bluuebunny/crossref_metadata_2025 huggingface dataset:
Shielding of Viruses such as SARS-CoV-2 from Ultraviolet Radiation in Particles Generated by Sneezing or Coughing: Numerical Simulations of Survival Fractions
Authors: Hill Steven C. , Doughty David C. , Mackowski Daniel W.
Published: March 2021

SARS-CoV-2 and other microbes within aerosol particles can be partially shielded from UV radiation. The particles refract and absorb light, and thereby reduce the UV intensity at various locations within the particle. Shielding has been demonstrated in calculations of UV intensities within spherical approximations of SARS-CoV-2 virions that are within spherical particles approximating dried-to-equilibrium respiratory fluids. The purpose of this paper is to calculate the survival fractions of virions (i.e., the fractions of virions that can infect cells) within spherical particles approximating dried respiratory fluids, and to investigate the implications of these calculations for using UV light for disinfection. The particles may be on a surface or in air. In this paper the survival fraction (S) of a set of virions illuminated with a UV fluence (F, in J/m2) is approximated as S=exp(-kF), where k is the UV inactivation rate constant (m2/J). The average survival fractions (Sp) of all the simulated virions in a particle are calculated using the calculated decreases in fluence. The results show that virions in particles of dried respiratory fluids can have significantly larger Sp than do individual virions. For individual virions, and virions in 1-, 5-, and 9-µm particles illuminated (normal incidence) on a surface with 260-nm UV light, the Sp = 0.00005, 0.0155, 0.22 and 0.28, respectively, when kF=10. The Sp decrease to <10−7, <10−7, 0.077 and 0.15, respectively, for kF=100. Calculated results also show that illuminating particles with UV beams from widely separated directions can strongly reduce the Sp. These results suggest that the size distributions and optical properties of the dried particles of virion-containing respiratory fluids are likely important in effectively designing and using UV germicidal irradiation systems for microbes in particles. The results suggest the use of reflective surfaces to increase the angles of illumination and decrease the Sp. The results suggest the need for measurements of the Sp of SARS-CoV-2 in particles having compositions and sizes relevant to the modes of disease transmission.
Understanding the prevalence of psychiatric disorders in people with cerebral palsy: A systematic review protocol
Authors: Eres R. , Dutia I. , Walsh M. , Mulraney M. , Sawyer S.M , Reddihough D.S , Coghill D.
Published: March 2021

Background

There is an abundance of research investigating physical health outcomes in people with cerebral palsy, however evidence from studies investigating psychiatric disorders in this group is less well developed. Specifically, there is little research synthesising the prevalence rates of psychiatric disorders in people with cerebral palsy, and there is no summary of the instruments used to measure this. This systematic review will summarise the current body of evidence investigating psychiatric disorders in people with cerebral palsy, as well as the measurement or diagnostic instruments used to measure psychiatric disorder.

Findings

To be included in the review, articles must report on psychiatric disorders in people with cerebral palsy or use standardised tools that allow for clinical thresholds to be derived, written in English, and published after 1980. A comprehensive, electronic database search strategy will be implemented targeting relevant papers indexed in MEDLINE, PsycINFO, Cochrane Library, and PubMed. Searches will include terms that relate to psychiatric disorders (E.g., mood disorders, anxiety disorders, ADHD, autism) in people with cerebral palsy. Data will be extracted based on age, psychiatric disorder, and cerebral palsy severity. We will summarise the findings as a narrative and will provide overall prevalence estimates for psychiatric disorders.

Discussion

The systematic review will provide novel insights into the prevalence of psychiatric disorders in people with cerebral palsy. It will also provide recommendations about the types of instruments that have been used and implemented in health research related to cerebral palsy. It will guide future work on interventions and primary research in clinical sciences and allied health disciplines.
Improving COVID-19 vaccination centre operation through computer modelling and simulation
Authors: Wood RM , Moss SJ , Murch BJ , Davies C , Vasilakis C
Published: March 2021

Mass vaccination is widely considered to offer the only route out of the COVID-19 pandemic in a way that social restrictions can be eased and economic activity can safely resume without compromising healthcare services. For many countries, dedicated vaccination centres are a key part of that effort. However, with no directly comparable historical experience there is little information to guide the operational configuration and management of these sites. In addressing this gap in knowledge, the objective of this study is to demonstrate the value of computer modelling. This is achieved through providing an account of its use in supporting management considerations and decisions at two major vaccination centres, at an early stage of the UK’s mass vaccination effort. We report on how modelling insight has influenced the initial setup of one site, including quantification of daily booking numbers. For the same site, we reveal how analysis has informed a significant operational shift in combining two key activities on the vaccination pathway into one. Finally, we describe how, at a second site, modelling has been used to examine pathway stability, in terms of resilience to unforeseen ‘shocks’ such as delayed arrivals and staff unavailability. Alongside the open-source simulation software, the modelling insights reported here can support managers to better plan and improve the operation of COVID-19 vaccination centres.
Dental mitigation strategies to reduce aerosolization of SARS-CoV-2
Authors: Vernon Jon J. , Black Emma V. I. , Dennis Thomas , Devine Deirdre A. , Fletcher Louise , Wood David J , Nattress Brian R
Published: March 2021

Limiting infection transmission is central to the safety of all in dentistry, particularly during the current SARS-CoV-2 pandemic. Aerosol-generating procedures (AGPs) are crucial to the practise of dentistry; it is imperative to understand the inherent risks of viral dispersion associated with AGPs and the efficacy of available mitigation strategies.

