bluuebunny/crossref_metadata_2025 huggingface dataset:
Group II metabotropic glutamate receptors modulate sound evoked and spontaneous activity in the mouse inferior colliculus
Authors: Kristaponyte Inga , Beebe Nichole L. , Young Jesse W. , Shanbhag Sharad J. , Schofield Brett R. , Galazyuk Alexander V.
Published: June 2020

Little is known about the functions of group II metabotropic glutamate receptors (mGluRs2/3) in the inferior colliculus (IC)—a midbrain structure that is a major integration region of the central auditory system. We investigated how these receptors modulate sound-evoked and spontaneous firing in the mouse ICin vivo. We first performed immunostaining and tested hearing thresholds to validate VGAT-ChR2 transgenic mice on a mixed CBA/CaJ x C57BL/6J genetic background. Transgenic animals allowed for optogenetic cell type identification. Extracellular single neuron recordings were obtained before and after pharmacological mGluR2/3 activation. We observed increased sound-evoked firing—as assessed by the rate-level functions—in a subset of both GABAergic and non-GABAergic IC neurons following mGluR2/3 pharmacological activation. These neurons also displayed elevated spontaneous excitability and were distributed throughout the IC area tested, suggesting a widespread mGluR2/3 distribution in the mouse IC.
Multi-Omic Analysis Reveals Disruption of Cholesterol Homeostasis by Cannabidiol in Human Cell Lines
Authors: Guard Steven E. , Chapnick Douglas A. , Poss Zachary C. , Ebmeier Christopher C. , Jacobsen Jeremy , Nemkov Travis , Ball Kerri A. , Webb Kristofor J. , Simpson Helen L. , Coleman Stephen , Bunker Eric , Ramirez Adrian , Reisz Julie A. , Sievers Robert , Stowell Michael H.B. , D’Alessandro Angelo , Liu Xuedong , Old William M.
Published: June 2020

The non-psychoactive cannabinoid, cannabidiol (CBD), is FDA-approved for treatment of two drug-resistant epileptic disorders, and is seeing increased use among the general public, yet the mechanisms that underlie its therapeutic effects and side-effect profiles remain unclear. Here, we report a systems-level analysis of CBD action in human cell lines using temporal multi-omic profiling. FRET-based biosensor screening revealed that CBD treatment resulted in a sharp rise in cytosolic calcium, and activation of AMPK and ERK kinases in human keratinocyte and neuroblastoma cell lines. CBD treatment led to alterations in the abundance of metabolites, mRNA transcripts, and proteins consistent with activation of cholesterol biosynthesis, transport and storage. We found that CBD rapidly incorporated into cellular membranes and altered cholesterol chemical activity, suggesting direct perturbation of cholesterol-dependent membrane properties. CBD treatment induced apoptosis in a dose-dependent manner in multiple human cell lines, which was rescued by inhibition of cholesterol synthesis, and potentiated by compounds that disrupt cholesterol trafficking and storage. Our data point to a pharmacological interaction of CBD with cholesterol homeostasis pathways, with potential implications in its therapeutic use.
Spatio-temporal surveys of the brown meagreSciaena umbrausing passive acoustics for management and conservation
Authors: Di Iorio Lucia , Bonhomme Patrick , Michez Noëmie , Ferrari Bruno , Gigou Alexandra , Panzalis Pieraugusto , Desiderà Elena , Navone Augusto , Boissery Pierre , Lossent Julie , Cadville Benjamin , Bravo-Monin Marie , Charbonnel Eric , Gervaise Cédric
Published: June 2020

Conservation of exploited fish populations is a priority for environmental managers. Spatio-temporal knowledge on reproductive sites is mandatory for species and habitat conservation but is often difficult to assess, particularly over vast geographic areas. Regular and long-term standardized surveys are necessary to identify reproductive sites, assess population trends and their distribution. Here we emphasize the utility of Passive Acoustic Monitoring (PAM) for the survey and management of a depleted vulnerable Mediterranean fish species, the brown meagre,Sciaena umbra. Acoustic surveys of reproductive calls were conducted combining 1) spatial data from standardized surveys within three MPAs and from 49 unprotected sites throughout the Northwestern Mediterranean basin, as well as 2) temporal data from a two-year-long survey at a presumed spawning location. The MPA surveys, which rapidly scanned ~30-50 km of the rocky coastlines per MPA, unveiled maps of distribution and reproductive activity of the brown meagre, including potential spawning sites. They were also effective in emphasizing effects linked to management actions: Full-protection zones had a higher number of vocalizations (70% of the listening sites) compared to less protected zones (30% of the sites) or sites outside MPAs (45% of the sites). This was also reflected in the number of singers that was generally low (< 3 individuals) in less protected zones and outside MPAs, implying lower fish densities. Highest calling aggregations were observed in potential spawning areas that represented only 0.04% of all listening sites, and were almost all in older, fully protected MPAs, which thus play a key role for fish stock recovery. The two-year survey revealed a 5-month reproductive season (from May to October) with a strong positive correlation between calling activity and temperature. Overall this study confirms the role of PAM as an efficient, replicable and standardized non-invasive method for population management that can identify functional sites and key protection zones, provide valuable information on reproduction, spatial and temporal occurrence, but also on population trends and climate-driven changes.

Highlights

Monitoring of threatened species and their key habitats is critical for environmental managers.

Management requires methods to assess population trends at large spatial and temporal scales.

