bluuebunny/crossref_metadata_2025 huggingface dataset:
Identifying baseline clinical features of people with COVID-19
Authors: Ferreira-Santos D. , Maranhão P. , Monteiro-Soares M.
Published: May 2020

Objectives

To describe baseline clinical characteristics of adult patients with COVID-19.

Methods

We conducted a scoping review of the evidence available at LitCovid, until March 23th, 2020, and selected articles that reported the prevalence of socio-demographic characteristics, symptoms and co-morbidities in adults with COVID-19.

Results

In total, 1 572 publications were published on LitCovid. We have included 56 articles in our analysis, with 89% conducted in China, and 75% contained inpatients. Three studies were conducted in North America and one in Europe. Participants’ age ranged from 28 to 70 years, with balanced gender distribution. Proportion of asymptomatic cases were from 2 to 79%. The most common reported symptoms were fever [4-99%], cough [4-92%], dyspnoea/shortness of breath [1-90%], fatigue 4-89%], myalgia [3-65%], and pharyngalgia [2-61%], while regarding co-morbidities we found cardiovascular disease [1-40%], hypertension [0-40%] and cerebrovascular disease [1-40%]. Such heterogeneity impairs the conduction of meta-analysis.

Conclusion

The infection by COVID-19 seems to affect people in a very diverse manner and with different characteristics. With the available data it is not possible to clearly identify those at higher risk of being infected with this condition. Furthermore, the evidence from countries other than China is, at the day, too scarce.
National age and co-residence patterns shape covid-19 vulnerability
Authors: Esteve Albert , Permanyer Inaki , Boertien Diederik , Vaupel James W.
Published: May 2020

Based on harmonized census data from 81 countries, we estimate how age and co-residence patterns shape the vulnerability of countries' populations to outbreaks of covid-19. We estimate variation in deaths arising due to a simulated random infection of 10% of the population living in private households and subsequent within-household transmission of the virus. The age-structures of European and North American countries increase their vulnerability to covid-related deaths in general. The co-residence patterns of elderly persons in Africa and parts of Asia increase these countries' vulnerability to deaths induced by within-household transmission of covid-19. Southern European countries, which have aged populations and relatively high levels of intergenerational co-residence are, all else equal, the most vulnerable to outbreaks of covid-19. In a second step, we estimate to what extent avoiding primary infections for specific age-groups would prevent subsequent deaths due to within-household transmission of the virus. Preventing primary infections among the elderly is the most effective in countries with small households and little intergenerational co-residence such as France, whereas confining younger age groups can have a greater impact in countries with large and inter-generational households such as Bangladesh.
Understanding the psychological impact of the COVID-19 pandemic and containment measures: an empirical model of stress.
Authors: Wissmath Bartholomäus , Mast Fred W , Kraus Fabian , Weibel David
Published: May 2020

Research suggests that epidemics and corresponding containment measures have negative consequences to the individual and cause stress. The psychological mechanisms that determine stress, caused by the COVID-19 pandemic and containment measures, are not yet clear. In a survey during the lockdown in Switzerland (n=1565), we found substantially increased levels of stress in the population. In particular, individuals who did not agree with the containment measures, as well as those who saw nothing positive in the crisis, experienced even higher levels of stress. In contrast, individuals who are part of a risk group or who are working in healthcare or in essential shops experienced similar stress levels as the general public. We conducted a path analysis to gain a deeper understanding of the psychological mechanisms during lockdown. Experiencing fear of the disease is a key driver for being worried. Our model further shows that worries about the individual, social, and economic consequences of the crisis, strongly boost stress. The infection rate in the canton (i.e. state) of residence also contributes to stress. Positive thinking and perceived social, organizational, and governmental support mitigate worries and stress. To prevent stress, authorities should explain containment measures well, highlight positive aspects of the crisis, address worries, and facilitate support.
Ketone body 3-hydroxybutyrate: a biomarker of aggression?
Authors: whipp alyce m , vuoksimaa eero , korhonen tellervo , pool rene , ligthart lannie , hagenbeek fiona , bartels meike , bogl leonie-helen , pulkkinen lea , rose richard j , boomsma dorret i , kaprio jaakko a
Published: May 2020

Human aggression is a complex behavior, the biological underpinnings of which remain poorly known. To gain insights into aggression biology, we studied relationships with aggression of 11 low-molecular-weight metabolites (amino acids, ketone bodies), processed using 1H nuclear magnetic resonance spectroscopy. We used a discovery sample of young adults and an independent adult replication sample. We studied 725 young adults from a population-based Finnish twin cohort born 1983-87, with aggression levels rated in adolescence (ages 12, 14, 17) by multiple raters and blood plasma samples at age 22. Linear regression models specified metabolites as the dependent and aggression ratings as independent variables, and included several fixed effects. All metabolites showed low correlations with aggression, with only one - 3-hydroxybutyrate, a ketone body produced during fasting - showing significant (negative) associations with aggression. Effect sizes for different raters were generally similar in magnitude, while teacher-rated (age 12) and self-rated aggression (age 14) were both significant predictors of 3-hydroxybutyrate in multi-rater models. In an independent replication sample of 960 adults from the Netherlands Twin Register, higher self-rated aggression was also related to lower levels of 3-hydroxybutyrate. These exploratory epidemiologic results warrant further studies on the role of ketone metabolism in aggression.
Forecasting undetected COVID-19 cases in Small Island Developing States using Bayesian approach
Authors: Adwibowo Andrio
Published: May 2020

