bluuebunny/crossref_metadata_2025 huggingface dataset:
Permutation tests for comparative data
Authors: Saulsbury James G.
Published: October 2020

The analysis of patterns in comparative data has come to be dominated by least-squares regression, mainly as implemented in phylogenetic generalized least-squares (PGLS). This approach has two main drawbacks: it makes relatively restrictive assumptions about distributions and can only address questions about the conditional mean of one variable as a function of other variables. Here I introduce two new non-parametric constructs for the analysis of a broader range of comparative questions: phylogenetic permutation tests, based on cyclic permutations and permutations conserving phylogenetic signal. The cyclic permutation test, an extension of the restricted permutation test that performs exchanges by rotating nodes on the phylogeny, performs well within and outside the bounds where PGLS is applicable but can only be used for balanced trees. The signal-based permutation test has identical statistical properties and works with all trees. The statistical performance of these tests compares favorably with independent contrasts and surpasses that of a previously developed permutation test that exchanges closely related pairs of observations more frequently. Three case studies illustrate the use of phylogenetic permutations for quantile regression with non-normal and heteroscedastic data, testing hypotheses about morphospace occupation, and comparative problems in which the data points are not tips in the phylogeny.
Investigating hsCRP as a clinical inflammation marker for human Bisphenol A food contamination offers protocol suggestions for conducting replicable, causal dietary intervention studies
Authors: Perdue W. Lewis , Reus Victor I. , Yeamans-Irwin Rebecca L.
Published: October 2020

Dietary intervention studies thus far have failed to be replicable or causal. The results, therefore, have failed to provide clinicians and the general public with consistent and useful information on which to base reliable food-related health decisions. This is particularly relevant regarding plastic-derived chemicals (PDCs), such as Bisphenol A, now that the federal CLARITY-BPA program has failed to achieve scientific consensus. Investigators propose a novel human dietary protocol that is both replicable and causal, based upon BPA’s demonstrated inflammatory effects in humans. This first-of-a-kind dietary intervention study explores a potential causal relationship between human serum levels of BPA and High-Sensitivity C-Reactive Protein (hsCRP), a proven clinical indicator of inflammation. Investigators used the equivalent of a USDA-defined “typical diet” followed by a PDC-reduced diet to compare blood levels of hsCRP. This proof-of-concept investigation is the first to use an easily accessible, medically-accepted clinical laboratory test to directly measure human health effects of PDC reduction. Unexpected new complications discovered during the investigation indicate that these results may yet be inconclusive for direct causal relationship. However, the novel lessons and techniques developed as a result of those discoveries offer further specific and improved methods and best practices that can enable future dietary interventions to produce replicable, causal results.
Circulating tumor DNA is readily detectable among Ghanaian breast cancer patients supporting non-invasive cancer genomic studies in Africa
Authors: Ahuno Samuel Terkper , Doebley Anna-Lisa , Ahearn Thomas U. , Yarney Joel , Titiloye Nicholas , Hamel Nancy , Adjei Ernest , Lamptey Joe-Nat Clegg- , Edusei Lawrence , Awuah Baffour , Song Xiaoyu , Vanderpuye Verne , Abubakar Mustapha , Duggan Maire , Stover Daniel , Nyarko Kofi , Bartlet John M S , Aitpillah Francis , Ansong Daniel , Gardner Kevin L , Boateng Felix Andy , Bowcock Anne M. , Caldas Carlos , Foulkes William D. , Wiafe Seth , Wiafe-Addai Beatrice , Garcia-Closas Montserrat , Kwarteng Alexander , Ha Gavin , Figueroa Jonine D. , Polak Paz
Published: October 2020

Circulating tumor DNA (ctDNA) sequencing studies could provide novel insights into the molecular pathology of cancer in sub-Saharan Africa. ctDNA was readily detected in 15 blood samples collected in Ghana at the time of suspected breast cancer. Genomic alterations previously associated with unfavorable prognostic outcomes were observed in the majority of patients. This supports the use of liquid biopsies for diagnosis, surveillance and clinical management of breast cancer in Ghana.
Effect of Seating Arrangement on Class Engagement in Team-based Learning: A Quasi-Experimental Study
Authors: Andrew Seet Hong An , Tan Emmanuel , Rajalingam Preman
Published: October 2020

Introduction

This study investigated the effects of seating distance and orientation on engagement in novice and experienced learners in a large classroom explicitly designed for Team-based Learning (TBL). Learning what affects TBL engagement may improve its implementation.

Methods

Participants were novice first-year and experienced second-year undergraduate medical students in Singapore (male=103, female=57). Their age ranged from 18 to 23 (M=19.5, SD=1.06). This quasi-experimental study considered two factors. Firstly, the distance from the teams’ table to the tutor’s table. Secondly, students’ orientation at each table, with either their front or back facing the tutor. Engagement was measured using two instruments, Situational Cognitive Engagement Measure and Classroom Engagement Survey at two TBL sessions – before and after swapping seating arrangements.

