bluuebunny/crossref_metadata_2025 huggingface dataset:
An Efficient and Accurate Distributed Learning Algorithm for Modeling Multi-Site Zero- Inflated Count Outcomes
Authors: Edmondson Mackenzie J. , Luo Chongliang , Duan Rui , Maltenfort Mitchell , Chen Zhaoyi , Locke Kenneth , Shults Justine , Bian Jiang , Ryan Patrick B. , Forrest Christopher B. , Chen Yong
Published: December 2020

Clinical research networks (CRNs), made up of multiple healthcare systems each with patient data from several care sites, are beneficial for studying rare outcomes and increasing generalizability of results. While CRNs encourage sharing aggregate data across healthcare systems, individual systems within CRNs often cannot share patient-level data due to privacy regulations, prohibiting multi-site regression which requires an analyst to access all individual patient data pooled together. Meta-analysis is commonly used to model data stored at multiple institutions within a CRN; while relatively simple to implement, meta-analysis can result in biased estimation, notably in rare-event contexts. We present a communication-efficient, privacy-preserving algorithm for modeling multi-site zero-inflated count outcomes within a CRN. Our method, a one-shot distributed algorithm for performing hurdle regression (ODAH), models zero-inflated count data stored in multiple sites without sharing patient-level data across sites, resulting in estimates closely approximating those that would be obtained in a pooled patient-level data analysis. We evaluate our method through extensive simulations and two realworld data applications using electronic health records (EHRs): examining risk factors associated with pediatric avoidable hospitalization and modeling serious adverse event frequency associated with a colorectal cancer therapy. Relative to existing methods for distributed data analysis, ODAH offers a highly accurate, computationally efficient method for modeling multi-site zero-inflated count data.
History of premorbid depression is a risk factor for COVID-related mortality: Analysis of 1,387 COVID+ patients
Authors: Clouston Sean A. P. , Luft Benjamin J. , Sun Edward
Published: December 2020

Background

The goal of the present work was to examine risk factors for mortality in a 1,387 COVID+ patients admitted to a hospital in Suffolk County, NY.

Methods

Data were collated by the hospital epidemiological service for patients admitted from 3/7/2020-9/1/2020. Time until final discharge or death was the outcome. Cox proportional hazards models were used to estimate time until death among admitted patients.

Findings

In total, 99.06% of cases had resolved leading to 1,179 discharges and 211 deaths. Length of stay was significantly longer in those who died as compared to those who did not p=0.007). Of patients who had been discharged (n=1,179), 54 were readmitted and 9 subsequently died. Multivariable-adjusted Cox proportional hazards regression revealed that in addition to older age, male sex, and heart failure that a history of premorbid depression was a risk factors for COVI-19 mortality (HR = 2.64 [1.54-4.54] P<0.001), and that this association remained after adjusting for age and for neuropsychiatric conditions as well as medical comorbidities including cardiovascular disease and pulmonary conditions. Sex-stratified analyses revealed that associations between mortality and depression was strongest in males (aHR = 4.45 [2.04-9.72], P<0.001), and that the association between heart failure and mortality was strongest in participants aged <65 years old (aHR = 30.50 [9.17-101.48], P<0.001).

Interpretation

While an increasing number of studies have identified a number of comorbid medical conditions and age of patient as risk factors for mortality in COVID+ patients, this study reports that history of depression is a risk factor for COVID mortality.

Funding

No funding was received for this study.
SARS-CoV-2 RNAemia with higher nasopharyngeal viral load is strongly associated with severity and mortality in patients with COVID-19
Authors: Kawasuji Hitoshi , Morinaga Yoshitomo , Tani Hideki , Yoshida Yoshihiro , Taekgoshi Yusuke , Kaneda Makito , Murai Yushi , Kimoto Kou , Ueno Akitoshi , Miyajima Yuki , Kawago Koyomi , Fukui Yasutaka , Kimura Miyuki , Yamada Hiroshi , Sakamaki Ippei , Yamamoto Yoshihiro
Published: December 2020

Objective

This study aimed to determine the frequency of SARS-CoV-2 RNA in serum and its association with the clinical severity of COVID-19.

Methods

An analytical cross-sectional study was performed in a single tertiary care hospital and included consecutive patients with confirmed COVID-19. The prevalence of SARS-CoV-2 RNAemia and the strength of its association with clinical severity variables, including required oxygen supplementation, ICU admission, invasive mechanical ventilation, and in-hospital mortality, were examined.

Results

Fifty-six patients were included in the study. The median age was 54.5 years, and individuals with RNAemia were older than those without detectable SARS-CoV-2 RNA in serum (78 vs. 50 years; P = .0013). RNAemia was detected in 19.6% of patients (11/56) and in 1.0% (1/25), 50.0% (6/12), and 100.0% (4/4) of moderate, severe, and critically ill cases, respectively. Patients with RNAemia required more frequent oxygen supplementation (90.0% vs. 13.3%; P < .0001) and ICU admission (81.8% vs. 6.7%; P < .0001) and required invasive mechanical ventilation (27.3% vs. 0.0%; P < .0001). Among patients with RNAemia, the median viral loads of NP swabs that were collected around the same time as the serum were significantly higher in critically ill cases (5.4 Log10 copies/μL [IQR: 4.2–6.3]) than in moderate–severe cases (2.6 Log10 copies/μL [1.1–4.5]; P =.030) and were significantly higher in nonsurvivor cases (6.2 Log10 copies/μL [IQR: 6.0–6.5]) than in survivor cases (3.9 Log10 copies/μL [1.6–4.6]; P =.045).