In a dental surgery setting, crown preparation and root canal access procedures were performed with an air turbine or electric speed-controlled hand-piece, with mitigation via rubber dam or high-volume aspiration and a no mitigation control. A phantom head was used with a 1.5 mL flow of artificial saliva infected with Φ6 bacteriophage (a surrogate virus for SARS-CoV-2) at ∼108plaque forming units mL-1, reflecting the upper limits of reported salivary SARS-CoV-2 levels. Bioaerosol dispersal was measured using agar settle plates lawned with the bacteriophage’s host,Pseudomonas syringae. Viral air concentrations were assessed using MicroBio MB2 air sampling, and particle quantities using Kanomax 3889 GEOα particle counters.

Compared to an air turbine, the electric hand-piece reduced settled bioaerosols by 99.72%, 100.00% and 100.00% for no mitigation, aspiration and rubber dam, respectively. Bacteriophage concentrations in the air were reduced by 99.98%, 100.00% and 100.00%, with the same mitigation strategies. Use of the electric hand-piece with high-volume aspiration, resulted in no detectable bacteriophage, both on settle plates and in air samples taken 6-10-minutes post-procedure.

To our knowledge, this study is the first to report the aerosolization of active virus as a marker for risk determination in the dental setting. Whilst this model represents a worst-case scenario for possible SARS-CoV-2 dispersal, these data showed that the use of electric hand-pieces can vastly reduce the risk of viral aerosolization, and therefore remove the need for clinic fallow time. Furthermore, our findings indicate that the use of particle analysis alone cannot provide sufficient insight to understand bioaerosol infection risk.
Detecting cognitive decline using speech only: The ADReSSOChallenge
Authors: Luz Saturnino , Haider Fasih , de la Fuente Sofia , Fromm Davida , MacWhinney Brian
Published: March 2021

Building on the success of the ADReSS Challenge at Inter-speech 2020, which attracted the participation of 34 teams from across the world, the ADReSSoChallenge targets three difficult automatic prediction problems of societal and medical relevance, namely: detection of Alzheimer’s Dementia, inference of cognitive testing scores, and prediction of cognitive decline. This paper presents these prediction tasks in detail, describes the datasets used, and reports the results of the baseline classification and regression models we developed for each task. A combination of acoustic and linguistic features extracted directly from audio recordings, without human intervention, yielded a baseline accuracy of 78.87% for the AD classification task, a root mean squared (RMSE) error of 5.28 for prediction of cognitive scores, and 68.75% accuracy for the cognitive decline prediction task.
COVID-19 RT-PCR diagnostic assay sensitivity and SARS-CoV-2 transmission: A missing link?
Authors: Sahahjpal Nikhil Shri , Hon Ephrem Chin Lip , Dallaire Stephanie , Williams Colin , Ananth Sudha , Mondal Ashis K , Rojiani Amyn M , Hegde Madhuri , Kolhe Ravindra
Published: March 2021

Background

The sensitivity of commercially available RT-PCR assays varies over 10,000 fold, ranging from 10 to 20,000 viral copies/ml. The reporting of high Ct value results has been under scrutiny, as the clinical significance of these values is not yet completely understood. The early detection of infected individuals (high Ct results) in the pre-symptomatic phase of the disease using highly sensitive RT-PCR methods has been argued as a strategy to prevent transmission, while on the contrary, the reporting of high Ct has been criticized as false-positive results causing unnecessary testing and having several negative implications. The purpose of this study was to verify the presence of SARS-CoV-2 genomes in samples with a wide range of RT-PCR Ct values including samples with high Ct (37 to 42) using next-generation sequencing (NGS).

Methods

The study evaluated a total of 547 previously positive samples tested with the PerkinElmer® New Coronavirus Nucleic Acid Detection RT-PCR kit. The samples included in this study ranged from Ct values of 17-42, with 44 samples having a Ct > 37. Of the 547 samples, 149 were sequenced using PerkinElmer NEXTFLEX Variant-Seq SARS-CoV2 assay on NovaSeq 6000, and 398 samples were sequenced using Illumina SARS-CoV-2 respiratory viral panel kits using the NextSeq 500/550 system.

Results

Between the two clinical laboratories, a total of ∼1.95 million samples were tested using the FDA-EUA PerkinElmer® New Coronavirus RT-PCR assay. Of the 1.95 million samples, ∼1.72 million were negative, ∼250,000 positive, and ∼16,500 in the range of 37-42. Of the 547 samples sequenced, the percentage of sequencing reads that aligned to the SARS-CoV-2 Wuhan-hu-1 reference genome (NC_045512.2) ranged from 25.5% to 99.69%. All samples sequenced showed high sequence specificity to the SARS-CoV-2 virus. Low Ct samples showed complete uniform coverage across the entire 29kb SAR-CoV-2 genome. The average coverage in samples with high Ct (>37) was found to be 55.5% (range 16.1-99.2%). However, as sample Ct increased, a gradual decrease in coverage uniformity was observed for few samples.