Results

For experienced students, seating distance did not significantly affect engagement (p=0.08–0.89). Novice student’s engagement levels decreased significantly for those who moved further; M=3.30 to 2.98 (p=0.009–0.023). However, overall engagement also decreased post-swap regardless of direction moved; M=3.26 to 3.00 (p=0.004). For both cohorts, seating orientation did not significantly affect engagement (p=0.07–0.62). Those unaffected by seating arrangement commended the classroom’s design, such as screens all around and quality audio-visual system. Novice students exhibited a stronger preference to sit nearer to the tutor than experienced students. Both groups preferred sitting with their front- facing the tutor.

Discussion

Within specially designed TBL classrooms, seating distance and orientation did not significantly affect engagement. Technologically enhanced team-centric spaces provide a favorable environment for TBL, though students’ preferences for seats may change with more TBL experience.
Fluctuating High Throughput Serological Assay Results in Recurrent Convalescent Plasma Donors
Authors: Luchsinger Larry L. , Rehmani Shiraz , Opalka Andrew , Strauss Donna , Hillyer Christopher D. , Shi Patricia , Sachais Bruce S.
Published: October 2020

The clinical and scientific communities rely on serology testing to analyze the degree of antibody-mediated immunity afforded to recovered patients from SARS-CoV-2 infection. Neutralizing antibodies present in COVID-19 convalescent plasma (CCP) remains a practical therapy to treat COVID-19 patients requiring hospitalization. However, it remains unclear how long antibody levels persist in CCP donors after recovery. An accurate estimation of antibody kinetics in CCP donors provide an important observation to further define the extent of long-term immunity in recovered patient and simultaneously inform CCP collection processes in efforts to improve CCP dosing and therapeutic outcome. In this study, we analyzed 63 donors and measured antibody levels using two high throughput screening assays (HTSA) designed to detect antibodies targeting the spike protein (S1) and nucleocapsid protein (NP) of SARS-CoV-2 and monitored antibody levels between 2-8 consecutive donations. We show that anti-S1 antibody levels, as measured using the Ortho Total Ig HTSA, increased over time in repeat CCP donors while anti-NP antibody levels, as measured using the Abbott IgG HTSA, were unchanged or decreased over time. When we normalized these data, we found that both the absolute levels of anti-S1 antibodies and the ratio between S1 and NP antibodies tends to increase over time. These data have important implications for the convalescent donation process, patient protection from future infection and characterization of the SARS-CoV-2 immune response.
Understanding bias when estimating life expectancy from age at death: A simulation approach applied to Morquio Syndrome A
Authors: Yin Xue , Ahn Jaeil , Boca Simina M.
Published: October 2020

Background

Life expectancy can be estimated accurately from a cohort of individuals born in the same year and followed from birth to death. Due to the difficult and time-consuming nature of following a cohort prospectively, life expectancy is often assessed based on death data, which may lead to potentially biased estimates. This is more likely to be a problem in rare diseases such as Morquio syndrome A.

Method

To investigate how accurate the estimation of life expectancy is using death data, we simulate the survival of individuals with Morquio syndrome A under four different survival scenarios. In each scenario, we estimate the mean and median survival times within a defined period and compare them with the true life expectancy.

Results

When life expectancy is constant during the entire period, using death data does not result in a biased estimate of life expectancy. However, when life expectancy increases during the follow-up period, using only death data leads to a substantial underestimation of life expectancy.

Conclusion

Life expectancy can change over time, along with changes in the environment and/or biomedical innovation. When the life expectancy is increasing — as is often expected to be the case in rare diseases — estimating it based on contemporary death data will result in a downward bias. Therefore, it is crucial to understand how estimates of life expectancy are obtained and to interpret them in an appropriate context, and to assess estimation methods within a sensitivity analysis framework, similar to the simulations performed herein.
Targeting influenza at the topologically conserved substructures
Authors: Ahamed Zubair , Vandana Kamjula , Bhuvaneswari Kakunuri
Published: October 2020

H9N2 avian influenza virus is a low pathogenic endemic strain in the domestic poultry of most of the Asian countries. Attempts have extensively failed in eradicating its diverse strains. To find the drug against the evolutionarily conserved substructures, the target protein sequence is analyzed through sequence and modelled structure for mapping the structurally conserved topology. The available drugs are screened against the deciphered topological map through the predicted ADMET and drug-likelihood scores. This study helps to build a theoretical framework to make the foremost potent drug.
Differences in pulmonary innate lymphoid cells are dependent on mouse age, sex and strain
Authors: Loering Svenja , Cameron Guy J. M , Bhatt Nirmal P , Belz Gabrielle T , Foster Paul S , Hansbro Philip M , Starkey Malcolm R
Published: October 2020

