bluuebunny/crossref_metadata_2025 huggingface dataset:
Convalescent Plasma for COVID-19: A multicenter, randomized clinical trial
Authors: Avendaño-Solà C , Ramos-Martínez A , Muñez-Rubio E , Ruiz-Antorán B , de Molina R Malo , Torres F , Fernández-Cruz A , Callejas-Díaz A , Calderón J , Payares-Herrera C , Salcedo I , Romera I , Lora-Tamayo J , Mancheño-Losa M , Paciello ML , Villegas C , Estrada V , Saez-Serrano I , Porras-Leal ML , Jarilla-Fernández MC , Paño-Pardo JR , Moreno-Chulilla JA , Arrieta-Aldea I , Bosch A , Belhassen-Garcia M , López-Villar O , Ramos-Garrido A , Blanco L , Madrigal-Sánchez ME , Contreras E , Muñiz-Díaz E , Domingo-Morera JM , Casas-Flecha I , Pérez-Olmeda M , Garcia-Pérez Javier , Alcamí J , Bueno JL , Duarte RF ,   for the ConPlas-19 Study Group
Published: September 2020

Background

Passive immunotherapy with convalescent plasma (CP) is a potential treatment for COVID-19 for which evidence from controlled clinical trials is lacking.

Methods

We conducted a multi-center, randomized clinical trial in patients hospitalized for COVID-19. All patients received standard of care treatment, including off-label use of marketed medicines, and were randomized 1:1 to receive one dose (250-300 mL) of CP from donors with IgG anti-SARS-CoV-2. The primary endpoint was the proportion of patients in categories 5, 6 or 7 of the COVID-19 ordinal scale at day 15.

Results

The trial was stopped after first interim analysis due to the fall in recruitment related to pandemic control. With 81 patients randomized, there were no patients progressing to mechanical ventilation or death among the 38 patients assigned to receive plasma (0%) versus 6 out of 43 patients (14%) progressing in control arm. Mortality rates were 0% vs 9.3% at days 15 and 29 for the active and control groups, respectively. No significant differences were found in secondary endpoints. At inclusion, patients had a median time of 8 days (IQR, 6-9) of symptoms and 49,4% of them were positive for anti-SARS-CoV-2 IgG antibodies.

Conclusions

Convalescent plasma could be superior to standard of care in avoiding progression to mechanical ventilation or death in hospitalized patients with COVID-19. The strong dependence of results on a limited number of events in the control group prevents drawing firm conclusions about CP efficacy from this trial. (Funded by Instituto de Salud Carlos III;NCT04345523).
Modelling COVID-19 contagion: Risk assessment and targeted mitigation policies
Authors: Cont Rama , Kotlicki Artur , Xu Renyuan
Published: September 2020

We use a spatial epidemic model with demographic and geographic heterogeneity to study the regional dynamics of COVID-19 across 133 regions in England.

Our model emphasises the role of variability of regional outcomes and heterogeneity across age groups and geographic locations, and provides a framework for assessing the impact of policies targeted towards sub-populations or regions. We define a concept of efficiency for comparative analysis of epidemic control policies and show targeted mitigation policies based on local monitoring to be more efficient than country-level or non-targeted measures. In particular, our results emphasise the importance of shielding vulnerable sub-populations and show that targeted policies based on local monitoring can considerably lower fatality forecasts and, in many cases, prevent the emergence of second waves which may occur under centralised policies.
Post-COVID-19 Functional Status: Relation to age, smoking, hospitalization and comorbidities
Authors: AR Mohamed Hussein Aliae , Galal Islam , Saad Mahmoud M , Zayan Hossam Eldeen E , Abdelsayed Mustafa Z , Moustafa Mohamed M , Ezzat Abdel Rahman , Helmy Radwa ED , Abd Elaal Howaida K , Aly Karim , Abdelrheem Shaimaa S
Published: September 2020

Rational

Recently, a new “Post-COVID-19 Functional Status (PCFS) scale” is recommended in the current COVID-19 pandemic. It is proposed that it could be used to display direct retrieval and the functional sequelae of COVID-19.

Aim of the study

To assess the Post COVID-19 functional status in Egypt and to evaluate if age, gender, comorbidities have any effect on functional limitations in recovered COVID-19 patients.

Patients and methods

A total of 444 registered confirmed COVID-19 patients were included. They were interviewed in our follow-up clinics or by calls and filled an Arabic translated PCFS scale in paper or online forms as well as their demographic and clinical data.

Results

80% of COVID-19 recovered cases have diverse degrees of functional restrictions ranging from negligible (63.1%), slight (14.4%), moderate (2%) to severe (0.5%) based on PCFS. Furthermore, there was a substantial variance between the score of PCFS with age (P= 0.003), gender (P= 0.014), the duration since the onset of the symptoms of COVID-19 (P <0.001), need for oxygen supplementation (P<0.001), need for ICU admittance (P= 0.003), previous periodic influenza vaccination (P<0.001), smoking status (P < 0.001) and lastly the presence of any comorbid disorder (P <0.001).