Conclusion

This study demonstrates for the first time that the viral RNA is present in the high Ct value range of 37-42 and the sequence is unique to SARS-CoV-2 confirmed using two separate sequencing assays. This confirms that the detected Ct values are reflective of the presence of the SARS-CoV-2 virus and they are not an artifact or contamination. In light of the recent work highlighting the majority of transmission being pre-symptomatic/ asymptomatic, and high Ct results being observed at both the early and late phases of infection warrants further investigation into the clinical utility of high Ct results to curtail the spread of the virus.
Survey data on European organic multi-species livestock farms
Authors: Ulukan Defne , Steinmetz Lucille , Moerman Marie , Bernes Gun , Blanc Mathilde , Brock Christopher , Destruel Marie , Dumont Bertrand , Lang Elise , Meischner Tabea , Moraine Marc , Oehen Bernadette , Parsons David , Primi Riccardo , Ronchi Bruno , Schanz Lisa , Vanwindekens Frédéric , Veysset Patrick , Winckler Christoph , Martin Guillaume , Benoit Marc
Published: March 2021

While there is increasing evidence of the sustainability benefits of diversified systems in the organic cropping sector, this has been much less investigated with organic livestock farming. To fill this knowledge gap, we surveyed a sample of 128 European organic multi-species livestock farms located across seven countries – Austria, Belgium, France, Germany, Italy, Sweden and Switzerland – and covering a large range of livestock species combinations. We recorded 1574 variables as raw data out of which we calculated 107 indicators describing farm structure, management and several sustainability dimensions: resource use efficiency and conservation, animal, land and work productivities, animal and human welfare. After technical validation of the data, we withdrew 26 farms and the database covers 102 farms. This database is well suited to unveil relationships between various dimensions of organic multi-species livestock farm sustainability and their structure and management. It can help reveal sustainable strategies for organic multi-species livestock farming systems and understand levers or barriers to their development.
Autism_genepheno: Text mining of gene-phenotype associations reveals new phenotypic profiles of autism-associated genes
Authors: Li Sijie , Guo Ziqi , Ioffe Jacob B. , Hu Yunfei , Zhen Yi , Zhou Xin
Published: March 2021

Autism is a spectrum disorder with wide variation in type and severity of symptoms. Understanding gene–phenotype associations is vital to unravel the disease mechanisms and advance its diagnosis and treatment. To date, several databases have stored a large portion of gene–phenotype associations which are mainly obtained from genetic experiments. However, a large proportion of gene–phenotype associations are still buried in the autism-related literature and there are limited resources to investigate autism-associated gene-phenotype associations. Given the abundance of the autism-related literature, we were thus motivated to develop Autism_genepheno, a text mining pipeline to identify sentence-level mentions of autism-associated genes and phenotypes in literature through natural language processing methods. We have generated a comprehensive database of gene-phenotype associations in the last five years’ autism-related literature that can be easily updated as new literature becomes available. We have evaluated our pipeline through several different approaches, and we are able to rank and select top autism-associated genes through their unique and wide spectrum of phenotypic profiles, which could provide a unique resource for the diagnosis and treatment of autism. The data resources and the Autism_genpheno pipeline are available at:https://github.com/maiziezhoulab/Autism_genepheno.
The fish pathogenAliivibrio salmonicidaLFI1238 can degrade and metabolize chitin despite major gene loss in the chitinolytic pathway
Authors: Skåne Anna , Minniti Giusi , Loose Jennifer S.M. , Mekasha Sophanit , Bissaro Bastien , Mathiesen Geir , Arntzen Magnus Ø. , Vaaje-Kolstad Gustav
Published: March 2021

The fish pathogenAliivibrio (Vibrio) salmonicidaLFI1238 is thought to be incapable of utilizing chitin as a nutrient source since approximately half of the genes representing the chitinolytic pathway are disrupted by insertion sequences. In the present study, we combined a broad set of analytical methods to investigate this hypothesis. Cultivation studies revealed thatAl. salmonicidagrew efficiently onN-acetylglucosamine (GlcNAc) and chitobiose ((GlcNAc)2), the primary soluble products resulting from enzymatic chitin hydrolysis. The bacterium was also able to grow on chitin particles, albeit at a lower rate compared to the soluble substrates. The genome of the bacterium contains five disrupted chitinase genes (pseudogenes) and three intact genes encoding a glycoside hydrolase family 18 (GH18) chitinase and two auxiliary activity family 10 (AA10) lytic polysaccharide monooxygenases (LPMOs). Biochemical characterization showed that the chitinase and LPMOs were able to depolymerize both α- and β-chitin to (GlcNAc)2and oxidized chitooligosaccharides, respectively. Notably, the chitinase displayed up to 50-fold lower activity compared to other well-studied chitinases. Deletion of the genes encoding the intact chitinolytic enzymes showed that the chitinase was important for growth on β-chitin, whereas the LPMO gene-deletion variants only showed minor growth defects on this substrate. Finally, proteomic analysis ofAl. salmonicidaLFI1238 growth on β-chitin showed expression of all three chitinolytic enzymes, and intriguingly also three of the disrupted chitinases. In conclusion, our results show thatAl. salmonicidaLFI1238 can utilize chitin as a nutrient source and that the GH18 chitinase and the two LPMOs are needed for this ability.