Passive acoustics (PA) is efficient in mapping and monitoring vulnerable fish species.

Distribution, reproductive sites and population dynamics can be assessed over vast geographical areas.

We show the utility of PA to identify key conservation zones and assess effects of management actions.
Decomposition of reinforcement learning deficits in gambling disorder via drift diffusion modeling and functional magnetic resonance imaging
Authors: Wiehler Antonius , Peters Jan
Published: June 2020

Gambling disorder is associated with deficits in feedback-based learning tasks, but the computational mechanisms underlying these learning impairments are still poorly understood. Here, we examined this question using a combination of computational modeling and functional resonance imaging (fMRI) in individuals that regular participate in gambling (n=23, seven fulfilled 1-3 DSM 5 criteria, sixteen fulfilled 4 or more) and matched controls (n=23). Participants performed a stationary reinforcement learning task with two pairs of stimuli (80% vs. 20% reinforcement rates per pair). As predicted, the gambling group made significantly fewer selections of the optimal stimulus, while overall response times (RTs) were not significantly different between groups. We then used comprehensive modeling using reinforcement learning drift diffusion models (RLDDMs) in combination with hierarchical Bayesian parameter estimation to shed light on the computational underpinnings of this performance impairment. In both groups, an RLDDM in which both non-decision time and response threshold (boundary separation) changed over the course of the experiment accounted for the data best. The model showed good parameter and model recovery, and posterior predictive checks revealed that in both groups, the model reproduced the evolution of both accuracy and RTs over time. The learning impairment in the gambling group was attributable to a more rapid reduction in boundary separation over time, and a reduced effect of value-differences on the drift rate, compared to controls. The gambling group also exhibted substantially shorter non-decision times. Imaging analyses replicated earlier effects of prediction error coding in the ventral striatum and value coding in the ventro-medial prefrontal cortex, but there was no credible evidence for group differences in these regions. Taken together, our findings highlight the computational mechanisms underlying reinforcement learning impairments in gambling disorder.
The therapeutic effects of intratumoral injection of IL12IL2GMCSF fusion protein on canine tumors
Authors: Du Xiaobo , Zhang Bin , Hu Fan , Xie Chuantao , Tian Haiyan , Gu Qiang , Gong Haohan , Bai Xiaoguang , Zhang Jinyu
Published: June 2020

Regulating the immune system through tumor immunotherapy to defeat tumors is currently one of the most popular methods of tumor treatment. We previously found that the combinations of IL12, IL2 and GMCSF has superior antitumor activities. In this study, IL12IL2GMCSF fusion protein was produced from 293 cells transduced by expression lentiviral vector. IL12IL2GMCSF fusion protein was injected into canine tumors, and the efficacy was monitored to evaluate the potential of tumor immunotherapy. In 14 canines injected with IL12IL2GMCSF protein, 6 had a complete response (CR), 7 had a partial response (PR), and 1 had stable disease (SD). IL12IL2GMCSF fusion protein has great anti-tumor potential. Intratumoral injection of IL12IL2GMCSF can effectively treat tumors without severe adverse effects. It provides a promising immune therapeutics in canine cancers.
The Atr-Chek1 pathway inhibits axon regeneration in response to Piezo-dependent mechanosensation
Authors: Li Feng , Lo Tsz Y. , Miles Leann , Wang Qin , Li Dan , Niu Jingwen , Goldshteyn Jessica I , Wang Chuxi , Wang Shuchao , Qiu Jingyun , Trombley Shannon , Pogoda Katarzyna , Brewster Megan , Rompolas Panteleimon , He Ye , Janmey Paul A. , Thomas Gareth M. , Song Yuanquan
Published: June 2020

Atr is a serine/threonine kinase, known to sense single-stranded DNA breaks and activate the DNA damage checkpoint by phosphorylating Chek1, which inhibits Cdc25, causing cell cycle arrest. This pathway has not been implicated in neuroregeneration. We show that inDrosophilasensory neurons, removing Atr or Chek1, or overexpressing Cdc25 promotes regeneration, whereas Atr or Chek1 overexpression, or Cdc25 knockdown impedes regeneration. Inhibiting the Atr-associated checkpoint complex in neurons promotes regeneration and improves synapse/behavioral recovery after CNS injury. Independent of DNA damage, Atr responds to the mechanical stimulus elicited during regeneration, via the mechanosensitive ion channel Piezo and its downstream NO signaling. Sensory neuron-specific knockout of Atr in adult mice, or pharmacological inhibition of Atr-Chek1 in mammalian neuronsin vitroand in fliesin vivoenhance regeneration. Our findings reveal the Piezo-Atr-Chek1-Cdc25 axis as an evolutionarily conserved inhibitory mechanism for regeneration, and identify potential therapeutic targets for treating nervous system trauma.
pH dependent inhibition from ammonium ions in the Pseudomonas mevalonii HMG-CoA Reductase crystallization environment
Authors: Purohit Vatsal , Steussy C. Nicklaus , Rosales Anthony R. , Critchelow Chandra J. , Schmidt Tim , Helquist Paul , Wiest Olaf , Mesecar Andrew , Stauffacher Cynthia V.
Published: June 2020

HMG-CoA reductase (Pseudomonas mevalonii) utilizes mevalonate, coenzyme A (CoA) and the cofactor NAD in a complex mechanism involving two hydride transfers with cofactor exchange, accompanied by large conformational changes by a 50 residue subdomain, to generate HMG-CoA. Details about this mechanism such as the conformational changes that allow intermediate formation, cofactor exchange and product release remain unknown. The formation of the proposed intermediates has also not been observed in structural studies with natural substrates. Having been shown to be an essential enzyme for the survival of gram-positive antibiotic resistant pathogenic bacteria, studying its mechanism in detail will be beneficial in developing novel antibacterials. The enzyme has been shown to be catalytically active inside the crystal with dithio-HMG-CoA and NADH but curiously is found to be inactive in the reverse direction in the structure bound to mevalonate, CoA and NAD.