In dealing with the COVID-19, the fundamental question is how many actually undetected cases are going around regarding the capabilities of current health systems to contain the virus?. Due to a large number of asymptomatic cases, most COVID-19 cases are possibly undetected. For that reason, this study aims to provide an efficient, versatile, easy to compute, and robust estimator for the number of undetected cases using Bayes theorem based on the actual COVID-19 cases. This theorem is applied to 25 Small Island Developing States (SIDS) due to SIDS vulnerability. The results in this study forecast that possibly undetected COVID-19 cases are approximately 4 times larger than the numbers of actual COVID-19 cases as observed. This finding highlights the importance of using modeling tool to get the better and comprehensive of current COVID-19 cases and to take immediately precaution approaches to mitigate the growing numbers of COVID-19 cases as well.
Gene expression signatures identify biologically and clinically distinct tuberculosis endotypes
Authors: DiNardo Andrew R. , Gandhi Tanmay , Heyckendorf Jan , Grimm Sandra L. , Rajapakshe Kimal , Nishiguchi Tomoki , Reimann Maja , Kahari Jaqueline , Dlamini Qiniso , Lange Christoph , Goldmann Torsten , Marwitz Sebastian ,   DZIF-TB cohort study group, Abhimanyu  , Cirillo Jeffrey D. , Kaufmann Stefan HE , Netea Mihai G. , van Crevel Reinout , Mandalakas Anna M. , Coarfa Cristian ,   Members of the DZIF-TB cohort study group
Published: May 2020

Background

In vitro, animal model, and clinical evidence suggests that tuberculosis is not a monomorphic disease, and that host response to tuberculosis is protean with multiple distinct molecular pathways and pathologies (endotypes). We applied unbiased clustering to identify separate tuberculosis endotypes with classifiable gene expression patterns and clinical outcomes.

Methods

A cohort comprised of microarray gene expression data from microbiologically confirmed tuberculosis patients were used to identify putative endotypes. One microarray cohort with longitudinal clinical outcomes was reserved for validation, as was one RNA-seq cohorts. Finally, a separate cohort of tuberculosis patients with functional immune results was evaluated to clarify stimulated from unstimulated immune responses.

Results

A discovery cohort, including 435 tuberculosis patients and 533 asymptomatic controls, identified two tuberculosis endotypes. Tuberculosis patient endotype A is characterized by increased expression of genes related to inflammation and immunity and decreased metabolism and proliferation; in contrast, endotype B increased activity of metabolism and proliferation pathways. An independent RNA-seq validation cohort, including 118 tuberculosis patients and 179 controls, validated the discovery results. Gene expression signatures for treatment failure were elevated in endotype A in the discovery cohort, and a separate validation cohort confirmed that endotype A patients had slower time to culture conversion, and a reduced incidence of cure. These observations suggest that endotypes reflect functional immunity, supported by the observation that tuberculosis patients with a hyperinflammatory endotype have less responsive cytokine production upon stimulation.

Conclusion

These findings provide evidence that metabolic and immune profiling could inform optimization of endotype-specific host-directed therapies for tuberculosis.
Genetic risk for Alzheimer disease, cognition and Mild Behavioral Impairment in healthy older adults
Authors: Creese Byron , Brooker Helen , Aarsland Dag , Corbett Anne , Ballard Clive , Ismail Zahinoor
Published: May 2020

BACKGROUND: Mild Behavioral Impairment (MBI) is a neuropsychiatric syndrome describing later-life emergent apathy, mood/anxiety symptoms, impulse dyscontrol, social inappropriateness and psychosis that are not attributable to psychiatric diagnoses. MBI is an at-risk state for incident cognitive decline and dementia, and is associated with dementia biomarkers including amyloid beta; and neurofilament light. Thus, MBI may be an early clinical marker of neurodegenerative disease. In this study, we hypothesized that stratification by MBI in a cognitively normal sample would moderate the signal between Alzheimer disease (AD) genetic risk and cognition.
METHODS: Genetic, cognitive and MBI data was available for 3,126 PROTECT study participants over 50 without dementia. A general cognitive composite score was constructed based on scores on paired associates learning, digit span, self-ordered search and verbal reasoning. MBI was assessed using the MBI Checklist. Polygenic scores for AD were split by tertile (representing low, medium and high risk) and the sample was stratified by MBI into those with no symptoms and those with any symptoms.
RESULTS: AD genetic risk was associated with poorer cognition in the MBI strata only (MBI: F(2,1746)=4.95, p=0.007; no MBI: F(2,1366)=0.72, p=0.49). The mean difference between low and high genetic risk groups was significant (p=0.005) and the standardised effect size in the MBI sample was higher than in the whole sample.
CONCLUSIONS: These findings justify MBI screening to enrich samples with at-risk individuals, and underscore the importance of late-life neuropsychiatric symptoms in cognitive ageing.
COVID-19 pandemic control: balancing detection policy and lockdown intervention under ICU sustainability
Authors: Charpentier Arthur , Elie Romuald , Laurière Mathieu , Tran Viet Chi
Published: May 2020

