalizing automatic spinal cord cross-sectional area measures
Authors: Bédard S. , Cohen-Adad J. 
Published: October 2021

AbstractSpinal cord cross-sectional area (CSA) is a relevant biomarker to assess spinal cord atrophy in various neurodegenerative diseases. However, the considerable inter-subject variability among healthy participants currently limits its usage. Previous studies explored factors contributing to the variability, yet the normalization models were based on a relatively limited number of participants (typically < 300 participants), required manual intervention, and were not implemented in an open-access comprehensive analysis pipeline. Another limitation is related to the imprecise prediction of the spinal levels when using vertebral levels as a reference; a question never addressed before in the search for a normalization method. In this study we implemented a method to measure CSA automatically from a spatial reference based on the central nervous system (the pontomedullary junction, PMJ), we investigated various factors to explain variability, and we developed normalization strategies on a large cohort (N=804).Cervical spinal cord CSA was computed on T1w MRI scans for 804 participants from the UK Biobank database. In addition to computing cross-sectional at the C2-C3 vertebral disc, it was also measured at 64 mm caudal from the PMJ. The effect of various biological, demographic and anatomical factors was explored by computing Pearson’s correlation coefficients. A stepwise linear regression found significant predictors; the coefficients of the best fit model were used to normalize CSA.The correlation between CSA measured at C2-C3 and using the PMJ was y = 0.98x + 1.78 (R2 = 0.97). The best normalization model included thalamus volume, brain volume, sex and interaction between brain volume and sex. With this model, the coefficient of variation went down from 10.09% (without normalization) to 8.59%, a reduction of 14.85%.In this study we identified factors explaining inter-subject variability of spinal cord CSA over a large cohort of participants, and developed a normalization model to reduce the variability. We implemented an approach, based on the PMJ, to measure CSA to overcome limitations associated with the vertebral reference. This approach warrants further validation, especially in longitudinal cohorts. The PMJ-based method and normalization models are readily available in the Spinal Cord Toolbox.
Predicting the Effects of Per- and Polyfluoroalkyl Substance Mixtures on Peroxisome Proliferator-Activated Receptor Alpha Activity in Vitro
Authors: Nielsen Greylin , Heiger-Bernays Wendy J. , Schlezinger Jennifer J. , Webster Thomas F. 
Published: October 2021

AbstractHuman exposure to per- and polyfluoroalkyl substances (PFAS) is ubiquitous, with mixtures of PFAS detected in drinking water, food, household dust, and other exposure sources. Animal toxicity studies and human epidemiology indicate that PFAS may act through shared mechanisms including activation of peroxisome proliferator activated receptor α (PPARα). However, the effect of PFAS mixtures on human relevant molecular initiating events remains an important data gap in the PFAS literature. Here, we tested the ability of modeling approaches to predict the effect of diverse PPARα ligands on receptor activity using Cos7 cells transiently transfected with a full length human PPARα (hPPARα) expression construct and a peroxisome proliferator response element-driven luciferase reporter. Cells were treated for 24 hours with two full hPPARα agonists (pemafibrate and GW7647), a full and a partial hPPARα agonist (pemafibrate and mono(2-ethylhexyl) phthalate), or a full hPPARα agonist and a competitive antagonist (pemafibrate and GW6471). Receptor activity was modeled with three additive approaches: effect summation, relative potency factors (RPF), and generalized concentration addition (GCA). While RPF and GCA accurately predicted activity for mixtures of full hPPARα agonists, only GCA predicted activity for full and partial hPPARα agonists and a full agonist and antagonist. We then generated concentration response curves for seven PFAS, which were well-fit with three-parameter Hill functions. The four perfluorinated carboxylic acids (PFCA) tended to act as full hPPARα agonists while the three perfluorinated sulfonic acids (PFSA) tended to act as partial agonists that varied in efficacy between 28-67% of the full agonist, positive control level. GCA and RPF performed equally well at predicting the effects of mixtures with three PFCAs, but only GCA predicted experimental activity with mixtures of PFSAs and a mixture of PFCAs and PFSAs at ratios found in the general population. We conclude that of the three approaches, GCA most accurately models the effect of PFAS mixtures on hPPARα activity in vitro.HighlightsPerfluorinated carboxylic acids are full human PPARα agonistsPerfluorinated sulfonic acids are partial human PPARα agonistsGCA predicts human PPARα activity for mixtures of full and partial agonistsGCA predicts human PPARα activity for mixtures of agonists and competitive antagonistsGCA accurately predicts human PPARα activity in response to PFAS mixtures
Oral and injected tamoxifen alter adult hippocampal neurogenesis in female and male mice
Authors: Smith Bryon M. , Saulsbery Angela I. , Sarchet Patricia , Devasthali Nidhi , Einstein Dalia , Kirby Elizabeth D. 
Published: October 2021