Conclusions

Most of the COVID-19 recovered cases have diverse degrees of functional restrictions ranging from negligible to severe based on PCFS. These restrictions were affected by age, gender, periodic influenza vaccination, smoking, duration since symptoms onset, need for oxygen or ICU admittance, and lastly the presence of coexisting comorbidity.
Epidemiological and socio-economic characteristics of the COVID-19 spring outbreak in Quebec, Canada: A population-based study
Authors: Jantzen Rodolphe , Noisel Nolwenn , Camilleri-Broët Sophie , Labbé Catherine , de Malliard Thibault , Payette Yves , Broët Philippe
Published: September 2020

Background

By mid-July 2020, more than 108,000 COVID-19 cases had been diagnosed in Canada with more than half in the province of Quebec. To be prepared for a potential second wave of COVID-19 in the fall, it seems of utmost importance to analyze the epidemiological and socio-economic characteristics of the spring outbreak in the population.

Method

We conducted an online survey of the participants of the CARTaGENE population-based cohort, composed of middle-aged and older adults. We collected information on socio-demographic, lifestyle, health condition, COVID-related symptoms and COVID-19 testing. We studied the association between these factors and two outcomes: the status of having been tested for SARS-CoV-2 and the status of having received a positive test when having been tested. These associations were evaluated with univariate and multivariate analyzes using a hybrid tree-based regression model.

Results

Among the 8,129 respondents from the CARTaGENE cohort, 649 were tested for COVID-19 and 41 were positive. Medical workers and individuals having a contact with a COVID-19 patient had the highest probabilities of being tested (32% and 42.4%, respectively) and of being positive (17.2% and 13.0%, respectively) among those tested. 7.6% of the participants declared that they have experienced at least one of the four COVID-related symptoms chosen by the Public Health authorities (fever, cough, dyspnea, anosmia) but were not tested. Results from the tree-based model analyzes adjusted on exposure factors show that the combination of dyspnea, dry cough and fever was highly associated with being tested whereas anosmia, fever, and headache were the most discriminant factors for having a positive test among those tested. During the spring outbreak, more than one third of the participants have experienced a decrease in access to health services. There were sex and age differences in the socio-economic and emotional impacts of the pandemic.

Conclusion

We have shown some discrepancies between the symptoms associated with being tested and being positive. In particular, the anosmia is a major discriminant symptom for positivity whereas ear-nose-throat symptoms seem not to be COVID-related. The results also emphasize the need of increasing the accessibility of testing for the general population.
Modeling Dynamic Network Strategies for SARS-CoV-2 Control on a Cruise Ship
Authors: Jenness Samuel M. , Willebrand Kathryn S. , Malik Amyn A. , Lopman Benjamin A. , Omer Saad B.
Published: September 2020

SARS-CoV-2 outbreaks have occurred on several nautical vessels, driven by the high-density contact networks on these ships. Optimal strategies for prevention and control that account for realistic contact networks are needed. We developed a network-based transmission model for SARS-CoV-2 on the Diamond Princess outbreak to characterize transmission dynamics and to estimate the epidemiological impact of outbreak control and prevention measures. This model represented the dynamic multi-layer network structure of passenger-passenger, passengercrew, and crew-crew contacts, both before and after the large-scale network lockdown imposed on the ship in response to the disease outbreak. Model scenarios evaluated variations in the timing of the network lockdown, reduction in contact intensity within the sub-networks, and diagnosis-based case isolation on outbreak prevention. We found that only extreme restrictions in contact patterns during network lockdown and idealistic clinical response scenarios could avert a major COVID-19 outbreak. Contact network changes associated with adequate outbreak prevention were the restriction of passengers to their cabins, with limited passenger-crew contacts. Clinical response strategies required for outbreak prevention included early mass screening with an ideal PCR test (100% sensitivity) and immediate case isolation upon diagnosis. Public health restrictions on optional leisure activities like these should be considered until longer-term effective solutions such as a COVID-19 vaccine become widely available.
Practical challenges to the clinical implementation of saliva for SARS-CoV-2 detection
Authors: Matic Nancy , Stefanovic Aleksandra , Leung Victor , Lawson Tanya , Ritchie Gordon , Li Lynne , Champagne Sylvie , Romney Marc G. , Lowe Christopher F.
Published: September 2020

Due to global shortages of flocked nasopharyngeal swabs and appropriate viral transport media during the COVID-19 pandemic, alternate diagnostic specimens for SARS-CoV-2 detection are sought. The accuracy and feasibility of saliva samples collected and transported without specialized collection devices or media were evaluated. Saliva demonstrated good concordance with paired nasopharyngeal swabs for SARS-CoV-2 detection in 67/74 cases (90.5%), though barriers to saliva collection were observed in long-term care residents and outbreak settings. SARS-CoV-2 RNA was stable in human saliva at room temperature for up to 48 hours after initial specimen collection, informing appropriate transport time and conditions.
MAIT cell activation and dynamics associated with COVID-19 disease severity and outcome
Authors: Parrot Tiphaine , Gorin Jean-Baptiste , Ponzetta Andrea , Maleki Kimia T. , Kammann Tobias , Emgârd Johanna , Perez-Potti André , Sekine Takuya , Rivera-Ballesteros Olga ,   the Karolinska COVID-19 Study Group, Folkesson Elin , Rooyackers Olav , Eriksson Lars I. , Norrby-Teglund Anna , Ljunggren Hans-Gustaf , Björkström Niklas K. , Aleman Soo , Buggert Marcus , Klingström Jonas , Strålin Kristoffer , Sandberg Johan K.
Published: September 2020