We consider here an extendedSIRmodel, including several features of the recent COVID-19 outbreak: in particular the infected and recovered individuals can either be detected (+) or undetected (−) and we also integrate an intensive care unit capacity. Our model enables a tractable quantitative analysis of the optimal policy for the control of the epidemic dynamics using both lockdown and detection intervention levers. With parametric specification based on literature on COVID-19, we investigate sensitivity of various quantities on optimal strategies, taking into account the subtle tradeoff between the sanitary and the economic cost of the pandemic, together with the limited capacity level of ICU. We identify the optimal lockdown policy as an intervention structured in 4 successive phases: First a quick and strong lockdown intervention to stop the exponential growth of the contagion; second a short transition phase to reduce the prevalence of the virus; third a long period with full ICU capacity and stable virus prevalence; finally a return to normal social interactions with disappearance of the virus. We also provide optimal intervention measures with increasing ICU capacity, as well as optimization over the effort on detection of infectious and immune individuals.
Meta-analysis of Transcriptomic Data Reveals Pathophysiological Modules Involved with Atrial Fibrillation
Authors: Bueno Rodrigo Haas , Recamonde-Mendoza Mariana
Published: May 2020

Atrial fibrillation (AF) is a complex disease and affects millions of people around the world. The biological mechanisms that are involved with AF are complex and still need to be fully elucidated. Therefore, we performed a meta-analysis of transcriptome data related to AF to explore these mechanisms aiming at more sensitive and reliable results. Public transcriptomic datasets were downloaded, analyzed for quality control, and individually pre-processed. Differential expression analysis was carried out for each individual dataset, and the results were meta-analytically aggregated using the r-th ordered p-value method. We analyzed the final list of differentially expressed genes through network analysis, namely topological and modularity analysis, and functional enrichment analysis. The meta-analysis of transcriptomes resulted in 589 differentially expressed genes, whose protein-protein interaction network presented 11 hubs-bottlenecks and four main identified functional modules. These modules were enriched for, respectively, 23, 54, 33, and 53 biological pathways involved with the pathophysiology of AF, especially with the disease's structural and electrical remodeling processes. Stress of the endoplasmic reticulum, protein catabolism, oxidative stress, and inflammation are some of the enriched processes. Among hubs-bottlenecks genes, which are highly connected and probably have a key role in regulating these processes, we found HSPA5, ANK2, CTNNB1, and VWF. Further experimental investigation of our findings may shed light on the pathophysiology of the disease and contribute to the identification of new therapeutic targets and treatments.
Post-Stroke Physical Activity Improves Middle Cerebral Artery Dynamic Response
Authors: Billinger Sandra A , Whitaker Alicen A , Morton Allegra , Kaufman Carolyn S , Perdomo Sophy J , Ward Jaimie L , Eickmeyer Sarah M , Bai Stephen X , Ledbetter Luke , Abraham Michael G
Published: May 2020

Background and Purpose: The primary aim was to characterize the middle cerebral artery blood velocity (MCAv) dynamic response to an acute bout of exercise at 3- and 6-months post stroke. As a secondary objective, we grouped individuals according to the MCAv dynamic response to the exercise bout as responder or non-responder. We tested whether physical activity, aerobic fitness and exercise mean arterial blood pressure (MAP) differed between groups.
Methods: Transcranial Doppler ultrasound measured MCAv during a 90-second baseline (BL) followed by a 6-minute moderate intensity exercise bout. Heart rate (HR), MAP and end tidal CO2 (PETCO2) were additional variables of interest. The MCAv dynamic response variables included: BL, time delay (TD), amplitude and time constant (τ).
Results: Individuals enrolled in the study at 3 months post-stroke and the follow up visit commenced at 6 months post-stroke. Linear mixed model revealed no significant differences in our selected outcomes across between 3- and 6-months post-stroke. Individuals characterized as responders demonstrated a faster TD, higher amplitude, reported higher levels of physical activity and aerobic fitness when compared to the non-responders. No between group differences were identified for BL, τ or exercise MAP. In the non-responders, we observed an immediate rise in MCAv following exercise onset followed by an immediate decline to near BL values while the responders showed an exponential rise until steady state was reached.
Conclusions: The MCAv dynamic response profile has the potential to provide valuable information during an acute exercise bout following stroke. Individuals with a greater MCAv response to the exercise stimulus reported regular participation in exercise than those who reported being sedentary.
Differential Redistribution of Activated Monocyte and Dendritic Cell Subsets to the Lung Associates with Severity of COVID-19
Authors: Sánchez-Cerrillo Ildefonso , Landete Pedro , Aldave Beatriz , Sánchez-Alonso Santiago , Azofra Ana Sánchez , Marcos-Jiménez Ana , Ávalos Elena , Alcaraz-Serna Ana , de los Santos Ignacio , Mateu-Albero Tamara , Esparcia Laura , López-Sanz Celia , Martínez-Fleta Pedro , Gabrie Ligia , del Campo Guerola Luciana , Calzada María José , González-Álvaro Isidoro , Alfranca Arantzazu , Sánchez-Madrid Francisco , Muñoz-Calleja Cecilia , Soriano Joan B , Ancochea Julio , Martín-Gayo Enrique
Published: May 2020