To understand the factors limiting activity in the HMGR crystal with mevalonate, CoA and NAD, we studied the effect of crystallization components and pH on enzymatic activity. We observed a strong inhibition in the crystallization buffer and an increase in activity with increasing pH. We attribute this inhibitive effect to the presence of ammonium ions present in the crystal since inhibition is also observed with several other ammonium salt buffers. Additionally, the lack of inhibition was observed in the absence of ammonium. The effect of each ligand (mevalonate, CoA and NAD) on the rate of the enzymatic reaction in the crystallization environment was further investigated by measuring their Kmin the crystallization buffer. The Kmmeasurements indicate that the hydride transfer step between NAD and mevalonate is inhibited in the crystallization environment. To test this further, we solved a crystal structure of pmHMGR bound to the post-hydride transfer intermediate (mevaldehyde) and cofactor Coenzyme A. The resulting turnover with the formation of a thiohemiacetal indicated that the crystallization environment inhibited the oxidative acylation of mevalonate and the reaction intermediate mevaldyl-CoA.
Human iPSC-derived alveolar and airway epithelial cells can be cultured at air-liquid interface and express SARS-CoV-2 host factors
Authors: Abo Kristine M. , Ma Liang , Matte Taylor , Huang Jessie , Alysandratos Konstantinos D. , Werder Rhiannon B. , Mithal Aditya , Beermann Mary Lou , Lindstrom-Vautrin Jonathan , Mostoslavsky Gustavo , Ikonomou Laertis , Kotton Darrell N. , Hawkins Finn , Wilson Andrew , Villacorta-Martin Carlos
Published: June 2020

Development of an anti-SARS-CoV-2 therapeutic is hindered by the lack of physiologically relevant model systems that can recapitulate host-viral interactions in human cell types, specifically the epithelium of the lung. Here, we compare induced pluripotent stem cell (iPSC)-derived alveolar and airway epithelial cells to primary lung epithelial cell controls, focusing on expression levels of genes relevant for COVID-19 disease modeling. iPSC-derived alveolar epithelial type II-like cells (iAT2s) and iPSC-derived airway epithelial lineages express key transcripts associated with lung identity in the majority of cells produced in culture. They expressACE2andTMPRSS2, transcripts encoding essential host factors required for SARS-CoV-2 infection, in a minor subset of each cell sub-lineage, similar to frequencies observed in primary cells. In order to prepare human culture systems that are amenable to modeling viral infection of both the proximal and distal lung epithelium, we adapt iPSC-derived alveolar and airway epithelial cells to two-dimensional air-liquid interface cultures. These engineered human lung cell systems represent sharable, physiologically relevant platforms for SARS-CoV-2 infection modeling and may therefore expedite the development of an effective pharmacologic intervention for COVID-19.
Equations governing dynamics of excitation and inhibition in the mouse corticothalamic network
Authors: Lin I-Chun , Okun Michael , Carandini Matteo , Harris Kenneth D.
Published: June 2020

Although cortical circuits are complex and interconnected with the rest of the brain, their macroscopic dynamics are often approximated by modeling the averaged activities of excitatory and inhibitory cortical neurons, without interactions with other brain circuits. To verify the validity of such mean-field models, we optogenetically stimulated populations of excitatory and parvalbumin-expressing inhibitory neurons in awake mouse visual cortex, while recording population activity in cortex and in its thalamic correspondent, the lateral geniculate nucleus. The cortical responses to brief test pulses could not be explained by a mean-field model including only cortical excitatory and inhibitory populations. However, these responses could be predicted by extending the model to include thalamic interactions that cause net cortical suppression following activation of cortical excitatory neurons. We conclude that mean-field models can accurately summarize cortical dynamics, but only when the cortex is considered as part of a dynamic corticothalamic network.
Hypothetical Human Immune Genome Complex Gradient May Help to Explain the Congenital Zika Symdrome Catastrophe in Brazil: A New Theory
Authors: Oliveira F.R.S , Bresani-Salvi C.C. , Morais C. N.L. , Bigham A.W. , Braga-Neto U. , Maestre G.E. , Wandebergh j. l. , Marques E.T.A , Acioli-Santos B.
Published: June 2020