Conclusions

This study demonstrated a relatively high proportion of SARS-CoV-2 RNAemia and an association between RNAemia and clinical severity. Moreover, among the patients with RNAemia, the viral loads of NP swabs were correlated with severity and mortality, thus suggesting the potential utility of combining serum testing with NP tests as a prognostic indicator for COVID-19 with a higher quality than each separate test.
Longitudinal analysis of COVID-19 patients shows age-associated T cell changes independent of ongoing ill-health
Authors: Townsend Liam , Dyer Adam H , Naughton Aifric , Kiersey Rachel , Holden Dean , Gardiner Mary , Dowds Joanne , O’Brien Kate , Bannan Ciaran , Nadarajan Parthiban , Dunne Jean , Martin-Loeches Ignacio , Fallon Padraic G , Bergin Colm , O’Farrelly Cliona , Ni Cheallaigh Cliona , Bourke Nollaig M , Conlon Niall
Published: December 2020

The trajectory of immunological and inflammatory changes following acute COVID-19 infection are unclear. We investigate immunological changes in convalescent COVID-19 and interrogate their potential relationships with persistent symptoms, termed long COVID.

We performed paired immunophenotyping at initial SARS-CoV-2 infection and convalescence (n=40, median 68 days) and validated findings in 71 further patients at median 101 days convalescence. Results were compared to 40 pre-pandemic controls. Fatigue and exercise tolerance were assessed and investigated their relationship with convalescent results.

We demonstrate persistent expansion of intermediate monocytes, effector CD8+, activated CD4+ and CD8+ T cells, and reduced naïve CD4+ and CD8+ T cells at 68 days, with activated CD8+ T cells remaining increased at 101 days. Patients >60 years also demonstrate reduced naïve CD4+ and CD8+ T cells and expanded activated CD4+ T cells at 101 days. Ill-health, fatigue, and reduced exercise tolerance were common but were not associated with immunological changes.

Graphical Abstract
Case finding of early pregnancies at risk of preeclampsia using maternal blood leptin/ceramide ratio: multi-omics discovery and validation from a longitudinal study
Authors: Huang Qianyang , Hao Shiying , You Jin , Yao Xiaoming , Li Zhen , Schilling James , Li Zhen , Thyparambil Sheeno , Liao Wei-li , Zhou Xin , Mo Lihong , Ladella Subhashini , Fan David , Whitin John C. , Cohen Harvey J. , McElhinney Doff B. , Wong Ronald J. , Shaw Gary M. , Stevenson David K. , Sylvester Karl G. , Ling Xuefeng B.
Published: December 2020

Objective

To evaluate whether longitudinal measurements of serological adipokines and sphingolipids can predict preeclampsia early in gestation.

Design

Retrospective multi-omics discovery and longitudinal validation.

Setting

Maternity units in two US hospitals.

Methods

A multi-omics approach integrating genomic and lipidomic discoveries was employed to identify leptin (Lep) and ceramide (Cer) as novel PE early gestational biomarkers. The levels of placental growth factor (PlGF), soluble fms-like tyrosine kinase (sFlt-1), Lep, and Cer in maternal sera were then determined by enzyme-linked immunosorbent (ELISA) and liquid chromatography-tandem mass spectrometric (LC/MS/MS) assays.

Main outcome measures

Interval from positive prediction to confirmative diagnosis.

Results

Genomic meta-analysis compiled six PE placental cohorts with 78 PE and 95 non-PE control placentas. The Testing Cohort included sera from 7 non-PE and 8 PE women collected at confirmatory diagnosis. The Validation Cohort included sera from 20 non-PE and 20 PE women collected longitudinally through gestation. Our findings revealed a marked elevation of maternal serum Leptin/Ceramide (d18:1/25:0) ratio from early gestation (a median of 23 weeks) when comparing later PE-complicated with uncomplicated pregnancies. The maternal Lep/Cer (d18:1/25:0) ratio significantly outperformed the established sFlt-1/PlGF ratio in predicting PE for sensitivity (85% vs. 40%), positive predictive value (89% vs. 42%), and AUC (0.92 vs. 0.52) from 5 to 25 weeks of gestation.

Conclusions

Non-invasive longitudinal assessment by serological evaluation of Lep/Cer (d18:1/25:0) ratio can case find early pregnancies at risk of preeclampsia, outperforming sFlt-1/PlGF ratio test.