The SARS-CoV-2 is responsible for the pandemic COVID-19 in infected individuals, who can either exhibit mild symptoms or progress towards a life-threatening acute respiratory distress syndrome (ARDS). It is known that exacerbated inflammation and dysregulated immune responses involving T and myeloid cells occur in COVID-19 patients with severe clinical progression. However, the differential contribution of specific subsets of dendritic cells and monocytes to ARDS is still poorly understood. In addition, the role of CD8+ T cells present in the lung of COVID-19 patients and relevant for viral control has not been characterized. With the aim to improve the knowledge in this area, we developed a cross-sectional study, in which we have studied the frequencies and activation profiles of dendritic cells and monocytes present in the blood of COVID-19 patients with different clinical severity in comparison with healthy control individuals. Furthermore, these subpopulations and their association with antiviral effector CD8+ T cell subsets were also characterized in lung infiltrates from critical COVID-19 patients. Collectively, our results suggest that inflammatory transitional and non-classical monocytes preferentially migrate from blood to lungs in patients with severe COVID-19. CD1c+ conventional dendritic cells also followed this pattern, whereas CD141+ conventional and CD123hi plasmacytoid dendritic cells were depleted from blood but were absent in the lungs. Thus, this study increases the knowledge on the pathogenesis of COVID-19 disease and could be useful for the design of therapeutic strategies to fight SARS-CoV-2 infection.

Single-sentence summary

Depletion from the blood and differential activation patterns of inflammatory monocytes and CD1c+ conventional dendritic cells associate with development of ARDS in COVID-19 patients.
Correlation between PCR Examination Rate among the Population and the Containment of Pandemic of COVID-19
Authors: Sonoo Masahiro , Idogawa Masashi , Kanbayashi Takamichi , Shimohata Takayoshi , Hayashi Hideyuki
Published: May 2020

We investigated the relation between PCR examination rate among population and the success of containment of COVID-19 for each country. Although there was moderate correlation, multiple regression revealed that the success of containment was solely explained by Gross Domestic Product per capita (GDP), which may well be related to the strict compliance to social distancing. Close inspection of individual countries supported this hypothesis. The social distancing must be the largest factor to achieve containment, and the contribution of broad PCR tests is small.
Analysis of the time and age dependence of the case-fatality-ratio for COVID-19 in seven countries with a high total-to-positive test ratio suggests that the true CFR may be significantly underestimated for the United States in current models
Authors: Rothman Jessica , Eidelberg David , Rothman Samantha , Holford Theodore , Rothman Douglas L
Published: May 2020

Background. Knowing the true infected and symptomatic case fatality ratios (IFR and CFR) for COVID-19 is of high importance for epidemiological model projections. A large correction factor is usually applied for missed cases. For the United State reported CFR of 5.96%, the estimated IFR values are 10-50-fold lower, justified by early reported CFR values of 0.1% to 0.5% in countries with more extensive testing. However, since then these values have risen 5 to 10-fold. We analyzed their age dependent CFR time courses to explain this increase and to determine whether a common factor can explain their CFRs.
Methods. Age dependent time to fatality corrected CFR was calculated using two independent methods. A linear model was developed that predicts CFR based on age dependent CFR coefficients and the age distribution of cases. The model was tested by a linear regression of each country's CFR against case percentage of 70 years and over. The model was further tested by calculating the percent of the population in New York City who have been infected.
Results. Corrected CFR values ranged from 0.58% to 5.0%. The large majority of CFR variation was explained by case age distribution above 70 years old. Using the CFR derived from the linear model we predicted between 14.7% and 22% of the adult population in NYC had been infected by COVID-19, in agreement with random testing studies (15.3% - 21%).
Conclusions. The large rise in the reported CFR is due to the delay time between infection/diagnosis and fatality with COVID-19. The linear model based on their age specific CFR values provides an alternative method for calculating the true CFR in other regions. Most of the variation in CFR between countries was dependent on case age distribution, which must be considered in measures for mitigating the extensive impacts of the pandemic.
Estimation of the true infection rate and infection fatality rate of coronavirus disease 2019 in each country
Authors: Sonoo Masahiro , Kanbayashi Takamichi , Shimohata Takayoshi , Kobayashi Masahito , Idogawa Masashi , Hayashi Hideyuki
Published: May 2020

The True Infection Rate (TIR) in the whole population of each country and the Infection Fatality Rate (IFR) for coronavirus disease 2019 (COVID-19) are unknown. We devised a simple method to infer TIR and IFR based on the open data. The estimated TIR was compared with local antibody surveys. Estimated IFR took on a wide range of values up to 10%. The importance of the attenuation of the viral virulence is emphasized.

Coronavirus disease 2019 (COVID-19) pandemic is a worldwide peril. The True Infection Rate (TIR) of COVID-19 in the whole population of each country and the Infection Fatality Rate (IFR) would be important parameters for guiding the strategy of public health, although they are unknown yet. We devised a simple method to infer TIR and IFR based on the open data.
A comparative analysis of statistical methods to estimate the reproduction number in emerging epidemics with implications for the current COVID-19 pandemic
Authors: O’Driscoll Megan , Harry Carole , Donnelly Christl A. , Cori Anne , Dorigatti Ilaria
Published: May 2020

As the SARS-CoV-2 pandemic continues its rapid global spread, quantification of local transmission patterns has been, and will continue to be, critical for guiding pandemic response. Understanding the accuracy and limitations of statistical methods to estimate the reproduction number, R0, in the context of emerging epidemics is therefore vital to ensure appropriate interpretation of results and the subsequent implications for control efforts. Using simulated epidemic data we assess the performance of 6 commonly-used statistical methods to estimate R0as they would be applied in a real-time outbreak analysis scenario – fitting to an increasing number of data points over time and with varying levels of random noise in the data. Method comparison was also conducted on empirical outbreak data, using Zika surveillance data from the 2015–2016 epidemic in Latin America and the Caribbean. We find that all methods considered here frequently over-estimate R0 in the early stages of epidemic growth on simulated data, the magnitude of which decreases when fitted to an increasing number of time points. This trend of decreasing bias over time can easily lead to incorrect conclusions about the course of the epidemic or the need for control efforts. We show that true changes in pathogen transmissibility can be difficult to disentangle from changes in methodological accuracy and precision, particularly for data with significant over-dispersion. As localised epidemics of SARS-CoV-2 take hold around the globe, awareness of this trend will be important for appropriately cautious interpretation of results and subsequent guidance for control efforts.