There are few data considering human genetics as an important risk factor for birth abnormalities related to ZIKV infection during pregnancy, even though sub-Saharan African populations are apparently more resistant to CZS as compared to populations in the Americas. We hypothesized that single nucleotide variants (SNVs), especially in innate immune genes, could make some populations more susceptible to Zika congenital complications than others. Differences in the SNV frequencies among continental populations provide great potential for Machine Learning techniques. We explored a key immune genomic gradient between individuals from Africa, Asia and Latin America, working with complex signatures, using 297 SNVs. We employed a two-step approach. In the first step, decision trees (DTs) were used to extract the most discriminating SNVs among populations. In the second step, machine learning algorithms were used to evaluate the quality of the SNV pool identified in step one for discriminating between individuals from sub-Saharan African and Latin-American populations. Our results suggest that 10 SNVs from 10 genes (CLEC4M, CD58, OAS2, CD80, VEPH1, CTLA4, CD274, CD209, PLAAT4, CREB3L1) were able to discriminate sub-Saharan Africans from Latin American populations using only immune genome data, with an accuracy close to 100%. Moreover, we found that these SNVs form a genome gradient across the three main continental populations. These SNVs are important elements of the innate immune system and in the response against viruses. Our data support theHuman Immune Genome Complex Gradienthypothesis as a new theory that may help to explain the CZS catastrophe in Brazil.
Elovl2 but not Elovl5 is essential for the biosynthesis of docosahexaenoic acid (DHA) in zebrafish: insight from a comparative gene knockout study
Authors: Liu Chengjie , Ye Ding , Wang Houpeng , He Mudan , Sun Yonghua
Published: June 2020

Teleost fish can synthesize one of the major omega-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFAs), docosahexaenoic acid (DHA, 22:6n-3), from dietary α-linolenic acid (ALA; 18:3n-3), via elongase of very long chain fatty acid (Elovl) and fatty acid desaturase (Fads). However, it remains unclear which elongase is responsible for the endogenous synthesis of DHA. Here in this study, the knockout models of the two major elongases, Elovl2 and Elovl5, were generated by CRISPR/Cas9 approach in zebrafish and comparatively analyzed. The homozygous mutants were validated by Sanger sequencing, mutation-mediated PCR and whole-mount in situ hybridization analysis of the endogenous target genes. Compared with wildtype (WT) counterparts, the content of DHA was significantly reduced by 67.1% (p<0.05) in the adult liver and by 91.7% (p<0.01) in the embryo at 3 day-post-fertilization (dpf) of the elovl2 mutant, but not of the elovl5 mutant. Further study revealed that elovl2 and fads2 was upregulated by 9.9-fold (p<0.01) and 9.7-fold (p<0.01) in the elovl5 mutant, and elovl5 and fads2 was upregulated by 15.1-fold (p<0.01) and 21.5-fold (p<0.01) in the elovl2 mutant. Our study indicates that although both Elovl2 and Elovl5 have the elongase activity toward C20, the upregulation of elovl2 could completely replace the genetic depletion of elovl5, but upregulation of elovl5 could not compensate the endogenous deficiency of elovl2 in mediating DHA synthesis. In conclusion, the endogenous synthesis of DHA in is mediated by Elovl2 but not Elovl5 in teleost, and a DHA-deficient genetic model of zebrafish has been generated.
Interplay of mesoscale physics and agent-like behaviors in the parallel evolution of aggregative multicellularity
Authors: Arias Del Angel Juan A. , Nanjundiah Vidyanand , Benítez Mariana , Newman Stuart A.
Published: June 2020

Myxobacteria and dictyostelids are prokaryotic and eukaryotic multicellular lineages, respectively, that after nutrient depletion aggregate and develop into structures called fruiting bodies. The developmental processes and the resulting morphological outcomes resemble one another to a remarkable extent despite their independent origins, the evolutionary distance between them and the lack of traceable levels of homology in the molecular mechanisms of the groups. We hypothesize that the morphological parallelism between the two lineages arises as the consequence of the interplay, within multicellular aggregates, betweengeneric processes, physical and physicochemical processes operating similarly in living and non-living matter at the mesoscale (~10-3-10-1m) andagent-like behaviors, unique to living systems, characteristic of the constituent cells. To this effect, we analyze the relative contribution of the generic and agent-like determinants in the main phenomena of myxobacteria and dictyostelid development, and their roles in the emergence of their shared traits. We show that as a consequence of aggregation collective cell-cell contacts mediate the emergence of liquid-like properties, making nascent multicellular masses subject to new sets of patterning and morphogenetic processes. In both lineages, this leads to behaviors such as streaming, rippling, and rounding up, similar to effects observed in non-living fluids. Later the aggregates solidify, leading them to exhibit additional generic properties and motifs. We consider evidence that the morphological phenotypes of the multicellular masses deviate from the predictions of generic physics due to the contribution of agent-like behaviors. These include directed migration, quiescence, and oscillatory signal transduction of the cells mediated by responses to external cues acting through species-specific regulatory and signaling mechanisms reflecting the evolutionary histories of the respective organisms. We suggest that the similar developmental trajectories of Myxobacteria and Dictyostelia are more plausibly due to shared generic physical processes in coordination with analogous agent-type behaviors than to convergent evolution under parallel selection regimes. Finally, we discuss the broader implications of the existence and synergy of these two categories of developmental factors for evolutionary theory.
Assessment of neuropsychological function in brain tumour treatment: A comparison of traditional neuropsychological assessment with app-based cognitive screening
Authors: Romero-Garcia Rafael , Owen Mallory , McDonald Alexa , Woodberry Emma , Assem Moataz , Coelho Pedro , Morris Rob C , Price Stephen J , Santarius Tom , Suckling John , Manly Tom , Erez Yaara , Hart Michael G
Published: June 2020

Background

Gliomas are typically considered to cause relatively few neurological impairments. However, cognitive difficulties can arise, for example during treatment, with potential detrimental effects on quality of life. Accurate, reproducible, and accessible cognitive assessment is therefore vital in understanding the effects of both tumour and treatments. Our aim is to compare traditional neuropsychological assessment with an app-based cognitive screening tool in patients with glioma before and after surgical resection. Our hypotheses were that cognitive impairments would be apparent, even in a young and high functioning cohort, and that app-based cognitive screening would complement traditional neuropsychological assessment.