Severe COVID-19 is characterized by excessive inflammation of the lower airways. The balance of protective versus pathological immune responses in COVID-19 is incompletely understood. Mucosa-associated invariant T (MAIT) cells are antimicrobial T cells that recognize bacterial metabolites, and can also function as innate-like sensors and mediators of antiviral responses. Here, we investigated the MAIT cell compartment in COVID-19 patients with moderate and severe disease, as well as in convalescence. We show profound and preferential decline in MAIT cells in circulation of patients with active disease paired with strong activation, as well as significant MAIT cell enrichment and pro-inflammatory IL-17A bias in the airways. Unsupervised analysis identified MAIT cell CD69high and CXCR3low immunotypes associated with poor clinical outcome. MAIT cell levels normalized in the convalescent phase, consistent with dynamic recruitment to the tissues and subsequent release with disease resolution. These findings indicate that MAIT cells are engaged in the immune response against SARS-CoV-2 and suggest their involvement in COVID-19 immunopathogenesis.

One sentence summary

MAIT cells are strongly activated by SARS-CoV-2 infection in a manner associated with disease severity and outcome, they decline in blood, are enriched in the airways as a prominent IL-17A expressing subset, and dynamically recover in circulation during convalescence.
Lysosomal enzyme deficiency andGBAmutations in Dystonia
Authors: Schreglmann Sebastian R. , Burke Derek , Batla Amit , Kresojevic Nikola , Wood Nicholas , Heales Simon , Bhatia Kailash P.
Published: September 2020

Glucocerebrosidase (GCase) deficiency due to mutations of the glucosidase acid beta (GBA) gene causes autosomal-recessive Gaucher’s disease, the most frequent lysosomal storage disorder. Over the past two decades,GBAmutations have been established as the most frequent genetic risk factor to develop Parkinson’s Disease. In dystonia, the underlying aetiology in a relevant proportion of cases remains unknown, hampering the development of causative treatment strategies. Here, we explored the possible role of lysosomal dysfunction in clinical (n=130) and post mortem (n=10) patients with dystonia.

As part of extensive diagnostic evaluations (screening for structural, acquired and degenerative causes of dystonia), lysosomal enzyme activity was measured in n=79 retrospectively collected cases of patients with combined dystonia and n=51 prospectively collected cases of patients with cervical dystonia using a clinically validated, fluorescence-based assay. Clinical information on all cases was extensively reviewed and an alternative aetiology of dystonia was identified in n=14 cases on follow-up. Of the remaining n=116 cases of dystonia of unknown origin, complete Sanger Sequencing ofGBAexons 1-11 was performed using an established protocol in all n=97 of cases with available DNA. Where there was suspicion based on clinical examination or family history, nigro-striatal degeneration was excluded in n=19 (17.2%) cases with dystonia of unknown origin. Furthermore, lysosomal enzyme activity was measured in different brain regions of age-, sex- and post-mortem delay-matched cases with dystonia of unknown origin (n=10) and healthy controls (n=10) from the Queen Square brain bank.

Among cases with dystonia of unknown origin, decreased white cell Glucocerebrosidase activity was measured in a range typical for homozygous (n=2; 1.7%) or heterozygous (n=23; 19.8%) GBA mutation carriers. The frequency ofGBAmutations (5/80=6.25%) was significantly higher in patients than in controls (3/257=1.17%) of a historical control group from the same ethnic background (P=0.02; Odds Ratio=5.64, 95% Confidence Interval=1.44 – 21.58) – known pathogenic mutations E326K, T369M and N370S were found. We also identified lower Glucocerebrosidase activity in the cerebellar dentate nucleus (P=0.048) of dystonia patients than healthy controls.

This study provides evidence for peripheral and central lysosomal dysfunction in a significant proportion and across the clinical spectrum of dystonia. As in Parkinson’s disease, this was found irrespective ofGBAmutation status, indicating a possible role of lysosomal dysfunction as a more general disease mechanism in dystonia.
Examining the possible causal relationship between Lung Function, COPD and Alzheimer’s Disease. A Mendelian Randomization Study
Authors: Higbee Daniel H , Granell Raquel , Walton Esther , Korologou-Linden Roxanna , Smith George Davey , Dodd James W
Published: September 2020

Rationale

Large retrospective case-control studies have reported an association between COPD, reduced lung function and an increased risk of Alzheimer’s disease. However, it remains unclear if these diseases are causally linked, or due to shared risk factors. Conventional observational epidemiology suffers from unmeasured confounding and reverse causation. Additional analyses addressing causality are required.

Objectives

To examine a causal relationship between COPD, lung function and Alzheimer’s disease.

Methods

Using two-sample Mendelian randomization, we utilised single nucleotide polymorphisms (SNPs) identified in a genome wide association study (GWAS) for lung function as instrumental variables (exposure). Additionally, we used SNPs discovered in a GWAS for COPD in those with moderate to very severe obstruction. The effect of these SNPs on Alzheimer’s disease (outcome) were taken from a GWAS based on a sample of 24,807 patients and 55,058 controls.