IMPORTANCE

The ability to utilize chitin as a source of nutrients is important for the survival and spread of marine microbial pathogens in the environment. One such pathogen isAliivibrio (Vibrio) salmonicida, the causative agent of cold water vibriosis. Due to extensive gene decay, many key enzymes in the chitinolytic pathway have been disrupted, putatively rendering this bacterium incapable of chitin degradation and utilization. In the present study we demonstrate thatAl. salmonicidacan degrade and metabolize chitin, the most abundant biopolymer in the ocean. Our findings shed new light on the environmental adaption of this fish pathogen.
Isolation and Purification of Lipoarabinomannan from Urine of Adults with Active Tuberculosis
Authors: Cantera Jason L. , Rashid Andrew A. , Lillis Lorraine L. , Peck Roger B. , Drain Paul K. , Pinter Abraham , Kawasaki Masanori , Moreau Emmanuel , Boyle David S.
Published: March 2021

Lipoarabinomannan (LAM) is a cell wall component ofMycobacterium tuberculosisthat is excreted in the urine of persons with active tuberculosis (TB). Limited diagnostic sensitivity of LAM immunoassays has been due to selecting antibodies against LAM derived fromin vitroculturedM. tuberculosis, rather than LAM purified fromin vivoclinical urine specimens. Urinary LAM (uLAM) is critical to enable the development of and/or screening of novel uLAM-specific antibodies but is typically dilute and in heterogeneous mixtures with other urine components. We used physical, enzymatic, and chemical processes for the scaled isolation and purification of uLAM. The purified material may then be used to develop more sensitive uLAM diagnostic tests for active TB disease.
Monitoring occurrence of SARS-CoV-2 in school populations: a wastewater-based approach
Authors: Gutierrez Victor Castro , Hassard Francis , Vu Milan , Leitao Rodrigo , Burczynska Beata , Wildeboer Dirk , Stanton Isobel , Rahimzadeh Shadi , Baio Gianluca , Garelick Hemda , Hofman Jan , Kasprzyk-Hordern Barbara , Kwiatkowska Rachel , Majeed Azeem , Priest Sally , Grimsley Jasmine , Lundy Lian , Singer Andrew C , Di Cesare Mariachiara
Published: March 2021

Clinical testing of children in schools is challenging, with economic implications limiting its frequent use as a monitoring tool of the risks assumed by children and staff during the COVID-19 pandemic. Here, a wastewater based epidemiology approach has been used to monitor 16 schools (10 primary, 5 secondary and 1 post-16 and further education for a total of 17 sites) in England. A total of 296 samples over 9 weeks have been analysed for N1 and E genes using qPCR methods. Of the samples returned, 47.3% were positive for one or both genes with a frequency of detection in line with the respective community. WBE offers a promising low cost, non-invasive approach for supplementing clinical testing and can offer longitudinal insights that are impractical with traditional clinical testing.
Implementation of the 2021 molecular ESGO/ESTRO/ESP risk groups in endometrial cancer
Authors: Imboden Sara , Nastic Denis , Ghaderi Mehran , Rydberg Filippa , Siegenthaler Franziska , Mueller Michael D , Rau Tilman T , Epstein Elisabeth , Carlson Joseph W.
Published: March 2021

Introduction

In 2021, a joint ESGO/ESTRO/ESP committee updated their evidence-based guidelines for endometrial cancer, recommending a new risk grouping incorporating both clinicopathologic and molecular parameters. We applied the new risk grouping and compared the results to those of the prior 2016 clinicopathologic system.

Materials and methods

We classified molecularly a cohort of 604 women diagnosed with endometrial cancer using immunohistochemistry for TP53 and MMR proteins on a tissue microarray, as well as Sanger sequencing for POLE mutations. These results, combined with clinicopathologic data, allowed the patients to be risk grouped using both the new 2021 molecular/clinicopathologic parameters and the prior 2016 clinicopathologic system. In addition, clinical treatment and outcome data were collected from medical records.

Results

The application of the 2021 molecular markers shows Kaplan-Meier curves with a significant difference between the groups for all survival. Molecular classification under the 2021 guidelines revealed a total of 39 patients (39/594, 7%) with a change in risk group in relation to the 2016 classification system: the shift was alone due to either P53abn or POLEmut molecular marker. In order to ensure correct 2021 molecular risk classification, not all patients with endometrial cancer need a molecular diagnostic: 386 (65.0%) cases would need to be analyzed by TP53 IHC, only 44 (7.4%) by MMR IHC and 109 (18.4%) POLE sequencing reactions.

Conclusion

Application of the 2021 molecular risk groups is feasible and shows significant differences in survival. IHC for TP53 and MMR and applying POLE sequencing is only needed in selected cases and leads to shifting risk groups both upward and downward for a sizeable number of patients.
Combined prenatal Lactobacillus reuteri and ω-3 supplementation synergistically modulates DNA methylation in neonatal T helper cells
Authors: Huoman Johanna , Martínez-Enguita David , Olsson Elin , Ernerudh Jan , Nilsson Lennart , Duchén Karel , Gustafsson Mika , Jenmalm Maria C
Published: March 2021