Tweetable abstract

Non-invasive longitudinal assessment by serological evaluation of Lep and Cer ratio can predict preeclampsia early in gestation.
Temporally specific patterns of neural activity in interconnected corticolimbic structures during reward anticipation
Authors: Young Megan E. , Spencer-Salmon Camille , Mosher Clayton , Tamang Sarita , Rajan Kanaka , Rudebeck Peter H.
Published: December 2020

Functional neuroimaging studies indicate that interconnected parts of the subcallosal anterior cingulate cortex (ACC), striatum, and amygdala play a fundamental role in affect in health and disease. Yet, while the patterns of neural activity engaged in striatum and amygdala during affective processing are well established, especially during reward anticipation, little is known about subcallosal ACC. Here we recorded neural activity in non-human primate subcallosal ACC and compared this to interconnected parts of basolateral amygdala and rostromedial striatum while macaque monkeys performed reward-based tasks. Applying multiple analysis approaches, we found that neurons in subcallosal ACC and rostromedial striatum preferentially signal anticipated reward using short bursts of activity that form temporally specific patterns. By contrast, basolateral amygdala uses a mixture of both temporally specific and more sustained patterns of activity to signal anticipated reward. Thus, dynamic patterns of neural activity across populations of neurons are engaged in affect, especially in subcallosal ACC.

HIGHLIGHTS

Sustained changes in neural activity signal anticipated reward in basolateral amygdala

Temporally specific patterns signal anticipated reward in all areas recorded

Neurons exhibit more punctate encoding when tasks become more complex

Temporally specific patterns of neural activity signal different anticipated rewards in BLA
Mangroves are an overlooked hotspot of insect diversity despite low plant diversity
Authors: Yeo Darren , Srivathsan Amrita , Puniamoorthy Jayanthi , Maosheng Foo , Grootaert Patrick , Chan Lena , Guénard Benoit , Damken Claas , Wahab Rodzay A. , Yuchen Ang , Meier Rudolf
Published: December 2020

We here compare the tropical arthropod fauna across a freshwater swamp and six different forest types (rain-, swamp, dry-coastal, urban, freshwater swamp, mangroves) based on 140,000 barcoded specimens belonging toca. 8,500 species. Surprisingly, we find that mangroves, a globally imperiled habitat that had been expected to be species-poor for insects, are an overlooked hotspot for insect diversity despite having low plant diversity. Our study reveals a species-rich mangrove insect fauna (>3,000 species) that is distinct (>50% of species are mangrove-specific), and has high species turnover across Southeast and East Asia. For most habitats, plant diversity is a good predictor for insect diversity, but mangroves are an exception and compensate for a comparatively low number of phytophagous and fungivorous insect species by supporting an unusually rich community of predators whose larvae feed in the productive mudflats. For the remaining tropical habitats, the insect communities have diversity patterns that are largely congruent across guilds. The discovery of such a sizeable and distinct insect fauna in a globally threatened habitat underlines how little is known about global insect biodiversity.
Absence of electroencephalographic evidence of implicit action-effect intentional binding with varying effect probability
Authors: Seignette Max , Christensen Mark Schram
Published: December 2020

The subjective experience of an attraction in time of an action, and the event caused by the action, is known as the intentional binding phenomenon. Intentional binding is a robust phenomenon and has previously been associated with subjective sense of agency, but recent studies have shown that binding can take place in the absence of action intentions. In this study, we tested possible electrophysiological equivalents to the intentional binding phenomenon under a simple action-effect task, where pressing of a button caused tones to occur at different pitches or delays with different probabilities. Changing the probabilities of the effect of an action has in some previous studies shown to influence the intentional binding phenomenon. We tested whether changes in action-effect probability gave rise to differences in movement related cortical potentials (MRCP) slopes, peak latency and auditory event related potential (aERP) changes of amplitude or latency of the N1, P2, P3 and N4 components of the central aERP, of which some has been related to sense of agency or intentional binding. We also tested differences in MRCP across the whole scalp prior to movements, and to differences in aERP across the whole scalp after the tone is played. We found no electrophysiological indications of intentional binding when action-effect contingencies were changed in accordance with conditions that have given rise to intentional binding in previous experiments. Our results are in line with several recent studies that have questioned whether intentional binding follows all voluntary actions and can be related to sense of agency at all.
The effect of perturbation magnitude on lower limb muscle activity during reactive stepping using functional data analysis
Authors: Saumur Tyler M. , Nestico Jacqueline , Mochizuki George , Perry Stephen D. , Mansfield Avril , Mathur Sunita
Published: December 2020

This study aimed to determine the effect of perturbation magnitude on stance and stepping limb muscle activation during reactive stepping using functional data analysis. Nineteen healthy, young adults responded to 6 small and 6 large perturbations using an anterior lean-and-release system, evoking a single reactive step. Muscle activity from surface electromyography was compared between the two conditions for medial gastrocnemius, biceps femoris, tibialis anterior, and vastus lateralis of the stance and stepping limb using functional data analysis. Stance limb medial gastrocnemius and biceps femoris activation increased in the large compared to small perturbation condition immediately prior to foot-off and at foot contact. In the stepping limb, significant increases in medial gastrocnemius, biceps femoris, and tibialis anterior activity occurred immediately prior to foot-off during the large perturbations. Similar to the stance limb, medial gastrocnemius and biceps femoris activity significantly increased during and following foot contact in the large, compared to small, perturbation condition. Lastly, vastus lateralis activity significantly increased for large, compared to small, perturbations during foot-off and immediately following foot contact. These findings highlight lower limb muscle activity modulation associated with perturbation magnitude throughout reactive stepping and the additional benefit of implementing functional data analysis to study reactive balance control.
Maternal vitamin D deficiency impairs heart formation in mouse offspring through a change in 3D-chromatin structure
Authors: Seipelt Eva M. , Bensadoun Paul , Sati Satish , Couturier Charlène , Astier Julien , Mounien Lourdes , Landrier Jean-François , Pucéat Michel
Published: December 2020

The origins of congenital heart diseases, the most common congenital diseases are still largely unknown. Environmental factors are now emerging as major causes of these diseases. Vitamin D deficiency has become a public health burden, notably for childbearing age, pregnant and breastfeeding women. Since maternal 25-hydroxyvitamin D (25(OH)D) determined fetal and neonatal 25(OH)D status, foetuses exposed to insufficient levels of vitamin D, may feature developmental defects.