AbstractInducible Cre recombinase facilitates temporal control of genetic recombination in numerous transgenic model systems, a feature which has made it a popular tool for studies of adult neurogenesis. One of the most common forms of inducible Cre, CreERT2, requires activation by the synthetic estrogen tamoxifen (TAM) to initiate recombination of LoxP-flanked sequences. To date, most studies deliver TAM via intraperitoneal injection. But the introduction of TAM-infused commercial chows has recently expanded the possible modes of TAM delivery. Despite the widespread use of TAM-inducible genetic models in adult neurogenesis research, the comparative efficiency and off-target effects of TAM administration protocols is surprisingly infrequently studied. Here we compare a standard, 5 day TAM injection regimen with voluntary consumption of TAM-infused chow. First, we used adult NestinCreERT2;Rosa-LoxP-STOP-LoxP-EYFP reporter mice to show that 2 weeks of TAM chow and 5 days of injections led to LoxP recombination in a similar phenotypic population of neural stem and progenitor cells in the adult dentate gyrus. However, TAM chow resulted in substantially less overall recombination than injections. TAM administration also altered adult neurogenesis, but in different ways depending on administration route: TAM injection disrupted neural progenitor cell proliferation 3 weeks after TAM, whereas TAM chow increased neuronal differentiation of cells generated during the diet period. These findings provide guidance for selection of TAM administration route and appropriate controls in adult neurogenesis studies using TAM-inducible Cre mice. They also highlight the need for better understanding of off-target effects of TAM in other neurological processes and organ systems.
An internal expectation guidesDrosophilaegg-laying decisions
Authors: Vijayan Vikram , Wang Zikun , Chandra Vikram , Chakravorty Arun , Li Rufei , Sarbanes Stephanie L. , Akhlaghpour Hessameddin , Maimon Gaby 
Published: October 2021

SummaryWhen presented with two egg-laying substrates,Drosophilalay most of their eggs on the option with higher relative value. How do flies make this relative-value decision? Might the strategy they use allow them to choose the best option even when they experience substrates with a more complex spatiotemporal profile than in canonical two-choice paradigms? We measuredDrosophilaegg-laying behavior in diverse substrate environments. In all cases, we found that flies dynamically increase or decrease their egg-laying rates as they explore substrates for a deposition site so as to target eggs to the best, recently visited option. Visiting the best option typically led to a strong reduction in egg laying on other substrates for several minutes, with this timescale varying across fly strains. Our data support a model in which flies compare the value of the current substrate with an internally constructedexpectationon the value of available options to regulate the likelihood of laying an egg. We show that dopamine-neuron activity is critical for learning and/or expressing this expectation, similar to its role in certain tasks in vertebrates. Integrating sensory experiences over minutes to generate an internal sense of the quality of available options, i.e., forming an expectation, allows flies to use a dynamic reference point for judging the current substrate and might be a general way in which decisions are made, even beyond flies and egg laying.