Significance Statement

In line with a real-time outbreak analysis we use simulated epidemic data to assess the performance of 6 commonly-used statistical methods to estimate the reproduction number, R0, at different time points during the epidemic growth phase. We find that estimates of R0are frequently overestimated by these methods in the early stages of epidemic growth, with decreasing bias when fitting to an increasing number of time points. Reductions in R0estimates obtained at sequential time points during early epidemic growth may reflect increased methodological accuracy rather than reductions in pathogen transmissibility or effectiveness of interventions. As SARS-CoV-2 continues its geographic spread, awareness of this bias will be important for appropriate interpretation of results and subsequent guidance for control efforts.
Triaging of Respiratory Protective Equipment on the assumed risk of SARS-CoV-2 aerosol exposure in patient-facing healthcare workers delivering secondary care: a rapid review
Authors: Ramaraj Prashanth , Super Jonathan Thomas , Doyle Ruben , Aylwin Christopher , Hettiaratchy Shehan
Published: May 2020

ABSTRACT

BACKGROUND
Objectives: "In patient-facing healthcare workers delivering secondary care, what is the evidence behind UK Government PPE Guidance on surgical masks versus respirators for SARS-CoV-2 protection?"

METHODS
Two independent reviewers searched MEDLINE, Google Scholar and grey literature 11th-30th April 2020. Studies published on any date containing primary data comparing surgical facemasks and respirators specific to SARS-CoV-2, and studies underpinning government PPE guidance, were included. Appraisal was performed using CASP checklists. Results were synthesised by comparison of findings and appraisals.

RESULTS
In all three laboratory studies of 14 different respirators and 12 surgical facemasks, respirators were significantly more effective than facemasks in protection factors, reduction factors, filter penetrations, and total inspiratory leakages at differing particle sizes, mean inspiratory flows, and breathing rates. Tests included live viruses and inert particles on dummies and humans.

In six clinical studies, 6,502 participants, there was no consistent definition of "exposure" to determine the efficacy of RPE. It is difficult to define "safe". The only statistically significant result found continuous use of respirators more effective in clinical respiratory illness compared to targeted use or surgical facemask.

CONCLUSIONS
There is a paucity of evidence on the comparison of FRSMs and respirators specific to SARS-CoV-2, and poor-quality evidence in other contexts. Indirectness results in extrapolation of non-SARS-CoV-2 specific data to guide UK Government PPE guidance. The appropriateness of this is unknown given the uncertainty over the transmission of SARS-CoV-2.

1. The evidence base for UK Government PPE guidelines is not based on SARS-CoV-2 and requires generalisation from low-quality evidence of other pathogens/particles.
2. There is a paucity of high-quality evidence regarding the efficacy of RPE specific to SARS-CoV-2.
3. HMG's PPE guidelines are underpinned by the assumption of droplet transmission of SARS-CoV-2.

Triaging the use of FFP3 respirators might increase the risk of COVID-19 faced by some.

FUNDING
This review was unfunded and unsponsored.
COVID-19: age, Interleukin-6, C-Reactive Protein and lymphocytes as key clues from a multicentre retrospective study in Spain
Authors: Jurado Aurora , Martín María C. , Abad-Molina Cristina , Orduña Antonio , Martínez Alba , Ocaña Esther , Yarce Oscar , Navas Ana M. , Trujillo Antonio , Fernández Luis , Vergara Esther , Rodríguez Beatriz , Quirant Bibiana , Martínez-Cáceres Eva , Hernández Manuel , Perurena-Prieto Janire , Gil Juana , Cantenys Sergi , González-Martínez Gema , Martínez-Saavedra María T. , Rojo Ricardo , Marco Francisco M. , Mora Sergio , Ontañón Jesús , López-Hoyos Marcos , Ocejo-Vinyals Gonzalo , Melero Josefa , Aguilar Marta , Almeida Delia , Medina Silvia , Vegas María C. , Jiménez Yesenia , Prada Álvaro , Monzón David , Boix Francisco , Cunill Vanesa , Molina Juan
Published: May 2020

Background

SARS-CoV-2 infection has widely spread to the hugest public health challenge to date, COVID-19 pandemic. Different fatality rates among countries are probably due to non-standardized records being carried out by local health authorities. Spanish case-fatality rate is 11.94%, far higher to those reported in Asia or by other European countries. A multicenter retrospective study was performed of demographic, clinical, laboratory and immunological features of 574 Spanish COVID-19 hospitalized patients and their outcomes. The use of use of renin-angiotensin system blockers was also analyzed as a risk factor.