Herein, we investigated the effects of maternal vitamin D deficiency on cardiovascular defects in early and later life of offsprings in two generations as well as the molecular mechanisms underlying vitamin D effect.

Eight weeks before and during pregnancy, C57BL/6JRj female mice received a sufficient or vitamin D deficient diet ((1.0 IU/g in control vs 0.0 IU/g in Vitamin D Deficient (VDD) group). E16.5 Embryos of maternal VDD diet featured hypertrophic heart revealed by a thicker left ventricular (LV) wall and septum. RNAseq analysis of LV revealed 1555 transcripts differentially expressed in the VDD group and among them cardiac transcription factors and constitutive cardiac genes (tbx5, gata4, myl2). Anti-Vitamin D receptor (VDR) Chip-seq from chromatin of E16.5 LV uncovered different targeting oftbx5andtbx3loci by VDR in the VDD vs control embryos. Anti-CTCF ChIP-loop experiments focusing on theTbx3andTbx5loci uncovered a change in the Topology Associated Domains associated with these loci.

Echocardiography of 2-months-old VDD offspring revealed a significantly thicker left ventricle and increased fractional shortening while 6-months-old mice featured cardiac decompensation and in turn failing LV.

Maternal vitamin D deficiency severely affects heart formation following a change in chromatin conformation on cardiac gene loci and impacts function of adult hearts in two generations. These defects are likely to be at the origin of cardiovascular diseases in the adulthood.
Analysis of Genetically Determined Gene Expression Suggests Role of Inflammatory Processes in Exfoliation Syndrome
Authors: Hirbo Jibril B. , Pasutto Francesca , Gamazon Eric R. , Evans Patrick , Pawar Priyanka , Berner Daniel , Sealock Julia , Tao Ran , Straub Peter S. , Konkashbaev Anuar I. , Breyer Max , Schlötzer-Schrehardt Ursula , Reis André , Brantley Milam A. , Khor Chiea C. , Joos Karen M. , Cox Nancy J.
Published: December 2020

Exfoliation syndrome (XFS) is an age-related systemic disorder characterized by excessive production and progressive accumulation of abnormal extracellular material, with pathognomonic ocular manifestations. It is the most common cause of secondary glaucoma, resulting in widespread global blindness. We performed Transcriptomic Wide Association Studies (TWAS) using PrediXcan models trained in 48 GTEx tissues to identify genetically- determined gene expression changes associated with XFS risk, leveraging on results from a global GWAS that included 123,457 individuals from 24 countries. We observed twenty-eight genes in a three-Megabase chr15q22-25 region that showed statistically significant associations, which were further whittled down to ten genes after additional statistical validations. In experimental analysist of these ten genes, mRNA transcript levels forARID3B, CD276, LOXL1, NEO1, SCAMP2,andUBL7were significantly decreased in iris tissues from XFS patients compared to control samples. Genes with genetically determined expression changes in XFS were significantly enriched for genes associated with inflammatory conditions. We further explored the health consequences of high susceptibility to XFS using a large electronic health record and observed a higher incidence of XFS comorbidity with inflammatory and connective tissue diseases. Our results implicate a role for connective tissues and inflammation in the etiology of XFS. Targeting the inflammatory pathway may be a potential therapeutic option to reduce progression in XFS.
Structural properties and peptide ligand binding of the capsid homology domains of human Arc
Authors: Hallin Erik I. , Bramham Clive R. , Kursula Petri
Published: December 2020

The activity-regulated cytoskeleton-associated protein (Arc) is important for synaptic scaling and the normal function of the brain. Arc interacts with many neuronal postsynaptic proteins, but the mechanistic details of its function have not been fully established. The C-terminal domain of Arc consists of tandem domains, termed the N- and C-lobe. The N-lobe harbours a peptide binding site, able to bind to multiple targets. By measuring the affinity of various peptides towards human Arc, we have refined the specificity determinants of this site. We found two sites in the GKAP repeat region that may bind to Arc and confirmed these interactions by X-ray crystallography. Comparison of the crystal structures of three human Arc-peptide complexes identifies 3 conserved C-H...πinteractions at the binding cavity, which explain the sequence specificity of short linear motif binding by Arc. By analysing the structures, we further characterise central residues of the Arc lobe fold, show the effects of peptide binding on protein dynamics, and identify acyl carrier proteins as structures similar to the Arc lobes. We hypothesise that Arc may affect protein-protein interactions and phase separation at the postsynaptic density, affecting protein turnover and re-modelling of the synapse.
Substrate-engaged type III secretion system structures reveal gating mechanism for unfolded protein translocation
Authors: Miletic Sean , Fahrenkamp Dirk , Goessweiner-Mohr Nikolaus , Wald Jiri , Pantel Maurice , Vesper Oliver , Kotov Vadim , Marlovits Thomas C.
Published: December 2020