Results

We found minimal evidence for an effect of either lung function (odds ratio [OR]:1.02 per SD; 95% confidence interval [CI]: 0.91-1.13; p-value 0.68). or liability for COPD on Alzheimer’s disease (OR: 0.97 per SD; 95% CI: 0.92 – 1.03; p-value 0.40).

Conclusion

Neither reduced lung function nor liability COPD are likely to be causally associated with an increased risk of Alzheimer’s, any observed association is likely due to unmeasured confounding. Scientific attention and health prevention policy may be better focused on overlapping risk factors, rather than attempts to reduce risk of Alzheimer’s disease by targeting impaired lung function or COPD directly.
Is genetic diversity of Plasmodium falciparum suggestive of malaria endemic zone in West Africa? An attempt to respond by a cross-sectional comparative study between Senegal and Nigeria
Authors: Oboh Mary M. , Ndiaye Tolla , Diongue Khadim , Ndiaye Yaye D. , Sy Mouhamad , Deme Awa B. , Volkman Sarah K. , Badiane Aida S. , Amambua-Ngwa Alfred , Ndiaye Daouda
Published: September 2020

Background

Characterization of malaria parasite populations in different endemic settings (from low to high) could be helpful for ascertaining the progress of malaria interventions in endemic settings. The present study aims to compare Plasmodium falciparum parasite population structure between two West African countries with very different level of endemicity using P. falciparum allelic polymorphic markers: msp1 and msp2.

Methods

Parasite genomic DNA was extracted from 187 dried blood spot collected from confirmed uncomplicated P. falciparum malaria infected patients in Senegal (94) being at the pre-elimination stage in most part of the country and Nigeria (93) which is still at the control stage. Allelic polymorphism of msp1 and msp2 genes were assessed by nested PCR.

Results

In Senegal as well as in Nigeria, K1 and IC3D7 allelic families were the most represented for msp1 and msp2 genes respectively. A higher multiplicity of infection (MOI) was found in both study sites in Senegal (Thies:1.51/2.53; Kedougou:2.2/2.0 for msp 1/2) than from sites in Nigeria (Gbagada: 1.39/1.96; Oredo: 1.35/1.75]). The heterozygosity of msp 1 gene was higher in P. falciparum isolates from Senegal (Thies: 0.62; Kedougou: 0.53) than isolates from Nigeria (Gbagada: 0.55; Oredo: 0.50). In Senegal, K1 alleles were associated with heavy (28) than with moderate (18) infections, in Nigeria however, equal proportions of K1 were observed in both infection types. The IC3D7 subtype allele of the msp 2 family showed high occurrence in heavily infected individuals from both countries (Senegal- 32; Nigeria- 26) than in the moderately infected participants.

Conclusion

With the unusual high genetic diversity obtained in low endemic setting in Senegal and low genetic diversity in a high endemic Nigerian setting, multiple holistic approach should be employed in evaluating the actual transmission of a place in order to effectively direct control measures.
DeepSOCIAL: Social Distancing Monitoring and Infection Risk Assessment in COVID-19 Pandemic
Authors: Rezaei Mahdi , Azarmi Mohsen
Published: September 2020

Social distancing is a recommended solution by the World Health Organisation (WHO) to minimise the spread of COVID-19 in public places. The majority of governments and national health authorities have set the 2-meter physical distancing as a mandatory safety measure in shopping centres, schools and other covered areas. In this research, we develop a generic Deep Neural Network-Based model for automated people detection, tracking, and inter-people distances estimation in the crowd, using common CCTV security cameras. The proposed model includes a YOLOv4-based framework and inverse perspective mapping for accurate people detection and social distancing monitoring in challenging conditions, including people occlusion, partial visibility, and lighting variations. We also provide an online risk assessment scheme by statistical analysis of the Spatio-temporal data from the moving trajectories and the rate of social distancing violations. We identify high-risk zones with the highest possibility of virus spread and infections. This may help authorities to redesign the layout of a public place or to take precaution actions to mitigate high-risk zones. The efficiency of the proposed methodology is evaluated on the Oxford Town Centre dataset, with superior performance in terms of accuracy and speed compared to three state-of-the-art methods.
Use of Metabolomic Profiling to Understand Variability in Adiposity Changes Following an Intentional Weight Loss Intervention in Older Adults
Authors: Quillen Ellen E. , Beavers Daniel P. , Cox Anderson O’Brien , Furdui Cristina M. , Lee Jingyun , Miller Ryan M. , Wu Hanzhi , Beavers Kristen M.
Published: September 2020

Introduction

Inter-individual response to dietary interventions remains a major challenge to successful weight loss among older adults. This study applied metabolomics technology to identify small molecule signatures associated with loss of fat mass and overall weight in a cohort of older adults on a nutritionally complete, high protein diet.

Methods

102 unique metabolites were measured using LC-MS for 38 adults aged 65-80 years randomized to dietary intervention and 36 controls. Metabolite values were analyzed in both baseline plasma samples and samples collected following the six-month dietary intervention to consider both metabolites that could predict response to diet and those that changed in response to diet or weight loss.

Results

Eight metabolites changed over intervention at a nominally-significant level: D-pantothenic acid, L-methionine, nicotinate, aniline, melatonin, deoxycarnitine, 6-deoxy-L-galactose, and 10-hydroxydecanoate. Within the intervention group, there was broad variation in achieved weight-loss and DXA-defined changes in total fat and visceral adipose tissue (VAT) mass. Change in VAT mass was significantly associated with baseline abundance of α-aminoadipate (p = 0.0007) and an additional mass spectrometry peak that may represent D-fructose, myo-inositol, mannose, α-D-glucose, allose, D-galactose, D-tagatose, or L-sorbose (p = 0.0001).