Results

In this study, 27.7% of cases presented a mild curse, 42% a moderate one and for 30.3% of cases, the course was severe. Ages ranged from 18 to 98 (average 63.2). Fifty eight percent (58.9%) of patients were male. Interleukin 6 was higher as severity increased. On the other hand, CD8 lymphocyte count was significantly lower as severity grew and subpopulations CD4, CD8, CD19 and NK showed concordant lowering trends. Severity-related natural killer percent descents were evidenced just within aged cases. A significant severity-related decrease of CD4 lymphocytes was found in males. The use of renin-angiotensin system blockers was associated with moderate or mild disease courses.

Conclusions

Age and age-related comorbidities, such as dyslipidaemia, hypertension or diabetes, determined more frequent severe forms of the disease in this study than in previous literature cohorts. Our cases are older than those so far reported and clinical course of the disease is found to be impaired by age. Immunosenescence might be therefore a suitable explanation for immune system effectors severity-related hampering. Adaptive immunity would go exhausted and a huge ineffective and almost deleterious innate response would account for COVID-19 severity. Renin-angiotensin system blockers treatment in hypertensive patients has a protective effect as regarding COVID-19 severity.
Spatially resolved gene regulatory and disease vulnerability map of the adult Macaque cortex
Authors: Lei Ying , Cheng Mengnan , Li Zihao , Zhuang Zhenkun , Wu Liang , Sun Yunong , Han Lei , Huang Zhihao , Wang Yuzhou , Wang Zifei , Xu Liqin , Yuan Yue , Liu Shang , Pan Taotao , Xie Jiarui , Liu Chuanyu , Volpe Giacomo , Ward Carl , Lai Yiwei , Xu Jiangshan , Wang Mingyue , Yu Hao , Sun Haixi , Yu Qichao , Wu Liang , Wang Chunqing , Wong Chi Wai , Liu Wei , Xu Liangzhi , Wei Jingkuan , Chen Dandan , Shang Zhouchun , Li Guibo , Ma Kun , Cheng Le , Ling Fei , Tan Tao , Chen Kai , Tasic Bosiljka , Dean Michael , Ji Weizhi , Yang Huanming , Gu Ying , Esteban Miguel A. , Li Yuxiang , Chen Ao , Niu Yuyu , Zeng Hongkui , Hou Yong , Liu Longqi , Liu Shiping , Xu Xun
Published: May 2020

Single cell approaches have increased our knowledge about the cell type composition of the non-human primate (NHP), but a detailed characterization of area-specific regulatory features remains outstanding. We generated single-cell chromatin accessibility (single-cell ATAC) and transcriptomic data of 358,237 cells from prefrontal cortex (PFC), primary motor cortex (M1) and primary visual cortex (V1) of adult cynomolgus monkey brain, and integrated this dataset with Stereo-seq (Spatio-Temporal Enhanced REsolution Omics-sequencing) of the corresponding cortical areas to assign topographic information to molecular states. We identified area-specific chromatin accessible sites and their targeted genes, including the cell type-specific transcriptional regulatory network associated with excitatory neurons heterogeneity. We reveal calcium ion transport and axon guidance genes related to specialized functions of PFC and M1, identified the similarities and differences between adult macaque and human oligodendrocyte trajectories, and mapped the genetic variants and gene perturbations of human diseases to NHP cortical cells. This resource establishes a transcriptomic and chromatin accessibility combinatory regulatory landscape at a single-cell and spatially resolved resolution in NHP cortex.
Superior Colliculus-Projecting GABAergic Retinal Ganglion Cells Mediate Looming-Evoked Flight Response
Authors: Luo Xue , Cai Danrui , Shen Kejiong , Deng Qinqin , Lei Xinlan , Jin Sen , Zeng Wen-Bo , Li Hua , Xu Fuqiang , Huang Lu , Ren Chaoran , Luo Min-Hua , Xie Ting , Shen Yin
Published: May 2020

The looming stimulus-evoked flight response is an experimental paradigm for studying innate defensive behaviors. However, how the visual looming stimulus is transmitted from the retina to the brain remains poorly understood. Here, we report that superior colliculus (SC)-projecting RGCs transmit the looming signal from the retina to the brain to mediate the looming-evoked flight behavior by releasing GABA. In the mouse retina, GABAergic RGCs are capable of projecting to many brain areas, including the SC. Superior colliculus (SC)-projecting GABAergic RGCs (spgRGCs) are mono-synaptically connected to the parvalbumin-positive SC neurons known to be required for the looming-evoked flight response. Optogenetic activation of spgRGCs triggers GABA-mediated inhibition in SC neurons. The ablation or silence of spgRGCs compromises looming-evoked flight response but not image-forming functions. Therefore, this study shows that spgRGCs control the looming-evoked flight response by regulating SC neurons via GABA, providing novel insight into the regulation of innate defensive behaviors.
mTOR signaling regulates the morphology and migration of outer radial glia in developing human cortex
Authors: Andrews Madeline G. , Subramanian Lakshmi , Kriegstein Arnold R.
Published: May 2020