Many bacterial pathogens strictly rely on the activity of type III secretion systems (T3SSs) to secrete and translocate effector proteins in order to establish infection. The central component of T3SSs is the needle complex, a supramolecular machine which assembles a continuous conduit crossing the bacterial envelope and the host cell membrane to allow bacterial effectors to gain entry into the host cell cytoplasm to modulate signal transduction processes. Disruption of this process impairs pathogenicity, providing an avenue for antimicrobial design. However, the molecular principles underlying T3 secretion remain elusive. Here, we report the first structure of an activeSalmonella entericasv. Typhimurium needle complex engaged with the late effector protein SptP in two functional states, revealing the complete 800Å-long secretion conduit and unravelling the critical role of the export apparatus (EA) subcomplex in T3 secretion. Unfolded substrates enter the EA through a hydrophilic constriction formed by SpaQ proteins, which enables side chain-independent transport, explaining heterogeneity and structural disorder of signal sequences in T3SS effector proteins. Above, a methionine gasket formed by SpaP proteins functions as a gate that dilates to accommodate substrates but prevents leaky pore formation to maintain the physical boundaries of compartments separated by a biological membrane. Following gate penetration, a moveable SpaR loop first folds up to then act akin to a linear ratchet to steer substrates through the needle complex. Together, these findings establish the molecular basis for substrate translocation through T3SSs, improving our understanding of bacterial pathogenicity and motility of flagellated bacteria, and paves the way for the development of novel concepts combating bacterial infections.
AI4AMP: Sequence-based antimicrobial peptides predictor using physicochemical properties-based encoding method and deep learning
Authors: Lin Tzu-Tang , Yang Li-Yen , Lu I-Hsuan , Cheng Wen-Chih , Hsu Zhe-Ren , Chen Shu-Hwa , Lin Chung-Yen
Published: December 2020

Motivation

Antimicrobial peptides (AMPs) are innate immune components that have aroused a great deal of interest among drug developers recently, as they may become a substitution for antibiotics. However, AMPs discovery through traditional wet-lab research is expensive and inefficient. Thus, we developed AI4AMP, a user-friendly web-server that provides an accurate prediction of the antimicrobial activity of a given protein sequence, to accelerate the process of AMP discovery.

Results

Our results show that our prediction model is superior to the existing AMP predictors.

Availability

AI4AMP is freely accessible athttp://symbiosis.iis.sinica.edu.tw/PC_6/

Contact

cylin@iis.sinica.edu.tw
Coordinated regulation of ribosomes and proteasomes by PRMT1 in the maintenance of neural stemness of cancer cells and neural stem cells
Authors: Chen Lu , Zhang Min , Fang Lei , Yang Xiaoli , Xu Liyang , Shi Lihua , Cao Ning , Cao Ying
Published: December 2020

Our studies suggest that neural stemness contributes to cell tumorigenicity. The basic cell physiological machineries and developmental programs, such as cell cycle, ribosomes, proteasomes, epigenetic factors, etc., which are upregulated in and promote cancers, are enriched in embryonic neural cells. How these machineries are coordinated is unknown. Here, we show that loss of neural stemness in cancer cells or neural stem cells leads to simultaneous downregulation of components of ribosomes and proteasomes, which are responsible for protein synthesis and degradation, respectively, and downregulation of major epigenetic factors. Inhibition of PRMT1 causes neuron-like differentiation, downregulation of a similar set of proteins, and alteration of subcellular localization of ribosome and proteasome components. PRMT1 interacts with these components, catalyzes arginine methylation of them and protects them from degradation, thereby maintaining a high level of expression of epigenetic factors that maintain neural stemness. PRMT1 inhibition results in repression of cell tumorigenicity. Therefore, PRMT1 coordinates ribosomes and proteasomes to match the needs for high protein production and protein homeostasis in cells with fast cell cycle and proliferation.
On the timing of interventions to preserve hospital capacity: lessons to be learned from the Belgian SARS-CoV-2 pandemic
Authors: Hens Niel , Faes Christel , Gilbert Marius
Published: December 2020

Using publicly available data on the number of new hospitalisations we use a newly developed phase portrait to monitor the epidemic allowing for assessing whether or not intervention measures are needed to keep hospital capacity under control. Using this phase portrait, we show that intervention measures were effective in mitigating a Summer resurgence but that too little too late was done to prevent a large autumn wave in Belgium.
Perceptions and Practices of Key Worker Stakeholder Groups in Hospital Animal-Assisted Intervention Programs on Occupational Benefits and Perceived Risks
Authors: Dalton Kathryn R. , Altekruse William , Campbell Peter , Ruble Kathy , Carroll Karen C. , Thorpe Roland J. , Agnew Jacqueline , Davis Meghan F.
Published: December 2020

Background

Animal-assisted intervention (AAI) programs, used widely for patient benefit, have increasingly been used for healthcare workers (HCW) to reduce occupational stress. However, there are barriers to these programs which limit their utilization, for both patients and HCW, specifically infectious disease concerns. The aim of the research project is to identify barriers and facilitators to AAI program use for healthcare worker benefit, and determine knowledge, beliefs, and practices regarding infectious disease risk and control policies, in order to understand the contextual parameters of program implementation.