Methods

Seventeen patients with diffuse gliomas completed a traditional neuropsychological assessment and an app-based touchscreen tablet assessment (OCS-BRIDGE) pre- and post-operatively. The app assessment was also conducted at 3- and 12-month follow-up. Impairment rates, mean performance, and pre- and post-operative changes were compared using standardized Z-scores.

Results

Approximately 2-3 hours of traditional assessment indicated an average of 2.88 cognitive impairments per patient, whilst the 30-minute screen indicated 1.18. As might be expected, traditional assessment using multiple items across the difficulty range proved more sensitive than brief screening measures in areas such as memory and attention. However, the capacity of the screening app to capture reaction times enhanced its sensitivity, relative to traditional assessment, in the area of non-verbal function. Where there was overlap between the two assessments, for example digit span tasks, the results were broadly equivalent.

Conclusions

Cognitive impairments were common in this sample and app-based screening complemented traditional neuropsychological assessment. Implications for clinical assessment and follow-up are discussed.
Suppressive myeloid cells are a hallmark of severe COVID-19
Authors: Schulte-Schrepping Jonas , Reusch Nico , Paclik Daniela , Baßler Kevin , Schlickeiser Stephan , Zhang Bowen , Krämer Benjamin , Krammer Tobias , Brumhard Sophia , Bonaguro Lorenzo , De Domenico Elena , Wendisch Daniel , Grasshoff Martin , Kapellos Theodore S. , Beckstette Michael , Pecht Tal , Saglam Adem , Dietrich Oliver , Mei Henrik E. , Schulz Axel R. , Conrad Claudia , Kunkel Désirée , Vafadarnejad Ehsan , Xu Cheng-Jian , Horne Arik , Herbert Miriam , Drews Anna , Thibeault Charlotte , Pfeiffer Moritz , Hippenstiel Stefan , Hocke Andreas , Müller-Redetzky Holger , Heim Katrin-Moira , Machleidt Felix , Uhrig Alexander , de Jarcy Laure Bousquillon , Jürgens Linda , Stegemann Miriam , Glösenkamp Christoph R. , Volk Hans-Dieter , Goffinet Christine , Raabe Jan , Kaiser Kim Melanie , Vinh Michael To , Rieke Gereon , Meisel Christian , Ulas Thomas , Becker Matthias , Geffers Robert , Witzenrath Martin , Drosten Christian , Suttorp Norbert , von Kalle Christof , Kurth Florian , Händler Kristian , Schultze Joachim L. , Aschenbrenner Anna C , Li Yang , Nattermann Jacob , Sawitzki Birgit , Saliba Antoine-Emmanuel , Sander Leif Erik ,   Deutsche COVID-19 OMICS Initiative (DeCOI)
Published: June 2020

‘Severe Acute Respiratory Syndrome - Coronavirus-2’ (SARS-CoV-2) infection causes Coronavirus Disease 2019 (COVID-19), a mild to moderate respiratory tract infection in the majority of patients. A subset of patients, however, progresses to severe disease and respiratory failure with acute respiratory distress syndrome (ARDS). Severe COVID-19 has been associated with increased neutrophil counts and dysregulated immune responses. The mechanisms of protective immunity in mild forms and the pathogenesis of dysregulated inflammation in severe courses of COVID-19 remain largely unclear. Here, we combined two single-cell RNA-sequencing technologies and single-cell proteomics in whole blood and peripheral blood mononuclear cells (PBMC) to determine changes in immune cell composition and activation in two independent dual-center patient cohorts (n=46+n=54 COVID-19 samples), each with mild and severe cases of COVID-19. We observed a specific increase of HLA-DRhiCD11chiinflammatory monocytes that displayed a strong interferon (IFN)-stimulated gene signature in patients with mild COVID-19, which was absent in severe disease. Instead, we found evidence of emergency myelopoiesis, marked by the occurrence of immunosuppressive pre-neutrophils and immature neutrophils and populations of dysfunctional and suppressive mature neutrophils, as well as suppressive HLA-DRtomonocytes in severe COVID-19. Our study provides detailed insights into systemic immune response to SARS-CoV-2 infection and it reveals profound alterations in the peripheral myeloid cell compartment associated with severe courses of COVID-19.
Discrete SIR modelling using empirical infection data shows that SARS-CoV-2 infection provides short-term immunity
Authors: McMahon Andrew , Robb Nicole C.
Published: June 2020

Background

The novel coronavirus SARS-CoV-2, which causes the COVID-19 disease, has resulted in a global pandemic. Since its emergence in December 2019, the virus has infected millions of people, caused the deaths of hundreds of thousands and resulted in incalculable social and economic damage. Understanding the infectivity and transmission dynamics of the virus is essential for understanding how best to reduce mortality whilst ensuring minimal social restrictions to the lives of the general population. Anecdotal evidence is available, but detailed studies have not yet revealed whether infection with the virus results in immunity.

Objective

The objective of the study was to use mathematical modelling to investigate the reinfection frequency of COVID-19.