Discussion

This hypothesis-generating study reflects the potential of metabolomic biomarkers for the development of personalized dietary interventions.
Host-to-Host Airborne Transmission As a Multiphase Flow Problem For Science-Based Social Distance Guidelines
Authors: Balachandar S. , Zaleski S. , Soldati A. , Ahmadi G. , Bourouiba L.
Published: September 2020

COVID-19 pandemic has strikingly demonstrated how important it is to develop fundamental knowledge related to generation, transport and inhalation of pathogen-laden droplets and their subsequent possible fate as airborne particles, or aerosols, in the context of human to human transmission. It is also increasingly clear that airborne transmission is an important contributor to rapid spreading of the disease. In this paper, we discuss the processes of droplet generation by exhalation, their potential transformation into airborne particles by evaporation, transport over long distances by the exhaled puff and by ambient air turbulence, and final inhalation by the receiving host as interconnected multiphase flow processes. A simple model for the time evolution of droplet/aerosol concentration is presented based on a theoretical analysis of the relevant physical processes. The modeling framework along with detailed experiments and simulations can be used to study a wide variety of scenarios involving breathing, talking, coughing and sneezing and in a number of environmental conditions, as humid or dry atmosphere, confined or open environment. Although a number of questions remain open on the physics of evaporation and coupling with persistence of the virus, it is clear that with a more reliable understanding of the underlying flow physics of virus transmission one can set the foundation for an improved methodology in designing case-specific social distancing and infection control guidelines.
Social Determinants Associated with COVID-19 Mortality in the United States
Authors: Debopadhaya Shayom , Sprague Ariella D. , Mou Hongxi , Benavides Tiburon L. , Ahn Sarah M. , Reschke Cole A. , Erickson John S. , Bennett Kristin P.
Published: September 2020

This study examines social determinants associated with disparities in COVID-19 mortality rates in the United States. Using county-level data, 42 negative binomial mixed models were used to evaluate the impact of social determinants on COVID-19 outcome. First, to identify proper controls, the effect of 24 high-risk factors on COVID-19 mortality rate was quantified. Then, the high-risk terms found to be significant were controlled for in an association study between 41 social determinants and COVID-19 mortality rates. The results describe that ethnic minorities, immigrants, socioeconomic inequalities, and early exposure to COVID-19 are associated with increased COVID-19 mortality, while the prevalence of asthma, suicide, and excessive drinking is associated with decreased mortality. Overall, we recognize that social inequality places disadvantaged groups at risk, which must be addressed through future policies and programs. Additionally, we reveal possible relationships between lung disease, mental health, and COVID-19 that need to be explored on a clinical level.
Unmasking the conversation on masks: Natural language processing for topical sentiment analysis of COVID-19 Twitter discourse
Authors: Sanders Abraham C. , White Rachael C. , Severson Lauren S. , Ma Rufeng , McQueen Richard , Alcântara Paulo Haniel C. , Zhang Yucheng , Erickson John S. , Bennett Kristin P.
Published: September 2020

In this exploratory study, we scrutinize a database of over one million tweets collected from March to July 2020 to illustrate public attitudes towards mask usage during the COVID-19 pandemic. We employ natural language processing, clustering and sentiment analysis techniques to organize tweets relating to mask-wearing into high-level themes, then relay narratives for each theme using automatic text summarization. In recent months, a body of literature has highlighted the robustness of trends in online activity as proxies for the sociological impact of COVID-19. We find that topic clustering based on mask-related Twitter data offers revealing insights into societal perceptions of COVID-19 and techniques for its prevention. We observe that the volume and polarity of mask-related tweets has greatly increased. Importantly, the analysis pipeline presented may be leveraged by the health community for qualitative assessment of public response to health intervention techniques in real time.
The importance of saturating density dependence for predicting SARS-CoV-2 resurgence
Authors: Nightingale E. S. , Brady O. J. ,   CMMID Covid-19 working group, Yakob L.
Published: September 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) associated mortality data from England show evidence for an increasing trend with population density until a saturating level, after adjusting for local age distribution, deprivation, proportion of ethnic minority population and proportion of key workers among the working population. Projections from a mathematical model that accounts for this observation deviate markedly from the current status quo for SARS-CoV-2 models which either assume linearity between density and transmission (30% of models) or no relationship at all (70%). Respectively, these standard model structures over- and under-estimate the delay in infection resurgence following the release of lockdown. Identifying saturation points for given populations and including transmission terms that account for this feature will improve model accuracy and utility for the current and future pandemics.
The influence of temporal predictability on express visuomotor responses
Authors: Contemori Samuele , Loeb Gerald E. , Corneil Brian D. , Wallis Guy , Carroll Timothy J.
Published: September 2020