Background

Environmental exposures may alter DNA methylation patterns of T helper cells. As T helper cells are instrumental for allergy development, changes in methylation patterns may constitute a mechanism of action for allergy preventive interventions. While epigenetic effects of separate perinatal probiotic or ω-3 fatty acid supplementation have been studied previously, the combined treatment has not been assessed. We aimed to investigate epigenome-wide DNA methylation patterns in cord blood samples from children in a randomised double-blind placebo-controlled allergy prevention trial using pre- and postnatal combined Lactobacillus reuteri and ω-3 fatty acid treatment. To this end, >866 000 CpG sites (MethylationEPIC 850K array) in cord blood CD4+ T cells were examined in samples from all four study arms (double-treatment: n=18, single treatments: probiotics n=16, ω-3 n=15, and double placebo: n=14). Statistical and bioinformatic analyses identified treatment-associated differentially methylated CpGs and genes, which were used to identify treatment-induced network modules. Pathway analyses inferred biological relevance, and comparisons were made to an independent allergy data set.

Results

Comparing the active treatments to the double placebo group, most differentially methylated CpGs and genes were hypermethylated, suggesting induction of transcriptional inhibition. The double-treated group showed the largest number of differentially methylated CpGs, of which many were unique, suggesting synergy between interventions. Clusters within the double-treated network module consisted of immune-related pathways, including T cell receptor signalling, and antigen processing and presentation, with similar pathways revealed for the single-treatment modules. CpGs derived from differential methylation and network module analyses were enriched in an independent allergy data set, particularly in the double-treatment group, proposing treatment-induced DNA methylation changes as relevant for allergy development.

Conclusion

Prenatal L. reuteri and/or ω-3 fatty acid treatment results in hypermethylation and affects immune- and allergy-related pathways in neonatal T helper cells, with potentially

synergistic effects between the interventions and relevance for allergic disease. Further studies need to address these findings on a transcriptional level, and whether the results associate to allergy development in the children. Understanding the role of DNA methylation in regulating effects of perinatal probiotic and ω-3 interventions may provide essential knowledge in the development of efficacious allergy preventive strategies.

Trial registration

ClinicalTrials.gov, ClinicalTrials.gov-ID: NCT01542970. Registered 27th of February 2012 – Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT01542970
Why ODE models for COVID-19 fail: Heterogeneity shapes epidemic dynamics
Authors: Großmann Gerrit , Backenköhler Michael , Wolf Verena
Published: March 2021

In the recent COVID-19 pandemic, mathematical modeling constitutes an important tool to evaluate the prospective effectiveness of non-pharmaceutical interventions (NPIs) and to guide policy-making. Most research is, however, centered around characterizing the epidemic based on point estimates like the average infectiousness or the average number of contacts.

In this work, we use stochastic simulations to investigate the consequences of a population’s heterogeneity regarding connectivity and individual viral load levels.

Therefore, we translate a COVID-19 ODE model to a stochastic multi-agent system. We use contact networks to model complex interaction structures and a probabilistic infection rate to model individual viral load variation.

We observe a large dependency of the dispersion and dynamical evolution on the population’s heterogeneity that is not adequately captured by point estimates, for instance, used in ODE models. In particular, models that assume the same clinical and transmission parameters may lead to different conclusions, depending on different types of heterogeneity in the population. For instance, the existence of hubs in the contact network leads to an initial increase of dispersion and the effective reproduction number, but to a lower herd immunity threshold (HIT) compared to homogeneous populations or a population where the heterogeneity stems solely from individual infectivity variations.

Author summary

Computational modeling can support decision-making in the face of pandemics like COVID-19. Models help to understand transmission data and predict important epidemiological properties (e.g.,When will herd immunity be reached?). They can also examine the effectiveness of certain measures, and—to a limited extent—extrapolate the dynamics under specific assumptions. In all these cases, the heterogeneity of the population plays an important role. For instance, it is known that connectivity differences in (and among) age groups influence the dynamics of epidemic propagation. Here we focus on two types of differences among individuals: their social interactions and on how infectious they are. We show that only considering population averages (e.g.,What is the average number of contacts of an individual?) may lead to misleading conclusions, because the individual differences (such as those related to the epidemic(over-)dispersion) play an important role in shaping the epidemic dynamics. Many commonly used model classes, such as SEIR-type ODE compartmental models, ignore differences within a population to a large extent. This omission bears the potential of misleading conclusions.
Characterizing the incidence of adverse events of special interest for COVID-19 vaccines across eight countries: a multinational network cohort study
Authors: Li Xintong , Ostropolets Anna , Makadia Rupa , Shaoibi Azza , Rao Gowtham , Sena Anthony G. , Martinez-Hernandez Eugenia , Delmestri Antonella , Verhamme Katia , Rijnbeek Peter R , Duarte-Salles Talita , Suchard Marc , Ryan Patrick , Hripcsak George , Prieto-Alhambra Daniel
Published: March 2021

Background

As large-scale immunization programs against COVID-19 proceed around the world, safety signals will emerge that need rapid evaluation. We report population-based, age- and sex- specific background incidence rates of potential adverse events of special interest (AESI) in eight countries using thirteen databases.