Methods

We have used the SIR (Susceptible, Infected, Recovered) framework and random processing based on empirical SARS-CoV-2 infection and fatality data from different regions to calculate the number of reinfections that would be expected to occur if no immunity to the disease occurred.

Results

Our model predicts that cases of reinfection should have been observed by now if primary SARS-CoV-2 infection did not protect from subsequent exposure in the short term, however, no such cases have been documented.

Conclusions

This work concludes that infection with the SARS-CoV-2 virus provides short-term immunity to reinfection and therefore provides a useful insight for serological testing strategies, lockdown easing and vaccine design.
County-Level Proportions of Black and Hispanic populations, and Socioeconomic Characteristics in Association with Confirmed COVID-19 Cases and Deaths in the United States
Authors: Khanijahani Ahmad
Published: June 2020

Objectives

The objective of this study was to investigate potential county-level disparities among racial/ethnic and economic groups in COVID-19 burden which was measured using confirmed cases and deaths in 100,000 population.

Design

Secondary data analysis using county-level data for 3,142 US counties was conducted in 2020. Hierarchical linear regression and concentration curve analyses were performed. The association of COVID-19 cases and deaths was examined separately by sociodemographic and economic characteristics of the county population. American Community Survey (ACS) 5-year estimates (2014-2018), Area Health Resources File (AHRF) 2018-2019, and 2020 COVID-19 data from Johns Hopkins University were used in this study.

Results

After adjusting for covariates, US counties with a higher proportion of black population, and a higher proportion of adults with less than high school diploma had disproportionately higher COVID-19 cases and deaths (β>0, p<0.05). A higher proportion of the Hispanic population was associated with higher confirmed cases (β= 1.03, 95% CI= 0.57-1.5), and higher housing cost to household income ratio was associated with higher deaths (β= 3.74, 95% CI= 2.14-5.37). This observed disparities can potentially aggravate the existing health disparities among these population groups.

Conclusions

Identification of disproportionately impacted population groups can pave the way towards narrowing the disparity gaps and guide policymakers and stakeholders in designing and implementing population group-specific interventions to mitigate the negative consequences of COVID-19 pandemic.
Modeling COVID-19 dynamics in Illinois under non-pharmaceutical interventions
Authors: Wong George N. , Weiner Zachary J. , Tkachenko Alexei V. , Elbanna Ahmed , Maslov Sergei , Goldenfeld Nigel
Published: June 2020

We present modeling of the COVID-19 epidemic in Illinois, USA, capturing the implementation of a Stay-at-Home order and scenarios for its eventual release. We use a non-Markovian age-of-infection model that is capable of handling long and variable time delays without changing its model topology. Bayesian estimation of model parameters is carried out using Markov Chain Monte Carlo (MCMC) methods. This framework allows us to treat all available input information, including both the previously published parameters of the epidemic and available local data, in a uniform manner. To accurately model deaths as well as demand on the healthcare system, we calibrate our predictions to total and in-hospital deaths as well as hospital and ICU bed occupancy by COVID-19 patients. We apply this model not only to the state as a whole but also its sub-regions in order to account for the wide disparities in population size and density. Without prior information on non-pharmaceutical interventions (NPIs), the model independently reproduces a mitigation trend closely matching mobility data reported by Google and Unacast. Forward predictions of the model provide robust estimates of the peak position and severity and also enable forecasting the regional-dependent results of releasing Stay-at-Home orders. The resulting highly constrained narrative of the epidemic is able to provide estimates of its unseen progression and inform scenarios for sustainable monitoring and control of the epidemic.
Three Risk Scores For Mortality Prediction In Minimally Invasive Cardiac Surgery
Authors: Margaryan R. , Bianchi G. , Concistre G. , Gasbarri T. , Kallushi E. , Farneti P. , Solinas M.
Published: June 2020

Objective

The Society of Thoracic Surgeons score performance relative to other scores in minimally invasive cardiac surgery is not known.

Methods

Patients who underwent surgery from 2003 to 2018 identified from database. Additional variables included for STS score calculation, EuroSCORE II and age, creatinine and ejection fraction score calculation.

Results

A total of 4751 patients were identified from main database. There were actual 47 (0.99%) hospitals deaths. The mean STS score predicted mortality were 2.0 ± 2.1. Discriminatory power was uniformly good (for STS Mortality: area under curve, 0.86; 95% confidence interval, 0.81 - 0.91). The mean EuroSCORE II predicted mortality were 2.9 ± 3.8. Discriminatory power was uniformly good similar to that of STS (for EuroSCORE II Mortality: area under curve, 0.9; 95% confidence interval, 0.86 - 0.93). The mean ACEF predicted mortality were 2.5 ± 2.3. Discriminatory power was uniformly good but inferior to that of STS and EuroSCORE II (for ACEF Mortality: area under curve, 0.72; 95% confidence interval, 0.65 - 0.8).

Calibration pattern for STS score was the best for of mortality prediction (p < 0.01), EuroSCORE II and ACEF were constantly overestimating mortality (respectively, p < 0.01 and p < 0.01). scores.