Innate lymphoid cells (ILC) are resident in the lung and are involved in both the maintenance of homeostasis and the pathogenesis of respiratory diseases. In this study, murine lung ILC were characterised using flow cytometry and the impact of mouse age, sex and strain were assessed. Lung ILC were found as early as postnatal day 4 and numbers peaked at 2 weeks, and then decreased as the lung matured. During postnatal lung development, ILC expressed differential amounts of ILC2-associated cell surface antigens including ST2, CD90.2 and ICOS. UsingIl5venusIl13td-tomatodual reporter mice, neonates were found to have increased constitutive IL-13 expression compared to adult mice. Neonates and adults had similar ratios of IL-5+CD45+leukocytes, however, these cells were mostly composed of ILC in neonates and T cells in adults. Sex-specific differences in ILC numbers were also observed, with females having greater numbers of lung ILC than males in both neonatal and adult mice. Female lung ILC also expressed higher levels of ICOS and decreased KLRG1. Mouse strain also impacted on lung ILC with BALB/c mice having more ILC in the lung and increased expression of ST2 and ICOS compared with C57BL/6J mice. Collectively, these data show that lung ILC numbers, cell surface antigen expression, IL-5 and IL-13 levels differed between neonatal and adult lung ILC. Additionally, cell surface antigens commonly used for ILC2 quantification, such as ST2, CD90.2, and ICOS, differ depending on age, sex and strain and these are important considerations for consistent universal identification of lung ILC2.
Understanding the impact of high-risk human papillomavirus on oropharyngeal squamous cell carcinomas in Taiwan: A retrospective cohort study
Authors: Hiles Guadalupe Lorenzatti , Chang Kai-Ping , Bellile Emily L. , Wang Chun-I , Yen Wei-Chen , Goudsmit Christine M. , Briggs Hannah L. , Thomas Trey B. , Peters Lila , Afsari Macy A. , Pinatti Lisa M. , Morris Anna C. , Jawad Nadine , Carey Thomas E. , Walline Heather M.
Published: October 2020

Background and Objectives

Human papillomavirus (HPV)-driven oropharyngeal squamous cell carcinoma (OPSCC) is increasing globally. In Taiwan, HPV-positive OPSCC is obscured by tobacco, alcohol, and betel quid use. We investigated the role of high-risk HPV (hrHPV) in a large retrospective Taiwan OPSCC cohort.

Methods and Results

The cohort of 541 OPSCCs treated at Chang Gung Memorial Hospital from 1998-2016 consisted of 507 men (94%) and 34 women (6%). Most used tobacco (81%), alcohol (51%), and betel quid (65%). Formalin-fixed, paraffin-embedded tissue was used for p16 staining (a surrogate marker for HPV) and testing for HPV DNA presence and type by Multiplex HPV PCR-MassArray. HPV DNA and/or p16 staining (HPV-positive) was found in 28.4% (150/528) tumors. p16 and HPV DNA were strongly correlated (F < 0.0001). HPV16 was present in 82.8%, and HPV58 in 7.5% of HPV-positive tumors. HPV was associated with higher age (55.5 vs. 52.7 years, p = 0.004), lower T-stage (p = 0.008) better overall survival (OS) (hazard ratio [HR] 0.58 [95% CI 0.42-0.81], p = 0.001), and disease-free survival (DFS) (HR 0.54 [95% CI 0.40-0.73], p < 0.0001). Alcohol was strongly associated with recurrence and death (OS: HR 2.06 [95% CI 1.54-2.74], p < 0.0001; DFS: HR 1.72 [95% CI 1.33-2.24], p < 0.0001). OS and DFS in HPV-positive cases decreased for alcohol users (p < 0.0001). Obscured by the strong alcohol effect, predictive associations were not found for tobacco or betel quid.

Conclusions

As with HPV-positive OPSCC globally, HPV is an increasingly important etiological factor in Taiwanese OPSCC. HPV-positive OPSCC has considerable survival benefit, but that is reduced by alcohol, tobacco, and betel quid use. hrHPV is a cancer risk factor in males and females. Vaccinating both sexes with a multivalent vaccine including HPV58, combined with alcohol and tobacco cessation policies will be effective cancer-prevention public health strategies in Taiwan.
Emergence of Clade III Candida auris of African Origin in Los Angeles
Authors: Price Travis K. , Mirasol Ruel , Ward Kevin W. , Dayo Ayrton J. , Chandrasekaran Sukantha , Garner Omai B. , de St Maurice Annabelle , Yang Shangxin
Published: October 2020

Candida auris is an emerging multi-drug resistant yeast responsible for invasive infections among hospitalized patients. We described a case series of C. auris isolated in the Los Angeles area from an ongoing outbreak. Genomic analysis showed a single Clade III lineage of African origin in all 6 cases since 2019.
Predicting the impact of COVID-19 interruptions on transmission of gambiense human African trypanosomiasis in two health zones of the Democratic Republic of Congo
Authors: Aliee Maryam , Castaño Soledad , Davis Christopher N , Patel Swati , Miaka Erick Mwamba , Spencer Simon EF , Keeling Matt J , Chitnis Nakul , Rock Kat S
Published: October 2020

Many control programmes against neglected tropical diseases have been interrupted due to COVID-19 pandemic, including those that rely on active case finding. In this study we focus on gambiense human African trypanosomiasis (gHAT), where active screening was suspended in the Democratic Republic of Congo (DRC) due to the pandemic. We use two independent mathematical models to predict the impact of COVID-19 interruptions on transmission and reporting, and the achievement of 2030 elimination of transmission (EOT) goal for gHAT in two moderate-risk regions of DRC. We consider different interruption scenarios, including reduced passive surveillance in fixed health facilities, and whether this suspension lasts until the end of 2020 or 2021. Our models predict an increase in the number of new infections in the interruption period only if both active screening and passive surveillance were suspended, and with slowed reduction - but no increase - if passive surveillance remains fully functional. In all scenarios, the EOT may be slightly pushed back if no mitigation such as increased screening coverage is put in place. However, we emphasise that the biggest challenge will remain in the higher prevalence regions where EOT is already predicted to be behind schedule without interruptions unless interventions are bolstered.
COVID-19 symptoms at hospital admission vary with age and sex: ISARIC multinational study
Authors: Pritchard Mark G ,   ISARIC Clinical Characterisation Group
Published: October 2020

Background

The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms.