Methods

This multi-national network cohort study included eight electronic medical record and five administrative claims databases from Australia, France, Germany, Japan, Netherlands, Spain, the United Kingdom, and the United States, mapped to a common data model. People observed for at least 365 days before 1 January 2017, 2018, or 2019 were included. We based study outcomes on lists published by regulators: acute myocardial infarction, anaphylaxis, appendicitis, Bell’s palsy, deep vein thrombosis, disseminated intravascular coagulation, encephalomyelitis, Guillain-Barre syndrome, hemorrhagic and non-hemorrhagic stroke, immune thrombocytopenia, myocarditis/pericarditis, narcolepsy, pulmonary embolism, and transverse myelitis. We calculated incidence rates stratified by age, sex, and database. We pooled rates across databases using random effects meta-analyses. We classified meta-analytic estimates into Council of International Organizations of Medical Sciences categories: very common, common, uncommon, rare, or very rare.

Findings

We analysed 126,661,070 people. Rates varied greatly between databases and by age and sex. Some AESI (e.g., myocardial infarction, Guillain-Barre syndrome) increased with age, while others (e.g., anaphylaxis, appendicitis) were more common in young people. As a result, AESI were classified differently according to age. For example, myocardial infarction was very rare in children, rare in women aged 35-54 years, uncommon in men and women aged 55-84 years, and common in those aged ≥85 years.

Interpretation

We report robust baseline rates of prioritised AESI across 13 databases. Age, sex, and variation between databases should be considered if background AESI rates are compared to event rates observed with COVID-19 vaccines.
Droplet Digital RT-PCR to detect SARS-CoV-2 variants of concern in wastewater
Authors: Heijnen Leo , Elsinga Goffe , de Graaf Miranda , Molenkamp Richard , Koopmans Marion P.G. , Medema Gertjan
Published: March 2021

Wastewater surveillance has shown to be a valuable and efficient tool to obtain information about the trends of COVID-19 in the community. Since the recent emergence of new variants, associated with increased transmissibility and/or antibody escape (variants of concern), there is an urgent need for methods that enable specific and timely detection and quantification of the occurrence of these variants in the community. In this study we demonstrate the use of RT-ddPCR on wastewater samples for specific detection of mutation N501Y. This assay enabled simultaneous enumeration of the concentration of variants with the 501Y mutation and Wild Type (WT, containing 501N) SARS-CoV-2 RNA. Detection of N501Y was possible in samples with mixtures of WT with low proportions of lineage B.1.351 (0.5%). The method could accurately determine the proportion of N501Y and WT in mixtures of SARS-CoV-2 RNA. The application to raw sewage samples from the cities of Amsterdam and Utrecht demonstrated that this method can be applied to determine the concentrations and the proportions of WT and N501Y containing SARS-CoV-2 RNA in wastewater samples. The emergence of N501Y in Amsterdam and Utrecht wastewater aligned with the emergence of B.1.1.7 as causative agent of COVID-19 in the Netherlands, indicating that RT-ddPCR of wastewater samples can be used to monitor the emergence of the N501Y mutation in the community. It also indicates that RT-ddPCR could be used for sensitive and accurate monitoring of current (like K417N, E484K) or future mutations present in SARS-CoV-2 variants of concern. Monitoring emergence of these mutations in the community via wastewater is rapid, efficient and valuable in supporting public health decision-making.
Aggresssion in School Children: Role of Gender, Family Factors and Exposure to Violence
Authors: Sehgal Mukul , Nayak Ajita
Published: March 2021

INTRODUCTION

Increasing instances of aggression in school children has become a cause of great concern for educationists, parents and mental health professionals. With increased globalization and information overload, today’s child is exposed to influences which probably adversely modify the child’s behavior. These aggressive tendencies could affect the child’s academic, social functioning and also may lead to psychiatric problems. Hence, this study was planned to find out the amount of aggression among school children and various potential contributing factors for the aggressive behavior. Identifying these risk factors could help design preventive strategies among school children.

OBJECTIVE

To evaluate the amount of aggression and its contributing factors among 10-12 year-old children.

SUBJECTS

The subjects involved the school children and their teachers in various schools across Mumbai. The age group of study was 10-12 years i.e. class 5th to class 8th

No. of subjects:-102

STUDY PROCEDURE

A total of 102, 10-12 year-old school children (5th to 8th class) in the Mumbai metropolitan area were interviewed to assess the presence of aggression. A validated scale, Children’s Aggression Scale – Teacher version (CAS-T), was used to assess the presence of aggression. Children were assessed & scored on basis of this scale with questions answered by their teachers. Data was analyzed on the basis of each factor using unpaired t-test, ANOVA test and Kruskal-Wallis Test (Nonparametric ANOVA). Institutional ethics committee approval was taken for research at Seth GS Medical College, Mumbai, India.

RESULTS

A high level of aggression was present in 4% other children while moderate levels were present in 8%. Boys were found to be more aggressive than girls (p-value 0.003). Aggression scores were significantly higher in children from English medium and with poor academic performance. Children exposed to physical abuse and violence on Television showed significantly high aggression. Perceived parental conflict in boys was found to be significantly associated with lower aggression scores. Among the various factors studied, aggression scores showed highest correlation with exposure to violence on television for more than 2 hours/day (11.67 vs 3.19 p-value <0.001).