Methods

We collected perceptions of key stakeholders involved with hospital AAI programs (HCW and AAI workers) through semi-structured in-depth interviews. We used framework analysis to guide thematic coding, completed independently by three researchers.

Results

We interviewed 37 participants. We divided our themes into two topic areas: program use for HCW and perceived infectious disease risk. Use for healthcare workers included perspectives on the benefits for HCW and program barriers and facilitators (specifically collaboration and leadership). Perceived risk included opinions on infection concerns with AAI, thoughts on control measures to reduce this risk, and responsibility for safety during these programs.

Conclusions

While significant benefits were reported for HCW, they were limited by administrative barriers and hazard concerns. Facilitators to surmount these barriers are best implemented with collaboration across the hospital and appropriate leadership roles to direct safe program implementation. By addressing these barriers through targeted facilitators in the form of evidence-backed guidelines, AAI programs can be used to benefit both patients and HCW.
Impact of the COVID-19 Pandemic and Vaccine Hesitancy among Farmworkers from Monterey County, California
Authors: Mora Ana M. , Lewnard Joseph A. , Kogut Katherine , Rauch Stephen , Morga Norma , Jewell Nicholas , Cuevas Maximiliano , Eskenazi Brenda
Published: December 2020

Objectives

To examine the impact of the COVID-19 pandemic on farmworkers from Monterey County, California.

Methods

We recruited adult farmworkers (n=1115) between July 16, 2020 and November 30, 2020. We collected information on sociodemographic characteristics, health behaviors, economic and social stressors experienced during COVID-19, and willingness to be vaccinated via interviews by phone.

Results

Study participants, particularly female farmworkers, reported adverse effects of the pandemic on their mental health and home environment (e.g., 24% overall reported depression and/or anxiety symptoms). The pandemic also resulted in greater financial burden for many farmworkers, with 37% food insecure and 51% unable to pay bills. Half of respondents reported that they were extremely likely to be vaccinated. Vaccine hesitancy was most common in participants who were women, younger, born in the United States, and living in more rural areas.

Conclusions

We found that the pandemic has substantially impacted the mental and physical health and economic and food security of farmworkers.

Public Health Implications

This study highlights the need to provide farmworkers with supplemental income, and increased mental and family health, and food support services.
Progressing adaptation of SARS-CoV-2 to humans
Authors: Konishi Tomokazu
Published: December 2020

The second and subsequent waves of coronavirus disease 2019 (COVID-19) have caused problems worldwide1. Here, using an objective analytical method2, we present the changes that occurred in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus of COVID-19, over time. The virus has mutated in three major directions, resulting in three groups to date. Analysis of the basic structure of the group of viruses was completed by April and shared across all continents. However, the virus continued to mutate independently in each country after the borders were closed. In particular, the virus mutated before the occurrence of the second and subsequent peaks. It seems that the mutations conferred higher infectivity to the virus, because of which the virus overcame previously effective protection and caused second waves of the disease. Currently, each country may possess such a unique, stronger variant. Some of them slowly entered other countries and caused epidemics. These viruses could also serve as sources of further mutations by exchanging parts of the genome, which could create variants with superior infectivity.
Genetic polymorphism of CYP2C19 and subcortical variability in the human adult brain
Authors: Stingl Julia C. , Scholl Catharina , Bosch Julia E. , Viviani Roberto
Published: December 2020

Pharmacogenetic studies have shown involvement of cytochrome P450 enzymes in the metabolism of psychotropic drugs. However, expression and activity on endogenous substrates in the brain may underlie a constitutive role of these enzymes beyond drug metabolism. CYP2C19, which is expressed in the human fetal brain during neurodevelopment, shows affinity for endogenous compounds including monoaminergic neurotransmitters, steroid hormones, and endocannabinoids. In this study (N=608), we looked at the genetic polymorphism of CYP2C19 and its potential associations with structural phenotypes of subcortical brain volume with structural imaging. Using two independent volume estimation techniques, we found converging evidence for a positive association betweenCYP2C19activity scores, as inferred from the genotype, and basal ganglia and hippocampal volume. This association was present only in female individuals, raising the possibility that effects on brain morphology may arise through a mechanism involving the metabolism of estrogen steroids.
Conditioned fear reactions are associated with gray matter density but not cortical microstructure
Authors: Fraenz Christoph , Metzen Dorothea , Merz Christian J. , Selpien Helene , Axmacher Nikolai , Genç Erhan
Published: December 2020