Outer radial glial (oRG) cells are a population of neural stem cells prevalent in the developing human cortex that contribute to its cellular diversity and evolutionary expansion. The mammalian Target of Rapamycin (mTOR) signaling pathway is active in human oRG cells. Mutations in mTOR pathway genes are linked to a variety of neurodevelopmental disorders and malformations of cortical development. We find that dysregulation of mTOR signaling specifically affects oRG cells, but not other progenitor types, by changing the actin cytoskeleton through the activity of the GTPase, CDC42. These effects change oRG cellular morphology, migration, and mitotic behavior. Thus, mTOR signaling can regulate the architecture of the developing human cortex by maintaining the cytoskeletal organization of oRG cells and the radial glia scaffold. Our study provides insight into how mTOR dysregulation may contribute to neurodevelopmental disease.
Functional redundancy in natural pico-phytoplankton communities depends on temperature and biogeography
Authors: Zhong Duyi , Listmann Luisa , Santelia Maria-Elisabetta , Schaum C-Elisa
Published: May 2020

Biodiversity affects ecosystem function, but how this relationship will pan out in a changing world is still a major question in ecology. It remains especially understudied for pico-phytoplankton communities, which contribute to carbon cycles and aquatic food webs year-round. Observational studies show a link between phytoplankton community diversity and ecosystem stability, but there is only scarce causal or empirical evidence. Here, we sampled phytoplankton communities from two biogeographically distinct (but close enough to not be confounded by differences in day length and precipitation) regions in the Southern Baltic Sea, and carried out a series of dilution/regrowth experiments across three assay temperatures. This allowed us to investigate the effects of loss of rare taxa and establish causal links in natural communities between species richness and several ecologically relevant traits (e.g. size, biomass production, and oxygen production), depending on sampling location and assay temperature. We found that the samples’ bio-geographical origin determined whether and how functional redundancy changed as a function of temperature for all traits under investigation. Samples obtained from the slightly warmer and more thermally variable regions showed overall high functional redundancy. Samples from the slightly cooler, less variable, stations showed little functional redundancy, i.e. function decreased the more species were lost from the community. The differences between regions were more pronounced at elevated assay temperatures. Our results imply that the importance of rare species and the amount of species required to maintain ecosystem function even under short-term warming (e.g. during heat waves) may differ drastically even within geographically closely related regions of the same ecosystem.
Correlates of auditory decision making in prefrontal, auditory, and basal lateral amygdala cortical areas
Authors: Napoli Julia L. , Camalier Corrie R. , Brown Anna Leigh , Jacobs Jessica , Mishkin Mortimer M. , Averbeck Bruno B.
Published: May 2020

Auditory selective listening and decision making underlies important processes, including attending to a single speaker in a crowded room, often referred to as the cocktail party problem. To examine the neural mechanisms underlying these behaviors, we developed a novel auditory selective listening paradigm for monkeys. In this task, monkeys had to detect a difficult to discriminate target embedded in noise when presented in a pre-cued location (either left or right) and ignore it if it was in the opposite location. While the animals carried out the task we recorded neural activity in primary auditory cortex (AC), dorsal lateral prefrontal cortex (dlPFC) and the basal lateral amygdala (BLA), given that these areas have been implicated in auditory decision making, selective listing, and/or reward-guided decision making. There were two main findings in the neural data. First, primary AC encoded the side of the cue and target, and the monkey’s choice, before either dlPFC or the amygdala. The BLA encoded cue and target variables negligibly, but was engaged at the time of the monkey’s choice. Second, decoding analyses suggested that errors followed primarily from a failure to encode the target stimulus in both AC and PFC, but earlier in AC. Thus, AC neural activity is poised to represent the sensory volley and decision making during selective listening before dlPFC, and they both precede activity in BLA.
Topography of Hippocampal Connectivity with Sensorimotor Cortex Revealed by Optimizing Smoothing Kernel and Voxel Size
Authors: Burman Douglas D.
Published: May 2020

Studies of the hippocampus use smaller voxel sizes and smoothing kernels than cortical activation studies, typically using a multivoxel seed with specified radius for connectivity analysis. This study identified optimal processing parameters for evaluating hippocampal connectivity with sensorimotor cortex (SMC), comparing effectiveness by varying parameters during both activation and connectivity analysis. Using both 3mm and 4mm isovoxels, smoothing kernels of 6-10mm were evaluated on the amplitude and extent of motor activation and hippocampal connectivity with SMC. Psychophysiological interactions identified hippocampal connectivity with SMC during volitional movements, and connectivity effects from multivoxel seeds were compared with alternate methods; a structural seed represented the mean connectivity map from all voxels within a region, whereas a functional seed represented the regional voxel with maximal SMC connectivity. With few exceptions, the same parameters were optimal for activation and connectivity. Larger isovoxels showed larger activation volumes in both SMC and the hippocampus; connectivity volumes from structural seeds were also larger, except from the posterior hippocampus. Regardless of voxel size, the 10mm smoothing kernel generated larger activation and connectivity volumes from structural seeds, as well as larger beta estimates at connectivity maxima; structural seeds also produced larger connectivity volumes than multivoxel seeds. Functional seeds showed lesser effects from voxel size and smoothing kernels. Optimal parameters revealed topography in structural seed connectivity along both the longitudinal axis and mediolateral axis of the hippocampus. These results indicate larger voxels and smoothing kernels improve sensitivity for detecting both cortical activation and hippocampal connectivity.
Identification of amyloid beta oligomers in locus coeruleus (LC) neurons of Alzheimer’s patients and their impact on LC oxidative stress, inhibitory neurotransmitter receptors and neuronal excitability
Authors: Kelly Louise , Seifi Mohsen , Ma Ruolin , Mitchell Scott , Rudolph Uwe , Viola Kirsten L. , Klein William L. , Lambert Jeremy J. , Swinny Jerome D.
Published: May 2020