CONCLUSION

About 12% of schoolchildren in the 10-12years group show aggressive behavior needing interventions. Boys from abusive families, with poor academic performance and exposed to excessive violence on TV seem particularly at risk for developing aggressive behavior.
The Hox transcription factor Ultrabithorax binds RNA and regulates co-transcriptional splicing through an interplay with RNA polymerase II
Authors: Carnesecchi Julie , Boumpas Panagiotis , van Nierop y Sanchez Patrick , Domsch Katrin , Pinto Hugo Daniel , Pinto Pedro Borges , Lohmann Ingrid
Published: March 2021

Transcription Factors (TFs) play a pivotal role in cell fate decision by coordinating distinct gene expression programs. Although most TFs act at the DNA regulatory layer, few TFs can bind RNA and modulate mRNA splicing. Yet, the mechanistic cues underlying TFs function in splicing remain elusive. Focusing on theDrosophilaHox TF Ultrabithorax (Ubx), our work shed light on a novel layer of Ubx function at the RNA level. Transcriptome and genome-wide binding profiles in embryonic mesoderm andDrosophilacells indicate that Ubx regulates mRNA expression and splicing to promote distinct functions in defined cellular contexts. Ubx modulates splicing via its DNA-binding domain, the Homeodomain (HD). Our results demonstrate a new RNA-binding ability of Ubx in cells andin vitro. Notably, the N51 amino acid of the HD, which mediates Ubx-DNA interaction, is non-essential for Ubx-RNA interactionin vitrobut is requiredin vivo. We find that the N51 amino acid is necessary to mediate interaction between Ubx and the active form of the RNA Polymerase II (Pol II S2Phos) inDrosophilacells. By combining molecular and imaging approaches, our results reveal that Ubx mediates elongation-coupled splicing via a dynamic interplay with active Pol II and chromatin binding. Overall, our work uncovered a novel role of the Hox TFs at the mRNA regulatory layer. This could be an essential function for other classes of TFs to control cell diversity.
Anti-cancer properties of cannabidiol and Δ9-tetrahydrocannabinol and potential synergistic effects with gemcitabine, cisplatin and other cannabinoids in bladder cancer
Authors: Tomko Andrea M. , Whynot Erin G. , Dupré Denis J.
Published: March 2021

Introduction

With the legalization of cannabis in multiple jurisdictions throughout the world, a larger proportion of the population consumes cannabis. Several studies have demonstrated anti-tumor effects of components present in cannabis in different models. Unfortunately, little is known about the potential anti-tumoral effects of cannabinoids in bladder cancer, and how cannabinoids could potentially synergize with chemotherapeutic agents. Our study aims to identify whether a combination of cannabinoids, like cannabidiol and Δ9-tetrahydrocannabinol with agents commonly used to treat bladder cancer, such as gemcitabine and cisplatin, is able to produce desirable synergistic effects. We also evaluated whether co-treatment of different cannabinoids also generated synergistic effects.

Materials and Methods

We generated concentration curves with different drugs to identify the range at which they could exert anti-tumor effects. We also evaluated the activation of the apoptotic cascade and whether cannabinoids have the ability to reduce invasion.

Results

Cannabidiol, Δ9-tetrahydrocannabinol and other cannabinoids reduce cell viability of bladder cancer cell lines, and their combination with gemcitabine or cisplatin may induce differential responses: from antagonistic to additive and synergistic effects, depending on the concentrations used. Cannabidiol and Δ9-tetrahydrocannabinol were also shown to induce caspase 3 cleavage and reduce invasion in a Matrigel assay. Cannabidiol and Δ9-tetrahydrocannabinol also display synergistic properties with other cannabinoids like cannabichromene or cannabivarin.

Discussion

Our results indicate that cannabinoids can reduce human bladder transitional cell carcinoma cell viability, and that they can potentially exert synergistic effects when combined with other agents. Ourin vitroresults will form the basis for future studiesin vivoand in clinical trials for the development of new therapies that could be beneficial for the treatment of bladder cancer in the future.
Antiviral Antibody Epitope Selection is a Heritable Trait
Authors: Venkataraman Thiagarajan , Valencia Cristian , Mangino Massimo , Morgenlander William , Clipman Steven J. , Liechti Thomas , Valencia Ana , Christofidou Paraskevi , Spector Tim , Roederer Mario , Duggal Priya , Larman H. Benjamin
Published: March 2021

There is enormous variability in human immune responses to viral infections. However, the genetic factors that underlie this variability are not well characterized. We used VirScan, a high-throughput viral epitope scanning technology, to analyze the antibody binding specificities of twins and SNP-genotyped individuals. These data were used to estimate the heritability and identify genomic loci associated with antibody epitope selection, response breadth, and the control of Epstein-Barr Virus (EBV) viral load. We identified 4 epitopes of EBV that were heritably targeted, and at least two EBNA-2 binding specificities that were associated with variants in the MHC class-II locus. We identified an EBV serosignature that predicted viral load in white blood cells and was associated with genetic variants in the MHC class-I locus. Our study provides a new framework for identifying genes important for pathogen immunity, with specific implications for the genetic architecture of EBV humoral responses and the control of viral load.