Methods

International, prospective observational study of 60⍰109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms.

Results

‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30-to 60-year-olds (respectively 80%, 79%, 69%; at least one 95%). They were reported less frequently in children (≤18 years: 69%, 48%, 23%; 85%), older adults (≥70 years: 61%, 62%, 65%; 90%), and women (66%, 66%, 64%; 90%; vs men 71%, 70%, 67%; 93%). The most common atypical presentation under 60 years of age was nausea and vomiting, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country.

Interpretation

Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men.

Adults over 60 and children admitted to hospital with COVID-19 are less likely to have typical symptoms. Nausea and vomiting are common atypical presentations under 30 and confusion over 60. Women are less likely to experience typical symptoms than men.
Intention to have the seasonal influenza vaccination during the COVID-19 pandemic among eligible adults in the UK
Authors: Sherman Susan M. , Sim Julius , Amlôt Richard , Cutts Megan , Dasch Hannah , Rubin G James , Sevdalis Nick , Smith Louise E.
Published: October 2020

We investigated likelihood of having the seasonal influenza vaccination in 645 participants who were eligible for the vaccination in the UK. 55.8% indicated they were likely to have the vaccination. Previous research suggests that increasing uptake of the influenza vaccination may help contain a COVID-19 outbreak, so steps need to be taken to convert intention into behaviour and to reach the 23.9% who were unlikely to have the vaccination and the 20.3% who were unsure.
Hyper-Exponential Growth of COVID-19 during Resurgence of the Disease in Russia
Authors: Baruah Hemanta K.
Published: October 2020

In Russia, COVID-19 has currently been growing hyper-exponentially. This type of a spread pattern was not seen during the first wave of the pandemic the world over. Indeed when the disease had first appeared, in the accelerating stage the spread pattern was observed to have followed a highly nonlinear pattern that could be said to be approximately exponential or sub-exponential. As to why in the resurgence the growth has become hyper-exponential is another matter. But this has been happening in Europe and how long this would continue cannot be predicted. It may so happen that in the countries in which retardation has already been taking place, there may be resurgence of the disease. It was observed that in the World as a whole, retardation was on the threshold during the second half of September. But if the resurgence happens to follow the hyper-exponential growth pattern in different countries, there may be resurgence in the World as a whole.
Altered hippocampal functional connectivity patterns in patients with cognitive impairments following ischaemic stroke: a resting-state fMRI study
Authors: Jung JeYoung , Laverick Rosanna , Nader Kurdow , Wilson Martin , Auer Dorothee P. , Rotshtein Pia , Hosseini Akram A.
Published: October 2020

Background

Ischemic stroke with cognitive impairment is a considerable risk factor for developing dementia. Identifying imaging markers of cognitive impairment following ischemic stroke will help to develop prevention strategies against post-stroke dementia.

Methods

Here, we investigated the hippocampal functional connectivity (FC) pattern following ischemic stroke, using resting-state fMRI (rs-fMRI). Thirty-three cognitively impaired patients after ischemic stroke and sixteen age-matched controls with no known history of neurological disorder, were recruited for the study. Importantly, no patient had a direct ischaemic insult to hippocampus on examination of brain imaging. Seven subfields of hippocampus were used as a seed region for FC analyses.

Results

Across all hippocampal subfields, FC with the inferior parietal lobe in patients was reduced as compared with healthy controls. This decreased FC included both supramarginal gyrus and angular gyrus. The FC of hippocampal subfields with cerebellum was increased. Importantly, the degree of the altered FC between hippocampal subfields and IPL was associated with their impaired memory function.

Conclusion

Our results demonstrated that decreased hippocampal-IPL connectivity was associated with cognitive impairment in patients with ischemic stroke. These findings provide novel insights into the role of hippocampus in cognitive impairment following ischemic stroke.
Reliability and Validity of Cognitive Workload in Older Adults
Authors: Devos Hannes , Gustafson Kathleen , Ahmadnezhad Pedram , Liao Ke , Mahnken Jonathan D. , Brooks William M. , Burns Jeffrey M.
Published: October 2020