Volitional visuomotor responses in humans are generally thought to manifest 100ms or more after stimulus onset. Under appropriate conditions, however, much faster target-directed responses can be produced at upper limb and neck muscles. These “express” responses have been termed stimulus-locked responses (SLRs) and are proposed to be modulated by visuomotor transformations performed subcortically via the superior colliculus. Unfortunately, for those interested in studying SLRs, these responses have proven difficult to detect consistently across individuals. The recent report of an effective paradigm for generating SLRs in 100% of participants appears to change this. The task required the interception of a moving target that emerged from behind a barrier at a time consistent with the target velocity. Here we aimed to reproduce the efficacy of this paradigm for eliciting SLRs and to test the hypothesis that its effectiveness derives from the predictability of target onset time as opposed to target motionper se. In one experiment, we recorded surface EMG from shoulder muscles as participants made reaches to intercept temporally predictable or unpredictable targets. Consistent with our hypothesis, predictably timed targets produced more frequent and stronger SLRs than unpredictably timed targets. In a second experiment, we compared different temporally predictable stimuli and observed that transiently presented targets produced larger and earlier SLRs than sustained moving targets. Our results suggest that target motion is not critical for facilitating the expression of an SLR and that timing predictability does not rely on extrapolation of a physically plausible motion trajectory. These findings provide support for a mechanism whereby an internal timer, probably located in cerebral cortex, primes the processing of both visual input and motor output within the superior colliculus to produce SLRs.
CUBIC-Cloud: An Integrative Computational Framework Towards Community-driven Whole-Mouse-Brain Mapping
Authors: Mano Tomoyuki , Murata Ken , Kon Kazuhiro , Shimizu Chika , Ono Hiroaki , Shi Shoi , Yamada Rikuhiro G. , Miyamichi Kazunari , Susaki Etsuo A. , Touhara Kazushige , Ueda Hiroki R.
Published: September 2020

Recent advancements in tissue clearing technologies have offered unparalleled opportunities for researchers to explore the whole mouse brain at cellular resolution. With the expansion of this experimental technique, however, a scalable and easy-to-use computational tool is in demand to effectively analyze and integrate whole-brain mapping datasets. To that end, here we present CUBIC-Cloud, a cloud-based framework to quantify, visualize and integrate whole mouse brain data. CUBIC-Cloud is a fully automated system where users can upload their whole-brain data, run analysis and publish the results. We demonstrate the generality of CUBIC-Cloud by a variety of applications. First, we investigated brain-wide distribution of PV, Sst, ChAT, Th and Iba1 expressing cells. Second, Aβ plaque deposition in AD model mouse brains were quantified. Third, we reconstructed neuronal activity profile under LPS-induced inflammation by c-Fos immunostaining. Last, we show brain-wide connectivity mapping by pseudo-typed Rabies virus. Together, CUBIC-Cloud provides an integrative platform to advance scalable and collaborative whole-brain mapping.
Combinatorial Intracellular Delivery Screening (CIDS) of Anticancer Drugs
Authors: Sola-Barrado Belén , Leite Diana Moreira , Scarpa Edoardo , Duro-Castano Aroa , Battaglia Giuseppe
Published: September 2020

Conventional drug solubilisation strategies limit the understanding of the full potential of poorly water-soluble drugs during drug screening. Here, we propose a screening approach in which poorly water-soluble drugs are entrapped in poly (2-(methacryloyloxyethyl phosphorylcholine)-poly(2-(diisopropylaminoethyl methacryate) (PMPC-PDPA) polymersomes (POs) to enhance drug solubility and facilitate intracellular delivery. By using a human paediatric glioma cell model, we demonstrated that PMPC-PDPA POs mediated intracellular delivery of cytotoxic and epigenetic drugs by receptor-mediated endocytosis. Additionally, when delivered in combination, drug-loaded PMPC-PDPA POs triggered both an enhanced drug efficacy and synergy compared to that of a conventional combinatorial screening. Hence, our comprehensive synergy analysis illustrates that our screening methodology, in which PMPC-PDPA POs are used for intracellular co-delivery of drugs, allows us to identify potent synergistic profiles of anticancer drugs.
Innate immune signaling and sex differences contribute to neurocognitive impairment, neuroinflammation, and mitochondrial rewiring in a mouse model of Gulf War illness
Authors: Bryant Joshua D. , Kodali Maheedhar , Shuai Bing , Menissy Saeed S. , Graves Paige J. , Shetty Ashok K. , West Laura Ciaccia , West A. Phillip
Published: September 2020

Gulf War Illness (GWI) is a chronic, multi-symptom disorder affecting approximately 30 percent of the nearly 700,000 veterans of the 1991 Persian Gulf War. Recent studies have revealed that GWI-related chemical (GWIC) exposure promotes immune activation and metabolic rewiring, which correlate with neurocognitive impairments and other symptoms of GWI. However, the molecular mechanisms and signaling pathways linking GWIC to inflammation, metabolic alterations, and neurological symptoms remain unclear. Mitochondrial dysfunction has been documented in veterans with GWI and rodent models, and because mitochondria are key immune regulators, we hypothesized that alterations to mitochondria-immune crosstalk could contribute to the development of GWI-related symptoms. Here we show that acute exposure of murine macrophages to GWIC alters mitochondrial respiration and potentiates innate immune signaling and inflammatory cytokine secretion. Using an established mouse model of GWI, we report that neurobehavioral changes, neuroinflammation, and mitochondrial protein rewiring are attenuated in mice lacking the cyclic GMP-AMP synthase (cGAS)-Stimulator of Interferon Genes (STING) and NOD-, LRR- or pyrin domain-containing protein 3 (NLRP3) innate immune pathways. Finally, we report sex differences in response to GWIC, with female mice showing more pronounced cognitive impairment, neuroinflammation, and mitochondrial protein alterations in the brain compared to male mice. Our results provide novel information on sex differences in this model and suggest that STING and NLRP3 are key mediators of the cognitive impairment, inflammation, and mitochondrial dysfunction observed in GWI.
Inter-subject pattern analysis for multivariate group analysis of functional neuroimaging. A unifying formalization
Authors: Wang Qi , Artières Thierry , Takerkart Sylvain
Published: September 2020