Research has shown that fear acquisition, in reaction to potentially harmful stimuli or situations, is characterized by pronounced interindividual differences. It is likely that such differences are evoked by variability in the macro- and microstructural properties of brain regions involved in the processing of threat or safety signals from the environment. Indeed, previous studies have shown that the strength of conditioned fear reactions is associated with the cortical thickness or volume of various brain regions. However, respective studies were exclusively targeted at single brain regions instead of whole brain networks. Here, we tested 60 young and healthy individuals in a differential fear conditioning paradigm while they underwent fMRI scanning. In addition, we acquired T1-weighted and multi-shell diffusion-weighted images prior to testing. We used task-based fMRI data to define global brain networks which exhibited increased BOLD responses towards CS+ or CS- presentations, respectively. From these networks, we obtained mean values of gray matter density, neurite density, and neurite orientation dispersion. We found that mean gray matter density averaged across the CS+ network was significantly correlated with the strength of conditioned fear reactions quantified via skin conductance response. Measures of neurite architecture were not associated with conditioned fear reaction in any of the two networks. Our results extend previous findings on the relationship between brain morphometry and fear learning. Most importantly, our study is the first to introduce neurite imaging to fear learning research and discusses how its implementation can be improved in future research.
A systems genomics approach uncovers molecular associates of RSV severity
Authors: McCall Matthew N , Chu Chin-Yi , Wang Lu , Benoodt Lauren , Thakar Juilee , Corbett Anthony , Holden-Wiltse Jeanne , Slaunwhite Christopher , Grier Alex , Gill Steven , Falsey Ann R. , Topham David J , Caserta Mary , Walsh Edward , Qiu Xing , Mariani Thomas J.
Published: December 2020

Globally, RSV infection results in millions of hospitalizations and thousands of deaths each year. Specific factors that contribute to disease severity, such as premature birth and certain comorbidities, are well established. Additionally, genetic variants resulting in alterations in the adaptive and innate immune response appear to be associated with RSV severity. While previous studies focused on a single aspect of the disease, we jointly modeled the association of disparate data modalities with RSV severity. To investigate the host response to respiratory syncytial virus (RSV) infection in infants, we performed a systems-level study of RSV pathophysiology, incorporating high-throughput measurements of the peripheral innate and adaptive immune systems and the airway epithelium and microbiota. Specifically, we developed and employed a novel multi-omic data integration method based on multilayered principal component analysis, penalized regression, and feature weight back-propagation. Our novel approach enabled us to identify cell type specific and shared cellular pathways associated with RSV severity. Of particular interest was the association between RSV severity, activation of pathways controlling Th17 and acute phase response signaling, and inhibition of B cell receptor signaling, which were present in both airway and immune cells. These data identify specific aspects of dysregulation between the humoral and mucosal response to RSV that may play a critical role in determining illness severity.
Targeted cancer therapy induces APOBEC fuelling the evolution of drug resistance
Authors: Mayekar Manasi K. , Caswell Deborah R. , Vokes Natalie I. , Law Emily K. , Wu Wei , Hill William , Gronroos Eva , Rowan Andrew , Al Bakir Maise , McCoach Caroline E. , Blakely Collin M. , Temiz Nuri Alpay , Nagano Ai , Kerr D. Lucas , Rotow Julia K. , Haderk Franziska , Dietzen Michelle , Ruiz Carlos Martinez , Almeida Bruna , Cech Lauren , Gini Beatrice , Przewrocka Joanna , Moore Chris , Murillo Miguel , Bakker Bjorn , Rule Brandon , Durfee Cameron , Nanjo Shigeki , Tan Lisa , Larson Lindsay K. , Argyris Prokopios P. , Brown William L. , Yu Johnny , Gomez Carlos , Gui Philippe , Vogel Rachel I. , Yu Elizabeth A. , Thomas Nicholas J. , Venkatesan Subramanian , Hobor Sebastijan , Chew Su Kit , Kanu Nnennaya , McGranahan Nicholas , Van Allen Eliezer M. , Downward Julian , Harris Reuben S. , Bivona Trever G. , Swanton Charles
Published: December 2020

Introductory paragraph

The clinical success of targeted cancer therapy is limited by drug resistance that renders cancers lethal in patients1-4. Human tumours can evolve therapy resistance by acquiringde novogenetic alterations and increased heterogeneity via mechanisms that remain incompletely understood1. Here, through parallel analysis of human clinical samples, tumour xenograft and cell line models and murine model systems, we uncover an unanticipated mechanism of therapy-induced adaptation that fuels the evolution of drug resistance. Targeted therapy directed against EGFR and ALK oncoproteins in lung cancer induced adaptations favoring apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC)-mediated genome mutagenesis. In human oncogenicEGFR-driven andALK-driven lung cancers and preclinical models, EGFR or ALK inhibitor treatment induced the expression and DNA mutagenic activity ofAPOBEC3Bvia therapy-mediated activation of NF-κB signaling. Moreover, targeted therapy also mediated downregulation of certain DNA repair enzymes such as UNG2, which normally counteracts APOBEC-catalyzed DNA deamination events. In mutantEGFR-driven lung cancer mouse models, APOBEC3B was detrimental to tumour initiation and yet advantageous to tumour progression during EGFR targeted therapy, consistent with TRACERx data demonstrating subclonal enrichment of APOBEC-mediated mutagenesis. This study reveals how cancers adapt and drive genetic diversity in response to targeted therapy and identifies APOBEC deaminases as future targets for eliciting more durable clinical benefit to targeted cancer therapy.
Functional idiosyncrasy has a shared topography with group-level connectivity alterations in autism
Authors: Benkarim Oualid , Paquola Casey , Park Bo-yong , Hong Seok-Jun , Royer Jessica , de Wael Reinder Vos , Lariviere Sara , Valk Sofie , Bzdok Danilo , Mottron Laurent , Bernhardt Boris
Published: December 2020