Conclusions

The STS score has acceptable discrimination power for this sub-population. However, it is not calibrated for the the subset. EuroSCORE II is has good discrimination power, but not calibrate for the this subset of patients. ACEF score had similar performance to EuroSCORE. No algorithm seems suitable for accurate risk estimation.
Review of published systematic reviews and meta-analyses on COVID-19
Authors: Ibrahim Nasrien E. , Ibrahim Ezzeldin M.
Published: June 2020

Purpose

The rapid spread of the COVID-19 pandemic has prompted researchers from all over the world to share their experience. The results were numerous reports with variable quality. The latter has provided an impetus to examine all published meta-analyses and systematic reviews on COVID-19 to date to examine available evidence. Methods: Using predefined selection criteria, a literature search identified 43 eligible meta-analyses and/or systematic reviews. Results: Most (N=17) studies addressed clinical manifestations and associated comorbidity, 6 studies addressed clinical manifestations in pregnant women and younger individuals, 8 studies addressed diagnostic data, 9 studies addressed various interventions, and 9 studies addressed prevention and control. The number of studies included in the various systemic reviews and meta-analyses ranged from 2 to 89. While there were some similarities and consistency for some findings, e.g. the relation between comorbidities and disease severity, we also noted occasionally conflicting data. Conclusion: As more data are collected from patients infected with COVID-19 all over the world, more studies will undoubtedly be published and attention to scientific accuracy in the performance of trials must be exercised to inform clinical decision-making and treatment guidelines.
Trends of per-patient healthcare cost and resource utilization of opioid use disorder among privately insured individuals in the United States from 2005-2014
Authors: Jiang Bibo , Wang Li , Leslie Douglas
Published: June 2020

Background

Little are known about how per-patient healthcare cost and resource utilization of Opioid Use Disorder (OUD) have changed over time when governments continue to reduce availability and utilization barrier of OUD treatment.

Objectives

Investigate trends of per-patient healthcare cost and utilization of outpatient, inpatient and emergency department services among privately insured individuals with OUD from 2005 to 2014.

Methods

The MarketScan® Commercial Claims and Encounters database was used to analyze healthcare cost and resource utilization of opioid used disorder from 2005 to 2014. A matched case-control design was employed to estimate the impact of OUD on healthcare cost and service utilization over this period.

Main findings

Excess annual per-patient healthcare cost of OUD stayed relatively stable with an average of $14,586 between 2005 and 2014. However, excess outpatient cost increased while excess inpatient cost decreased over time. Among OUD patients, the increase of OUD related outpatient care utilization rate and average number of visits coincided with the decrease of inpatient and ED service utilization rates and average number of ED visits.

Conclusions

Among OUD patients, the increasing per-patient utilization of OUD related outpatient care, together with the decline in per-patient utilization of more urgent care including inpatient and emergency department care might indicate increased awareness and diagnosis of OUD and a better control of the disease among existing patients with private insurance.
Dominant and rare SARS-Cov2 variants responsible for the COVID-19 pandemic in Athens, Greece
Authors: Nikolaos Spanakis , Katerina Kassela , Nikolas Dovrolis , Maria Bampali , Elisavet Gatzidou , Athanasia Kafasi , Elisavet Froukala , Anastasia Stavropoulou , Konstantinos Lilakos , Stavroula Veletza , Sotirios Tsiodras , Athanasios Tsakris , Ioannis Karakasiliotis
Published: June 2020

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is a novel Coronavirus responsible for the Coronavirus Disease-2019 (COVID-19) pandemic. Since the beginning of the pandemic, the virus has spread in almost the entire world. Tracing and tracking virus international and local transmission has been an enormous challenge. Chains of infections starting from various countries worldwide seeded the outbreak of COVID-19 in Athens, capital city of Greece. Full-genome analysis of isolates from Athens’ Hospitals and other healthcare providers revealed the variety of SARS-CoV-2 that initiated the pandemic before lock-down and passenger flight restrictions. The present work may serve as reference for resolving future lines of infection in the area and Europe especially after resumption of passenger flight connections to Athens and Greece during summer of 2020.
Risk factors for rhinitis, allergic conjunctivitis and eczema among schoolchildren in Uganda
Authors: Mpairwe Harriet , Nkurunungi Gyaviira , Tumwesige Pius , Akurut Hellen , Namutebi Milly , Nambuya Irene , Nnaluwooza Marble , Apule Barbara , Onen Caroline , Katongole Tonny , Niwagaba Emmanuel , Mukasa Mike , Webb Emily L , Elliott Alison M , Pearce Neil
Published: June 2020

Background

The prevalence of allergy-related diseases (ARDs), including rhinitis, allergic conjunctivitis and eczema, is on the increase in Africa and globally. The causes of this increase are not well established.

Objectives

To investigate the risk factors for ARDs among schoolchildren in Uganda.

Methods

We conducted a secondary data analysis of a large asthma case-control study involving 1,700 schoolchildren, 5-17 years, in urban Uganda. ARDs were defined according to the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. Skin prick testing (SPT) was conducted using standard procedures and allergen-specific IgE (asIgE) using ImmunoCAP®. We used inverse probability weighting to account for the differences in the sampling fractions in all our analyses.

Results

The lifetime prevalence of reported rhinitis, allergic conjunctivitis and eczema was 43.3%, 39.5%, and 13.5%, respectively. There was overlap of ARDs, with 66.3% of 1,193 schoolchildren who reported having ever an ARDs (including asthma) reporting two or more. The important risk factors for ‘rhinitis ever’ were city residence at birth [adjusted odds ratio (95% confidence interval) 1.97 (1.26-3.10) compared to rural]; father’s [2.08 (1.57-2.75)] and mother’s history of allergic disease [2.29 (1.81-2.91)]; frequent de-worming in the last 12 months [1.80 (1.32-2.45), ≥2 versus none]; current high frequency of ‘trucks passing on the street near home’ [1.90 (1.19-3.03), ‘almost all the time’ versus rarely] and positive SPT [1.56 (1.24-1.96)] but not asIgE [1.33 (0.81-2.18)]. The same pattern of risk factors was observed for allergic conjunctivitis and eczema.