Background and objective

In medical imaging, population studies have to overcome the differences that exist between individuals to identify invariant image features that can be used for diagnosis purposes. In functional neuroimaging, an appealing solution to identify neural coding principles that hold at the population level is inter-subject pattern analysis, i.e. to learn a predictive model on data from multiple subjects and evaluate its generalization performance on new subjects. Although it has gained popularity in recent years, its widespread adoption is still hampered by the blatant lack of a formal definition in the literature. In this paper, we precisely introduce the first principled formalization of inter-subject pattern analysis targeted at multivariate group analysis of functional neuroimaging.

Methods

We propose to frame inter-subject pattern analysis as a multi-source transductive transfer question, thus grounding it within several well defined machine learning settings and broadening the spectrum of usable algorithms. We describe two sets of inter-subject brain decoding experiments that use several open datasets: a magnetoencephalography study with 16 subjects and a functional magnetic resonance imaging paradigm with 100 subjects. We assess the relevance of our framework by performing model comparisons, where one brain decoding model exploits our formalization while others do not.

Results

The first set of experiments demonstrates the superiority of a brain decoder that uses subject-by-subject standardization compared to state of the art models that use other standardization schemes, making the case for the interest of the transductive and the multi-source components of our formalization The second set of experiments quantitatively shows that, even after such transformation, it is more difficult for a brain decoder to generalize to new participants rather than to new data from participants available in the training phase, thus highlighting the transfer gap that needs to be overcome.

Conclusion

This paper describes the first formalization of inter-subject pattern analysis as a multi-source transductive transfer learning problem. We demonstrate the added value of this formalization using proof-of-concept experiments on several complementary functional neuroimaging datasets. This work should contribute to popularize inter-subject pattern analysis for functional neuroimaging population studies and pave the road for future methodological innovations.
X-ray mediated scintillation increases synaptic activity via Cerium-doped LSO and Channelrhodopsin-2
Authors: Bartley Aundrea F. , Fischer Máté , Bagley Micah E. , Barnes Justin A. , Burdette Mary K. , Cannon Kelli E. , Bolding Mark S. , Foulger Stephen H. , McMahon Lori L. , Weick Jason P. , Dobrunz Lynn E.
Published: September 2020

Optogenetics is a widely used tool for studying neural circuits. However, non-invasive methods for light delivery in the brain are needed to avoid physical damage typically caused by intracranial insertion of light guides. An innovative strategy could employ X-ray activation of radioluminescent particles (RLPs) to emit localized light. We previously reported that RLPs composed of cerium doped lutetium oxyorthosilicate (LSO:Ce), an inorganic scintillator that emits blue light, are biocompatible with neuronal function and synaptic transmission. However, little is known about the consequences of acute X-ray exposure on synaptic function and long-term plasticity. Furthermore, modulation of neuronal or synaptic function by X-ray induced radioluminescence from RLPs has not yet been demonstrated. Here we show that 30 minutes of X-ray exposure at a rate of 0.042 Gy/second caused no change in the strength of basal glutamatergic transmission during extracellular dendritic field recordings in mouse hippocampal slices. Additionally, long-term potentiation (LTP), a robust measure of synaptic integrity, was able to be induced after X-ray exposure and expressed at a magnitude not different from control conditions (absence of X-rays). This is important as synaptic plasticity is critical to learning and memory. Next, we used molecular and electrophysiological approaches to determine if X-ray dependent radioluminescence emitted from RLPs can activate light sensitive proteins. We found that X-ray stimulation of RLPs elevated cAMP levels in HEK293T cells expressing OptoXR, a chimeric opsin receptor that combines the extracellular light-sensitive domain of channelrhodopsin-2 (ChR2) with an intracellular second messenger signaling cascade. This demonstrates that X-ray radioluminescence from LSO:Ce particles can activate OptoXR. Next, we tested whether X-ray activation of the RLPs can enhance synaptic activity in whole-cell recordings from hippocampal neurons expressing ChR2, both in cell culture and acute hippocampal slices. Importantly, X-ray radioluminescence caused an increase in the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in both systems, indicating activation of ChR2 and excitation of neurons. Together, our results show that X-ray activation of LSO:Ce particles can heighten cellular and synaptic function. The combination of LSO:Ce inorganic scintillators and X-rays is therefore a viable method for optogenetics as an alternative to more invasive light delivery methods.
cFos ensembles in the dentate gyrus rapidly segregate over time and do not form a stable map of space
Authors: Lamothe-Molina Paul J. , Franzelin Andreas , Beck Lennart , Li Dong , Auksutat Lea , Fieblinger Tim , Laprell Laura , Alhbeck Joachim , Gee Christine E. , Kneussel Matthias , Engel Andreas K. , Hilgetag Claus C. , Morellini Fabio , Oertner Thomas G.
Published: September 2020