Cognitive workload (mental effort) is a measure of attention allocation to a task, which can be administered through self-report or physiological measures. Cognitive workload is increasingly recognized as an important determinant of performance in cognitive tests and daily life activities. However, the reliability and validity of these measures have not been established in older adults with a wide range of cognitive ability. The aim of this study was to establish the test-retest reliability of the NASA-Task Load Index (NASA-TLX) and Index of Cognitive Activity (ICA), extracted from pupillary size. The convergent validity of these measures against event-related potentials (ERPs) was also investigated. A total of 38 individuals with scores on the Montreal Cognitive Assessment ranging between 17 and 30 completed a working memory test (n-back) with three levels of difficulty at baseline and two-week follow-up. Intraclass correlation coefficients (ICC) values of the NASA-TLX ranged between 0.71 and 0.81, demonstrating good to excellent reliability. Mean ICA scores showed fair to good reliability, with ICC’s ranging between 0.56 and 0.73. Mean ICA and NASA-TLX scores showed significant and moderate correlations (Pearson r range between 0.30 and 0.33) with P3 ERP at the midline channels. We conclude that ICC and NASA-TLX are reliable measures of cognitive workload in older adults. Further research is needed in dissecting the subjective and objective constructs of cognitive workload.
SARS-CoV-2 seroprevalence and detection fraction in Utah urban populations from a probability-based sample
Authors: Samore Matthew H. , Looney Adam , Orleans Brian , Greene Tom , Seegert Nathan , Delgado Julio C , Presson Angela , Zhang Chong , Ying Jian , Zhang Yue , Shen Jincheng , Slev Patricia , Gaulin Maclean , Yang Mu-Jeung , Pavia Andrew T. , Alder Stephen C.
Published: October 2020

This project’s aim was to generate an unbiased estimate of the incidence of SARS-CoV-2 infection in four urban counties in Utah. A multi-stage sampling design was employed to randomly select community-representative participants 12 years and over. Between May 4 and June 30, 2020, surveys were completed and sera drawn from 8,108 individuals belonging to 5,125 households. A qualitative chemiluminescent microparticle immunoassay was used to detect the presence of IgG antibody to SARS-CoV-2. The overall prevalence of IgG antibody to SARS-CoV-2 was estimated at 0.8%. The estimated seroprevalence-to-case count ratio was 2.4, corresponding to a detection fraction of 42%. Only 0.2% of individuals who had a nasopharyngeal swab collected were reverse transcription polymerase chain reaction (RT-PCR) positive. The prevalence of antibodies to SARS-CoV-2 in Utah urban areas between May and June was low and the prevalence of positive RT-PCR even lower. The detection fraction for COVID-19 in Utah was comparatively high.

Article Summary

Probability-based sampling provides an effective method for robust estimates of community-based SARS-CoV-2 seroprevalence and detection fraction among urban populations in Utah.
Discovery of runs-of-homozygosity diplotype clusters and their associations with diseases in UK Biobank
Authors: Naseri Ardalan , Zhi Degui , Zhang Shaojie
Published: October 2020

Runs of homozygosity (ROH) segments, contiguous homozygous regions in a genome were traditionally linked to families and inbred populations. However, a growing literature suggests that ROHs are ubiquitous in outbred populations. Still, most existing genetic studies of ROH in populations are limited to aggregated ROH content across the genome, which does not offer the resolution for mapping causal loci. This limitation is mainly due to a lack of methods for efficient identification of shared ROH diplotypes. Here, we present a new method, ROH-DICE, to find large ROH diplotype clusters, sufficiently long ROHs shared by a sufficient number of individuals, in large cohorts. ROH-DICE identified over 1 million ROH diplotypes that span over 100 SNPs and shared by more than 100 UK Biobank participants. Moreover, we found significant associations of clustered ROH diplotypes across the genome with various self-reported diseases, with the strongest associations found between the extended HLA region and autoimmune disorders. We found an association between a diplotype covering the HFE gene and haemochromatosis, even though the well-known causal SNP was not directly genotyped nor imputed. Using genome-wide scan, we identified a putative association between carriers of an ROH diplotype in chromosome 4 and an increase of mortality among COVID-19 patients. In summary, our ROH-DICE method, by calling out large ROH diplotypes in a large outbred population, enables further population genetics into the demographic history of large populations. More importantly, our method enables a new genome-wide mapping approach for finding disease-causing loci with multi-marker recessive effects at population scale.
Age-adjusted Charlson comorbidity index score is the best predictor for severe clinical outcome in the hospitalized patients with COVID-19 infection: a result from nationwide database of 5,621 Korean patients
Authors: Kim Do Hyoung , Park Hayne Cho , Cho Ajin , Kim Juhee , Yun Kyu-sang , Kim Jinseog , Lee Young-Ki
Published: October 2020