Conclusion

We found extensive multi-morbidity of, and overlap in the risk factors for, rhinitis, conjunctivitis, and eczema - similar to asthma risk factors - among schoolchildren in urban Uganda. This suggests a similar underlying cause for all ARDs, associated with exposure to urban lifestyles and environment in Uganda. Thus, epidemiological research should investigate causes of all ARDs as one disease entity.
Modelling daily infections with Covid-19 in Germany, France, and Sweden with a trend line based on day-to-day reproduction rates
Authors: Mergel Dieter
Published: June 2020

The number of persons daily infected with Covid-19 as a function of time is fitted with a trend line based on an iterative power law (n = ¼) with a day-to-day reproduction rate modelled with a polyline. From the trend line, an effective reproduction rate Reff of Covid-19 is calculated. In all three states, Reff decreases in the initial phase to one indicating that there is no exponential growth. In Sweden, a steady state with Reff around 1 and a high daily infection rates. In Germany, Reff = 1 is reached before public and private life is restricted. With these restrictions, Reff is reduced further to 0.87 (CI95 [0.83.; 0.91]) after 40 days so that, speculatively estimated, 9500 premature fatalities within two months may have been avoided. In France, it seems that only strongly restricting private life sends Reff down to 1 and further down to about 0.7 (CI95 [0.3; 1.1]) after 45 days. With Reff permanently below 1, an exponential decline of the number of daily infections is observed in Germany and France.
Exploring the Feasibility of Using Real-World Data from a Large Clinical Data Research Network to Simulate Clinical Trials of Alzheimer’s Disease
Authors: Chen Zhaoyi , Zhang Hansi , Guo Yi , George Thomas J , Prosperi Mattia , Hogan William R , He Zhe , Shenkman Elizabeth A , Wang Fei , Bian Jiang
Published: June 2020

In this study, we explored the feasibility of using real-world data (RWD) from a large clinical research network to simulate real-world clinical trials of Alzheimer’s disease (AD). The target trial (i.e.,NCT00478205) is a Phase III double-blind, parallel-group trial that compared the 23 mg donepezil sustained release with the 10 mg donepezil immediate release formulation in patients with moderate to severe AD. We followed the target trial’s study protocol to identify the study population, treatment regimen assignments, and outcome assessments, and to set up a number of different simulation scenarios and parameters. We considered two main scenarios: (1) a one-arm simulation: simulating a standard-of-care arm that can serve as an external control arm; and (2) a two-arm simulation: simulating both intervention and control arms with proper patient matching algorithms for comparative effectiveness analysis. In the two-arm simulation scenario, we used propensity score matching controlling for baseline characteristics to simulate the randomization process. In the two-arm simulation, higher SAE rates were observed in the simulated trials than the rates reported in original trial, and a higher SAE rate was observed in the 23mg arm than the 10 mg standard-of-care arm. In the one-arm simulation scenario, similar estimates of SAE rates were observed when proportional sampling was used to control demographic variables. In conclusion, trial simulation using RWD is feasible in this example of AD trial in terms of safety evaluation. Trial simulation using RWD could be a valuable tool for post-market comparative effectiveness studies and for informing future trials’ design. Nevertheless, such approach may be limited, for example, by the availability of RWD that matches the target trials of interest, and further investigations are warranted.
Disparities in COVID-19 related knowledge, attitudes, beliefs and behaviours by health literacy
Authors: McCaffery KJ , Dodd RH , Cvejic E , Ayre J , Batcup C , Isautier JMJ , Copp T , Bonner C , Pickles K , Nickel B , Dakin T , Cornell S , Wolf MS
Published: June 2020

Objectives

To explore the variation in understanding, attitudes and uptake of COVID-19 health advice during the 2020 pandemic lockdown by health literacy.

Study design

National cross sectional community survey.

Setting

Australian general public.

Participants

Adults aged over 18 years (n = 4362).

Main outcome measures

Knowledge, attitudes and behaviours related to COVID-19; health literacy and socio-demographic factors.

Results

People with inadequate health literacy had poorer understanding of COVID-19 symptoms (49% vs 68%; p<0.001), were less able to identify behaviours to prevent infection (59% vs 72%; p<0.001), and experienced more difficulty finding information and understanding government messaging about COVID-19 than people with adequate health literacy. They were less likely to rate social distancing as important (6.1 vs 6.5, p<0.001) and reported more difficulty remembering/accessing medication since lockdown (3.6 vs 2.7, p<0.001). Importantly there was higher endorsement of misinformation beliefs related to COVID-19 and vaccination in people with lower health literacy. Similar results were observed among people who primarily speak a language other than English at home.

Conclusion

Our findings show important disparities by health literacy and language in COVID-19 related knowledge, attitudes and behaviours that have the potential to undermine efforts to reduce viral transmission and may lead to social inequalities in health outcomes in Australia. Those with the greatest burden of chronic disease are most disadvantaged, and most likely to experience severe disease and die from COVID-19. Addressing the health literacy needs of the community in public health messaging about COVID-19 must now be a priority in Australia.