Abstract Figure
Parasitic nematode fatty acid- and retinol-binding proteins compromise host immunity by interfering with host lipid signaling pathways
Authors: Parks Sophia C. , Nguyen Chau , Nasrolahi Shyon , Juncaj Damian , Lu Dihong , Ramaswamy Raghavendran , Dhillon Harpal , Buchman Anna , Akbari Omar S. , Yamanaka Naoki , Boulanger Martin J. , Dillman Adler R.
Published: March 2021

Parasitic nematodes cause significant morbidity and mortality globally. Excretory/secretory products (ESPs) such as fatty acid- and retinol- binding proteins (FARs) are hypothesized to suppress host immunity during infection, yet little is known about their interactions with host tissues. Leveraging the insect parasitic nematode,Steinernema carpocapsae, we provide the firstin vivostudy that shows FARs modulate animal immunity, causing an increase in susceptibility to bacterial infection. Next we determined that FARs dampen various aspects of the fly immune response including the phenoloxidase cascade and antimicrobial peptide (AMP) production. Finally, we found that FARs deplete lipid signaling precursorsin vivoas well as bind to these fatty acidsin vitro, suggesting that FARs elicit their immunomodulatory effects by altering the availability of lipid signaling molecules necessary for a functional immune response. Collectively, these data reveal a complex role for FARs in immunosuppression and provide detailed mechanistic insight into parasitism in phylum Nematoda.

Significance

A central aspect of parasitic nematode success is their ability to modify host biology, including evasion and/or subversion of host immunity. Modulation of host biology and the pathology caused by parasitic nematodes is largely effected through the release of proteins and small molecules. There are hundreds of proteins released by nematodes during an infection and few have been studied in detail. Fatty acid- and retinol-binding proteins (FARs) are a unique protein family released during infection. We report that nematode FARs fromS. carpocapsae,C. elegansandA. ceylanicumdampen fly immunity decreasing resistance to infection. Mechanistically, this is achieved through modulation of the phenoloxidase cascade and antimicrobial peptide production. Furthermore, FARs alter the availability of lipid immune signaling precursorsin vivoand show binding specificityin vitro.

Graphical Abstract
Model-based data analysis of tissue growth in thin 3D printed scaffolds
Authors: Browning Alexander P , Maclaren Oliver J , Buenzli Pascal R , Lanaro Matthew , Allenby Mark C , Woodruff Maria A , Simpson Matthew J
Published: March 2021

Tissue growth in three-dimensional (3D) printed scaffolds enables exploration and control of cell behaviour in biologically realistic geometries. Cell proliferation and migration in these experiments have yet to be explicitly characterised, limiting the ability of experimentalists to determine the effects of various experimental conditions, such as scaffold geometry, on cell behaviour. We consider tissue growth by osteoblastic cells in melt electro-written scaffolds that comprise thin square pores with sizes that we deliberately vary. We collect highly detailed temporal measurements of the average cell density, tissue coverage, and tissue geometry. To quantify tissue growth in terms of the underlying cell proliferation and migration processes, we introduce and calibrate a mechanistic mathematical model based on the Porous-Fisher reaction-diffusion equation. Parameter estimates and uncertainty quantification through profile likelihood analysis reveal consistency in the rate of cell proliferation and steady-state cell density between pore sizes. This analysis also serves as an important model verification tool: while the use of reaction-diffusion models in biology is widespread, the appropriateness of these models to describe tissue growth in 3D scaffolds has yet to be explored. We find that the Porous-Fisher model is able to capture features relating to the cell density and tissue coverage, but is not able to capture geometric features relating to the circularity of the tissue interface. Our analysis identifies two distinct stages of tissue growth, suggests several areas for model refinement, and provides guidance for future experimental work that explores tissue growth in 3D printed scaffolds.

Author Summary

Advances in 3D printing technology have led to cell culture experiments that realistically capture natural biological environments. Despite the necessity of quantifying cell behaviour with parameters that can be compared between experiments, many existing mathematical models of tissue growth in these experiments neglect information relating to population size. We consider tissue growth by cells on 3D printed scaffolds that comprise square pores of various sizes in this work. We apply a relatively simple mathematical model based on the Porous-Fisher reaction-diffusion equation to interpret highly detailed measurements relating to both the cell density and the quantity of tissue deposited. We analyse the efficacy of such a model in capturing cell behaviour seen in the experiments and quantify cell behaviour in terms of parameters that carry a biologically meaningful interpretation. Our analysis identifies important areas for model refinement and provides guidance for future data-collection and experimentation that explores tissue growth in 3D printed scaffolds.
Evolved changes in DNA methylation in response to the sustained loss of parental care in the burying beetle
Authors: Mashoodh R , Sarkies P , Westoby J , Kilner RM
Published: March 2021

Levels of parental care critically influence the developmental environment with the capacity to impact the growth, survival, physiology, and behaviour of offspring. Plastic changes in DNA methylation have been hypothesised to modulate gene expression responses to parental environments. Moreover, these effects can be inherited and so may affect the process of adaptive evolution. In this study, using experimental evolution, we investigated how plastic changes in DNA methylation induced by the loss of parental care have evolved in a biparental insect (Nicrophorus vespilloides) using experimental evolution. We show that removal of care in a single generation is associated with changes in gene expression in stress-related pathways in 1st instar larvae. However, in larvae that have adapted to the loss of parental care after being deprived of care for 30 generations, gene expression is shifted from stress-related gene expression towards growth and brain development pathways. We found that changes in gene body methylation arose both as a direct response to the loss of parental care and stochastically as populations diverged. Overall, our results suggest that a complex interplay between transcription and DNA methylation shapes the molecular adaptation to environmental change.