Aged population with comorbidities demonstrated high mortality rate and severe clinical outcome in the patients with coronavirus disease 2019 (COVID-19). However, whether age-adjusted Charlson comorbidity index score (CCIS) predict fatal outcomes remains uncertain. This retrospective, nationwide cohort study was performed to evaluate patient mortality and clinical outcome according to CCIS among the hospitalized patients with COVID-19 infection. We included 5,621 patients who had been discharged from isolation or had died from COVID-19 by April 30, 2020. The primary outcome was composites of death, admission to intensive care unit (ICU), use of mechanical ventilator or extracorporeal membrane oxygenation. The secondary outcome was mortality. Multivariate Cox proportional hazard model was used to evaluate CCIS as the independent risk factor for death. Among 5,621 patients, the high CCIS (≥3) group showed higher proportion of elderly population and lower plasma hemoglobin and lower lymphocyte and platelet counts. The high CCIS group was an independent risk factor for composite outcome (HR 3.63, 95% CI 2.45-5.37, P < 0.001) and patient mortality (HR 22.96, 95% CI 7.20-73.24, P < 0.001). The nomogram demonstrated that the CCIS was the most potent predictive factor for patient mortality. The predictive nomogram using CCIS for the hospitalized patients with COVID-19 may help clinicians to triage the high-risk population and to concentrate limited resources to manage them.
DAGBagM: Learning directed acyclic graphs of mixed variables with an application to identify prognostic protein biomarkers in ovarian cancer
Authors: Chowdhury Shrabanti , Wang Ru , Yu Qing , Huntoon Catherine J. , Karnitz Larry M. , Kaufmann Scott H. , Gygi Steven P. , Birrer Michael J. , Paulovich Amanda G. , Peng Jie , Wang Pei
Published: October 2020

Motivation

Directed gene/protein regulatory networks inferred by applying directed acyclic graph (DAG) models to proteogenomic data has been shown effective for detecting causal biomarkers of clinical outcomes. However, there remain unsolved challenges in DAG learning to jointly model clinical outcome variables, which often take binary values, and biomarker measurements, which usually are continuous variables. Therefore, in this paper, we propose a new tool, DAGBagM, to learn DAGs with both continuous and binary nodes. By using appropriate models for continuous and binary variables, DAGBagM allows for either type of nodes to be parents or children nodes in the learned graph. DAGBagM also employs a bootstrap aggregating strategy to reduce false positives and achieve better estimation accuracy. Moreover, the aggregation procedure provides a flexible framework to robustly incorporate prior information on edges for DAG reconstruction.

Results

As shown by simulation studies, DAGBagM performs better in identifying edges between continuous and binary nodes, as compared to commonly used strategies of either treating binary variables as continuous or discretizing continuous variables. Moreover, DAGBagM outperforms several popular DAG structure learning algorithms including the score-based hill climbing (HC) algorithm, constraint-based PC-algorithm (PC-alg), and the hybrid method max-min hill climbing (MMHC) even for constructing DAG with only continuous nodes. The HC implementation in the R package DAGBagM is much faster than that in a widely used DAG learning R package bnlearn. When applying DAGBagM to proteomics datasets from ovarian cancer studies, we identify potential prognostic protein biomarkers in ovarian cancer.

Availability and implementation

DAGBagMis made available as a github repositoryhttps://github.com/jie108/dagbagM.
Size-dependent tradeoffs in aggressive behavior towards kin
Authors: Fouilloux Chloe , Fromhage Lutz , Valkonen Janne K. , Rojas Bibiana
Published: October 2020

Aggression between juveniles can be unexpected, as their primary motivation is to survive until their reproductive stage. However, instances of aggression, which may escalate to cannibalism, can be vital for survival, although the factors (e.g. genetic or environmental) leading to cannibalism vary across taxa. While cannibalism can greatly accelerate individual growth, it may also reduce inclusive fitness when kin are consumed. As a solution to this problem, some cannibals demonstrate kin discrimination and preferentially attack unrelated individuals. Here, we used both experimental and modeling approaches to consider how physical traits (e.g. size in relation to opponent) and genetic relatedness mediate aggressive behavior in dyads of cannibalisticDendrobates tinctoriustadpoles. We paired sibling, half-sibling, and non-sibling tadpoles of different sizes together in an arena and recorded their aggression and activity. We found that the interaction between size and relatedness predicts aggressive behavior: large non-siblings are significantly more aggressive than large siblings. Unexpectedly, although siblings tended to attack less overall, in size mismatched pairs they attacked faster than in non-sibling treatments. Ultimately, it appears that larval aggression reflects a balance between relatedness and size where individuals trade-off their own fitness with that of their relatives.
A validated generally applicable approach using the systematic assessment of disease modules by GWAS reveals a multi-omic module strongly associated with risk factors in multiple sclerosis
Authors: Badam Tejaswi V.S. , de Weerd Hendrik A. , Martínez-Enguita David , Olsson Tomas , Alfredsson Lars , Kockum Ingrid , Jagodic Maja , Lubovac-Pilav Zelmina , Gustafsson Mika
Published: October 2020

Background

There are few (if any) practical guidelines for predictive and falsifiable multi-omics data integration that systematically integrate existing knowledge. Disease modules are popular concepts for interpreting genome-wide studies in medicine but have so far not been systematically evaluated and may lead to corroborating multi-omic modules.

Methods

We assessed eight module identification methods in 57 previously published expression and methylation studies of 19 diseases using GWAS enrichment analysis. Next, we applied the same strategy for multi-omics integration of 19 datasets of multiple sclerosis (MS), and further validated the resulting module using both GWAS and risk-factor associated genes from several independent cohorts.