Autism spectrum disorder (ASD) is commonly understood as a network disorder, yet case-control analyses against typically-developing controls (TD) have yielded somewhat inconsistent patterns of results. The current work was centered on a novel approach to profile functional network idiosyncrasy, the inter-individual variability in the association between functional network organization and brain anatomy, and we tested the hypothesis that idiosyncrasy contributes to connectivity alterations in ASD. Studying functional network idiosyncrasy in a multi-centric dataset with 157 ASD and 172 TD, our approach revealed higher idiosyncrasy in ASD in the default mode, somatomotor and attention networks together with reduced idiosyncrasy in the lateral temporal lobe. Idiosyncrasy was found to increase with age in both ASD and TD, and was significantly correlated with symptom severity in the former group. Association analysis with structural and molecular brain features indicated that patterns of functional network idiosyncrasy were not correlated with ASD-related cortical thickness alterations, but closely with the spatial expression patterns of intracortical ASD risk genes. In line with our main hypothesis, we could demonstrate that idiosyncrasy indeed plays a strong role in the manifestation of connectivity alterations that are measurable with conventional case-control designs and may, thus, be a principal driver of inconsistency in the autism connectomics literature. These findings support important interactions between the heterogeneity of individuals with an autism diagnosis and group-level functional signatures, and help to consolidate prior research findings on the highly variable nature of the functional connectome in ASD. Our study promotes idiosyncrasy as a potential individualized diagnostic marker of atypical brain network development.
A phenotypic screen identifies a compound series that induces differentiation of acute myeloid leukemia cellsin vitroand shows anti-tumour effectsin vivo
Authors: Josa-Culleré Laia , Madden Katrina S. , Cogswell Thomas J. , Jackson Thomas R. , Carter Tom S. , Zhang Douzi , Trevitt Graham , Davies Stephen G. , Vyas Paresh , Wynne Graham M. , Milne Thomas A. , Russell Angela J.
Published: December 2020

Induction of differentiation is a promising therapeutic strategy against acute myeloid leukemia. However, current differentiation therapies are effective only to specific patient populations. To identify novel differentiation agents with wider efficacy, we developed a phenotypic high-throughput screen with a range of genetically diverse cell lines. From the resulting hits, one chemical scaffold was optimised in terms of activity and physicochemical properties to yield OXS007417, which was also able to decrease tumour volume in a murine in vivo xenograft model.
WNT11 is a novel ligand for ROR2 in human breast cancer
Authors: Menck Kerstin , Heinrichs Saskia , Wlochowitz Darius , Sitte Maren , Noeding Helen , Janshoff Andreas , Treiber Hannes , Ruhwedel Torben , Schatlo Bawarjan , von der Brelie Christian , Wiemann Stefan , Pukrop Tobias , Beißbarth Tim , Binder Claudia , Bleckmann Annalen
Published: December 2020

Breast cancer has been associated with activation of the WNT signaling pathway, although the underlying molecular mechanisms are still unclear. Here, we found the WNT receptor ROR2 to be highly expressed in aggressive breast tumors and associated with worse metastasis-free survival. In order to understand the molecular basis of these observations, we overexpressed ROR2 in human breast cancer cell lines, inducing a BRCAness-like phenotype and rendering them resistant to PARP inhibition. High levels of ROR2 were associated with defects in cell morphology and cell-cell-contacts leading to increased tumor invasiveness. Using gene expression analysis we demonstrated an upregulation of several non-canonical WNT ligands in ROR2-overexpressing breast cancer cells, in particular WNT11. Co-immunoprecipitation confirmed that WNT11 is indeed a novel ligand for ROR2 that interacts with its cysteine-rich domain and triggers the invasion-promoting signaling via RHO/ROCK. Knockdown of WNT11 reversed the pro-invasive phenotype and the cellular changes in ROR2-overexpressing cells. Taken together, our studies revealed a novel auto-stimulatory loop in which ROR2 triggers the expression of its own ligand, WNT11, resulting in enhanced tumor invasion associated with breast cancer metastasis.
Previous motor actions outweigh sensory information in sensorimotor learning
Authors: Feulner Barbara , Postin Danilo , Schwiedrzik Caspar M. , Pooresmaeili Arezoo
Published: December 2020

Humans can use their previous experience in form of statistical priors to improve decisions. It is however unclear how such priors are learned and represented. Importantly, it has remained elusive whether prior learning is independent of the sensorimotor system involved in the learning process or not, as both modality-specific and modality-general learning have been reported in the past. Here, we used a saccadic eye movement task to probe the learning and representation of a spatial prior across a few trials. In this task, learning occurs in an unsupervised manner and through encountering trial-by-trial visual hints drawn from a distribution centered on the target location. Using a model-comparison approach, we found that participants’ prior knowledge is largely represented in the form of their previous motor actions, with minimal influence from the previously seen visual hints. By using two different motor contexts for response (looking either at the estimated target location, or exactly opposite to it), we could further compare whether prior experience obtained in one motor context can be transferred to the other. Although learning curves were highly similar, and participants seemed to use the same strategy for both response types, they could not transfer their knowledge between contexts, as performance and confidence ratings dropped to naïve levels after a switch of the required response. Together, our results suggest that humans preferably use the internal representations of their previous motor actions, rather than past incoming sensory information, to form statistical sensorimotor priors on the timescale of a few trials.