Transgenic cFos reporter mice are used to identify and manipulate neurons that store contextual information during fear learning. It is not clear, however, how spatial information acquired over several training days is integrated in the hippocampus. Using a water maze task, we observed that cFos expression patterns in the dentate gyrus are temporally unstable and shift daily. Surprisingly, cFos patterns did not get more stable with increasing spatial memory precision. Despite the fact that cFos was no longer expressed, optogenetic inhibition of neurons that expressed cFos on the first training day affected performance days later. Triggered by training, ΔFosB accumulates and provides a negative feedback mechanism that makes the cFos ensemble in the dentate gyrus dependent on the history of activity. Shifting cFos expression to a different set of granule cells every day may aid the formation of episodic memories.
Pseudouridine synthases modify human pre-mRNA co-transcriptionally and affect splicing
Authors: Martinez Nicole M. , Su Amanda , Nussbacher Julia K. , Burns Margaret C. , Schaening Cassandra , Sathe Shashank , Yeo Gene W. , Gilbert Wendy V.
Published: September 2020

Eukaryotic messenger RNAs are extensively decorated with modified nucleotides and the resulting epitranscriptome plays important regulatory roles in cells1. Pseudouridine (Ψ) is a modified nucleotide that is prevalent in human mRNAs and can be dynamically regulated2–5. However, it is unclear when in their life cycle RNAs become pseudouridylated and what the endogenous functions of mRNA pseudouridylation are. To determine if pseudouridine is added co-transcriptionally, we conducted pseudouridine profiling2on chromatin-associated RNA to reveal thousands of intronic pseudouridines in nascent pre-mRNA at locations that are significantly associated with alternatively spliced exons, enriched near splice sites, and overlap hundreds of binding sites for regulatory RNA binding proteins. Multiple distinct pseudouridine synthases with tissue-specific expression pseudouridylate pre-mRNA sites, and genetic manipulation of the predominant pre-mRNA modifying pseudouridine synthases PUS1, PUS7 and RPUSD4 induced widespread changes in alternative splicing in cells, supporting a role for pre-mRNA pseudouridylation in alternative splicing regulation. Consistently, we find that individual pseudouridines identified in cells are sufficient to directly affect splicingin vitro. Together with previously observed effects of artificial pseudouridylation on RNA-RNA6–8and RNA-protein9–11interactions that are relevant for splicing, our results demonstrate widespread co-transcriptional pre-mRNA pseudouridylation and establish the enormous potential for this RNA modification to control human gene expression.
Bronchoscopy on Intubated COVID-19 Patients is Associated with Low Infectious Risk to Operators at a High-Volume Center Using an Aerosol-minimizing Protocol
Authors: Gao Catherine A. , Bailey Joseph I. , Walter James M. , Coleman John M. , Malsin Elizabeth S. , Argento A. Christine ,   NU COVID Investigators, Wunderink Richard G. , Smith Sean B.
Published: September 2020

Background

The coronavirus disease 2019 (COVID-19) pandemic raised concern for exposure to healthcare providers through aerosol generating procedures, such as bronchoalveolar lavage (BAL). Current society guidelines recommended limiting use of BAL to reduce operators’ risk for infection, yet data on the infection rate for providers after BAL is sparse. Since March 2020, our institution used a modified protocol to perform over 450 BALs on intubated COVID-19 patients. We therefore sought to describe the subsequent infectious risks to providers associated with BAL.

Methods

Fifty-two pulmonary and critical care providers (faculty and fellows) at our tertiary-care, urban medical center were surveyed. Survey participants were asked to provide the number of BALs on COVID-19 patients they performed, the number of weeks they cared for intensive care unit (ICU) patients with COVID-19, and the results of any SARS-CoV-2 testing that they received. Participants were asked to assess the difficulty of BAL on intubated COVID-19 patients as compared to routine ICU BAL using a numeric perceived difficulty score ranging from 1 (easier) to 10 (harder).

Results

We received forty-seven responses from fifty-two surveyed (90% response rate), with 2 declining to participate. Many respondents (19/45, 42%) spent >5 weeks on an ICU service with COVID-19 patients. The number of BALs performed by providers ranged from 0 to >60. Sixteen of the 35 providers (46%) who performed BALs underwent at least one nasopharyngeal (NP) swab to test for SARS-CoV-2, but none were positive. Twenty-seven of the 35 providers (77%) who performed BALs underwent SARS- CoV-2 serology testing, and only one (3.7%) was positive. Respondents indicated occasionally not being able to follow aerosol-minimizing steps but overall felt BALs in COVID-19 patients was only slightly more difficult than routine bronchoscopy.

Discussion

At a high-volume center having performed >450 BALs on intubated COVID-19 patients with aerosol-limiting precautions, our survey of bronchoscopists found no positive NP SARS-CoV-2 tests and only one positive antibody test result. While the optimal role for COVID-19 BAL remains to be determined, these data suggest that BAL can be safely performed in intubated COVID-19 patients if experienced providers take precautions to limit aerosol generation and wear personal protective equipment.