Amyloid β oligomers (AβO) are potent modulators of two key Alzheimer’s pathological processes, namely synaptic dysfunction and tau tangle formation in various brain regions. Remarkably, the impact of AβO in one of the earliest brain regions to exhibit Alzheimer’s pathology, the locus coeruleus (LC), remains to be determined. Of particular importance is the effect of AβO on the excitability of individual LC neurons. This parameter determines brain-wide noradrenaline (NA) release, and thus NA-mediated brain functions, including cognition, emotion and immune function, which are all severely compromised in Alzheimer’s. Using a mouse model of increased Aβ production (APP-PSEN1), together with correlative histopathological analyses in post mortem Alzheimer’s patient samples, we determined the impact of Aβ pathology on various correlates of LC neuronal integrity. AβO immunoreactivity in the LC of APP-PSEN1 mice was replicated in patient samples, presenting as individual clusters located both intraneuronally, in mitochondrial compartments, as well as extracellularly in association with inhibitory synapses. No specific signal was detected in either patient control or wild type mouse samples. Accompanying this AβO expression profile was LC neuronal hyperexcitability and indicators of oxidative stress in APP-PSEN1 mice. LC hyperexcitability arose from a diminished inhibitory effect of GABA, due to impaired expression and function of the GABA-A receptor (GABAAR) α3 subunit. Importantly, this altered LC α3-GABAAR expression profile overlapped with AβO expression in both APP-PSEN1 mice and Alzheimer’s patient samples. Finally, strychnine-sensitive glycine receptors (GlyRs) remained resilient to AβO-induced changes and their activation reversed LC hyperexcitability. Alongside this first demonstration of AβO expression in the LC of Alzheimer’s patients, the study is also first to reveal a direct association between AβO and LC neuronal excitability. GlyR-α3-GABAAR modulation of AβO-dependent LC hyperexcitability could delay the onset of cognitive and psychiatric symptoms arising from LC-NA deficits, thereby significantly diminishing the disease burden for Alzheimer’s patients.
Replicating infant astrocyte behavior in the adult after brain injury improves outcomes
Authors: Teo Leon , Boghdadi Anthony G. , Homman-Ludiye Jihane , Carril-Mundiñano Iñaki , Kwan William C. , Bourne James A.
Published: May 2020

Infants and adults respond differently to brain injuries. Specifically, improved neuronal sparing along with reduced astrogliosis and glial scarring often observed earlier in life, likely contributes to improved long-term outcomes. Understanding the underlying mechanisms could enable the recapitulation of neuroprotective effects, observed in infants, to benefit adult patients after brain injuries. We reveal that in primates, Eph/ ephrin signaling contributes to age-dependent reactive astrocyte behavior. Ephrin-A5 expression on astrocytes was more protracted in adults, whereas ephrin-A1 was associated only with infant astrocytes. Furthermore, ephrin-A5 exacerbated major hallmarks of astrocyte reactivity via EphA2 and EphA4 receptors, which was subsequently alleviated by ephrin-A1. Rather than suppressing reactivity, ephrin-A1 signaling shifted astrocytes towards GAP43+ neuroprotection, accounting for improved neuronal sparing in infants. Reintroducing ephrin-A1 after middle-aged ischemic stroke significantly attenuated glial scarring, improved neuronal sparing and preserved circuitry. Therefore, beneficial infant mechanisms can be recapitulated in adults to improve outcomes after CNS injuries.
Loss of FSTL1-expressing adipocyte progenitors drives the age-related involution of brown adipose tissue
Authors: Huang Zan , Zhang Zengdi , Heck Ryan , Hu Ping , Nanda Hezkiel , Ren Kaiqun , Sun Zequn , Bartolomucci Alessandro , Gao Yan , Chung Dongjun , Zhu Weiyun , Shen Steven , Ruan Hai-Bin
Published: May 2020

In humans, brown adipose tissue (BAT) undergoes progressive involution or atrophy with increasing age, as manifested by decreased prevalence and mass, transformation to white adipose tissue (WAT), and reduction in thermogenic activity. This involution process cannot be fully recapitulated in rodent models and thus underlying cellular mechanisms are poorly understood. Here, we show that the interscapular BAT (iBAT) in rabbits involutes rapidly in early life, similarly to that in humans. The transcriptomic remodeling and identity switch of mature adipocytes are accompanied with the loss of brown adipogenic competence of their precursor cells. Through single-cell RNA sequencing, we surveyed the heterogenous populations of mesenchymal cells within the stromal vascular fraction of rabbit and human iBAT. An analogousFSTL1highpopulation of brown adipocyte progenitors exists in both species while gradually disappear during iBAT involution in rabbits. In mice, FSTL1 is highly expressed by adipocyte progenitors in iBAT and genetic deletion of FSTL1 causes defective WNT signaling and iBAT atrophy in neonates. Our results underscore the BAT-intrinsic contribution fromFSTL1highprogenitors to age-related tissue involution and point to a potential therapeutic approach for obesity and its comorbidities.

HIGHLIGHTS

Rabbit BAT irreversibly transforms to WAT before puberty.

iBAT adipocyte progenitors reprogram transcriptome and lose brown adipogenic ability.

ComparableFSTL1highbrown adipocyte progenitors exist in rabbit and human iBAT.

Loss of FSTL1 in brown adipocyte progenitors causes iBAT atrophy in mice.