Results

Our benchmark of modules showed that in immune-associated diseases modules inferred from clique-based methods were the most enriched for GWAS-genes. The multi-omics case study using MS revealed the robust identification of a module of 220 genes. Strikingly, most genes of the module was differentially methylated upon the action of one or several environmental risk factors in MS (n = 217, P = 10-47) and were also independently validated for association with five different risk factors of MS, which further stressed the high genetic and epigenetic relevance of the module for MS.

Conclusion

We believe our analysis provides a workflow for selecting modules and our benchmark study may help further improvement of disease module methods. Moreover, we also stress that our methodology is generally applicable for combining and assessing the performance of multi-omics approaches for complex diseases.
Condensation of Rubisco into a proto-pyrenoid in higher plant chloroplasts
Authors: Atkinson Nicky , Mao Yuwei , Chan Kher Xing , McCormick Alistair J.
Published: October 2020

Photosynthetic CO2 fixation in plants is limited by the inefficiency of the CO2-assimilating enzyme Rubisco (D-ribulose-1,5-bisphosphate carboxylase/ oxygenase)1–3. In plants possessing the C3 pathway, which includes most major staple crops, Rubisco is typically evenly distributed throughout the chloroplast stroma. However, in almost all eukaryotic algae Rubisco aggregates within a microcompartment known as the pyrenoid, in association with a CO2-concentrating mechanism that improves photosynthetic operating efficiency under conditions of low inorganic carbon4. Recent work has shown that the pyrenoid matrix is a phase-separated, liquid-like condensate5. In the alga Chlamydomonas reinhardtii, condensation is mediated by two components: Rubisco and the linker protein EPYC1 (Essential Pyrenoid Component 1)6,7. Here we show that expression of mature EPYC1 and a plant-algal hybrid Rubisco leads to spontaneous condensation of Rubisco into a single phase-separated compartment in Arabidopsis chloroplasts, with liquid-like properties similar to a pyrenoid matrix. The condensate displaces the thylakoid membranes and is enriched in hybrid Rubisco containing the algal Rubisco small subunit required for phase separation. Promisingly, photosynthetic CO2 fixation and growth is not impaired in stable transformants compared to azygous segregants. These observations represent a significant initial step towards enhancing photosynthesis in higher plants by introducing an algal CO2-concentrating mechanism, which is predicted to significantly increase the efficiency of photosynthetic CO2 uptake8,9.
The Big Five personality traits and CNS arousal in the resting state
Authors: Jawinski Philippe , Markett Sebastian , Sander Christian , Huang Jue , Ulke Christine , Hegerl Ulrich , Hensch Tilman
Published: October 2020

Based on Eysenck’s pioneering work, CNS arousal has long been considered an encouraging biological candidate that may explain individual differences in human personality. Yet, results from empirical studies remained inconclusive. Notably, the vast majority of published results have been derived from small samples, and EEG alpha power has usually served as exclusive indicator for CNS arousal. In this study, we selectedN= 468 individuals of the LIFE-Adult cohort and investigated the associations between the Big Five personality traits and CNS arousal by using the low-resolution electromagnetic tomography-based analysis tool VIGALL. Our analyses revealed that subjects who reported higher levels of extraversion and openness to experience, respectively, exhibited lower levels of CNS arousal in the resting state. Bayesian and frequentist analysis results were especially convincing for openness to experience. Among the lower-order personality traits, we obtained strongest evidence for neuroticism facet ‘impulsivity’ and reduced CNS arousal. We regard these findings as well in line with the postulations of Eysenck and Zuckerman and consistent with the assumptions of the ‘arousal regulation model’. Our results also agree with meta-analytically derived effect sizes in the field of individual differences research, highlighting the need for large studies with at least several hundreds of subjects.
The Social Role of Self-Control
Authors: Dunbar R.I.M. , Shultz Susanne
Published: October 2020

The capacity to inhibit prepotent actions (inhibitory self-control) plays an important role in many aspects of the behaviour of birds and mammals. Although a number of studies have used it as an index of foraging skills, inhibition is also crucial for maintaining the temporal and spatial coherence of bonded social groups. Using three different sets of comparative data, we show that, across primate species, the capacity for self-control correlates better with the demands of social contexts than with the demands of foraging contexts, whereas a more generalised capacity for causal reasoning correlates better with foraging contexts. In addition, we confirm the Passingham-Wise Conjecture that the capacity for self-control is unique to anthropoid primates. These results suggest that the capacity for self-control most likely evolved because it was crucial for the evolution of bonded social groups.

Significance Statement

The capacity for self-control has commonly been viewed as an index of foraging skills. In fact, it plays a much more important role in the social domain by enabling groups of animals to maintain social cohesion as they travel through time and space. In this respect, it is particularly important for species that live in stable bonded social groups (congregations). We show that, in this respect, it is uniquely characteristic of the anthropoid primates, in contrast to other kinds of reasoning tasks such as causal reasoning on which primates often perform no better than other birds and mammals.
Impact of the expectation on memory reconsolidation using a post retrieval extinction paradigm
Authors: Marinos Julia , Ashbaugh Andrea
Published: October 2020

Objective

The present study examined if the expectation for learning enhances reconsolidation of conditioned fear memories using the post-retrieval extinction paradigm in an undergraduate sample (n = 48).

Methods

The study took place over three consecutive days. The expectation for learning was manipulated through oral instructions prior to memory reactivation. On day one, participants underwent differential fear conditioning to two spider images (CS+ and CS-). On day two, participants were assigned to either a reactivation with expectation for learning group, a reactivation with no expectation for learning group, or a no reactivation group. On day three, return of fear in response to the CS+ spider image was measured following reinstatement (i.e., four shocks). Fear potentiated startle (FPS) and skin conductance response (SCR) were taken as measures of fear.

Results

The study found evidence that the expectation for learning may enhanced reconsolidation with FPS as a measure of fear as it was only the expectation for learning group in which FPS to the CS+ remained stable following reinstatement, however this effect was small and non-robust. In contrast, no evidence of reconsolidation was observed for SCR, as all participants exhibited a return of fear following reinstatement.

Implications

These findings suggest that a verbal manipulation of the expectation for learning may not be salient enough to induce reconsolidation as measured by SCR but may be sufficient as measured by FPS. Additionally, given in the inconsistent findings between SCR and FPS, the study’s results bring into question whether the post-retrieval extinction paradigm is appropriate to investigate reconsolidation using both physiological measures concurrently.
Integrating indigenous knowledge, ontology, and molecular barcoding to characterize spider monkey (Ateles paniscus) filariasis
Authors: Milstein Marissa S. , Shaffer Christopher A. , Lindsey Laramie L. , Wolf Tiffany M. , Suse Philip , Marawanaru Elisha , Kipp Evan J. , Garwood Tyler , Travis Dominic A. , Terio Karen A. , Larsen Peter A.
Published: October 2020

Zoonotic disease risk is greatly influenced by cultural practices and belief systems. Yet, few studies have integrated traditional ecological knowledge and ontology with western ways of knowing to better understand potential zoonoses. Here, we integrate molecular phylogenetics, histopathology, and ethnography to characterize a filarial nematode found within the abdominal cavity of spider monkeys (Ateles paniscus). The filarid is recognized as ‘spider monkey cotton’ by indigenous Waiwai in the Konashen Community Owned Conservation Area, Guyana. Ethnographic data revealed that the Waiwai perceive of ‘spider monkey cotton’ as a normal characteristic within the ‘spider monkey person.’ Further, the Waiwai indicated that ‘cotton’ was ubiquitous with spider monkeys and is not understood to be infectious nor zoonotic. This distinction is in contrast to other internal parasites found within spider monkeys that the Waiwai know to cause disease in both monkeys and humans. Our morphological and molecular characterization support the classification of the filarid asDipetalonema caudispina, a minimally studied and seemingly non-zoonotic parasite, consistent with Waiwai beliefs. Thus, our findings allow us to establish commensurability between scientific knowledge and indigenous ontology. More broadly, this work highlights the importance of integrating multiple knowledge systems and leveraging advanced genomics to better understand and prevent emerging zoonotic diseases.
Deep-learning based identification, tracking, pose estimation, and behavior classification of interacting primates and mice in complex environments
Authors: Marks Markus , Qiuhan Jin , Sturman Oliver , von Ziegler Lukas , Kollmorgen Sepp , von der Behrens Wolfger , Mante Valerio , Bohacek Johannes , Yanik Mehmet Fatih
Published: October 2020

The quantification of behaviors of interest from video data is commonly used to study brain function, the effects of pharmacological interventions, and genetic alterations. Existing approaches lack the capability to analyze the behavior of groups of animals in complex environments. We present a novel deep learning architecture for classifying individual and social animal behavior, even in complex environments directly from raw video frames, while requiring no intervention after initial human supervision. Our behavioral classifier is embedded in a pipeline (SIPEC) that performs segmentation, identification, pose-estimation, and classification of complex behavior, outperforming the state of the art. SIPEC successfully recognizes multiple behaviors of freely moving individual mice as well as socially interacting non-human primates in 3D, using data only from simple mono-vision cameras in home-cage setups.
Deep learning enables fast and dense single-molecule localization with high accuracy
Authors: Speiser Artur , Müller Lucas-Raphael , Matti Ulf , Obara Christopher J. , Legant Wesley R. , Kreshuk Anna , Macke Jakob H. , Ries Jonas , Turaga Srinivas C.
Published: October 2020

Single-molecule localization microscopy (SMLM) has had remarkable success in imaging cellular structures with nanometer resolution, but the need for activating only single isolated emitters limits imaging speed and labeling density. Here, we overcome this major limitation using deep learning. We developed DECODE, a computational tool that can localize single emitters at high density in 3D with highest accuracy for a large range of imaging modalities and conditions. In a public software benchmark competition, it outperformed all other fitters on 12 out of 12 data-sets when comparing both detection accuracy and localization error, often by a substantial margin. DECODE allowed us to take live-cell SMLM data with reduced light exposure in just 3 seconds and to image microtubules at ultra-high labeling density. Packaged for simple installation and use, DECODE will enable many labs to reduce imaging times and increase localization density in SMLM.