bluuebunny/crossref_metadata_2025 huggingface dataset:
Public perspectives on social distancing and other protective measures in Europe: a cross-sectional survey study during the COVID-19 pandemic
Authors: Meier Karien , Glatz Toivo , Guijt Mathijs C , Piccininni Marco , van der Meulen Merel , Atmar Khaled , Jolink Anne-Tess C , Kurth Tobias , Rohmann Jessica L , Najafabadi Amir H Zamanipoor
Published: April 2020

Objectives

The extent to which people implement government-issued protective measures is critical in preventing further spread of coronavirus disease 2019 (COVID-19) caused by coronavirus SARS-CoV-2. Our study aimed to evaluate the public belief in the effectiveness of protective measures, the reported implementation of these measures in daily life, and to identify communication channels used to acquire relevant information on COVID-19 in European countries.

Design

A cross-sectional online survey available in multiple languages was disseminated on social media starting March 19th, 2020. After five days, we computed descriptive statistics for countries with more than 500 respondents. Each day, we compiled and categorized community containment measures enacted in each country by stringency (stage I-IV). Response collection continued for one week to explore possible dynamics as containment strategies intensified.

Participants

In total, 9,796 adults responded, of whom 8,611 resided in the Netherlands (stage III), 604 in Germany (stage III), and 581 in Italy (stage IV). An additional 1,365 respondents completed the survey in the following week.

Results

Participants indicated support for governmental measures related to avoiding social gatherings, selective closure of public places, and hand hygiene and respiratory measures (range for all measures: 95.0%-99.7%). Respondents from the Netherlands were less likely to consider a complete social lockdown effective (59.2%), compared to respondents in Germany (76.6%) or Italy (87.2%). Italian residents did not only apply enforced social distancing measures more frequently (range: 90.2%-99.3%, German and Dutch residents: 67.5%-97.0%), but also self-initiated hygienic and social distancing behaviors (range: 36.3%-96.6%, German and Dutch residents: 28.3%-95.7%). Respondents largely reported being sufficiently informed about the COVID-19 outbreak and about behaviors to avoid infection (range across countries: 90.2%-91.1%). Information channels most commonly reported included television (range: 53.0%-82.0%), newspapers (range: 31.0%-63.0%), official health websites (range: 39.0%-54.1%), and social media (range: 40.0%-55.8%). We observed no major changes in answers over time.

Conclusions

In European countries, the degree of public belief in the effectiveness of protective measures was high and residents reported to be sufficiently informed by various communication channels. In March 2020, implementation of enacted and self-initiated measures differed between countries and were highest among Italian respondents, who were subjected to the most elaborate measures of social lockdown and greatest COVID-19 burden in Europe.
Surge capacities and predicted demands of Brazil’s health system associated with severe COVID-19 cases
Authors: Cavalcante Eric Luis Barroso , Ferreira Juliana Cristina Cardoso
Published: April 2020

Objective

To estimate surge capacities and demands of Brazil’s health system in view of severe cases of the novel coronavirus disease.

Methods

Three types of hospital equipments demanded by severe COVID-19 patients are considered: available intensive care unit (ICU) beds, existing surgery operating rooms and respirators located in other hospital areas. They are taken into account on a cumulative basis forming three levels of hospital equipment usage. Based on a mean duration of hospitalization for the disease, it is estimated the daily admission capacity of infected patients per state and for the entire country for each level of hospital equipment usage. Furthermore, an exponential regression model is fitted by means of the daily national number of new documented patients. The prediction intervals for the number of new patients for certain days in the immediate future are then calculated and compared to the admissible daily demand for the three incremental groups of equipments. The data are made publicly available by the Brazilian federal government and are gathered and analyzed by means of the Python programming language.

Results

41% of the (adult) ICU beds in Brazil were available during 2019, indicating that this hospital equipment has not been on average operating near capacity in national numbers. Nevertheless, there is a marked heterogeneity in the absolute and relative numbers of available and existing ICU beds and existing surgery operating rooms and extra respirators between its states.

Conclusions

The remarkable differences between states’ hospital resources directly reflect into the number of possible daily admissions of COVID-19 patients with respiratory failure for the three considered levels of hospital equipment usage. In national numbers, Brazil’s health system is estimated to be capable of daily admitting 693, 1243 and 2166 severe patients under the three studied scenarios. The fitted model predicted that only the first limit, if any, would be reached.
Explaining national differences in the mortality of Covid-19: individual patient simulation model to investigate the effects of testing policy and other factors on apparent mortality
Authors: Michaels Jonathan A , Stevenson Matt D
Published: April 2020

There has been extensive speculation on the apparent differences in mortality between countries reporting on the confirmed cases and deaths due to Covid-19. A number of explanations have been suggested, but there is no clear evidence about how apparent fatality rates may be expected to vary with the different testing regimes, admission policies and other variables. An individual patient simulation model was developed to address this question. Parameters and sensitivity analysis based upon recent international data sources for Covid-19 and results were averaged over 100 iterations for a simulated cohort of over 500,000 patients.

Different testing regimes for Covid-19 were considered; testing admitted patients only, various rates of community testing of symptomatic cases and active contact-tracing and screening.

In the base case analysis, apparent mortality ranged from 10.5% under a policy of testing only admitted patients to 0.4% with intensive contact tracing and community testing. These findings were sensitive to assumptions regarding admission rates and the rate of spread, with more selective admission policies and suppression of spread increasing the apparent mortality and the potential for apparent mortality rates to exceed 18% under some circumstances. Under all scenarios the proportion of patients tested in the community had the greatest impact on apparent mortality.

Whilst differences in mortality due to health service and demographic factors cannot be excluded, the current international differences in reported mortality are all consistent with differences in practice regarding screening, community testing and admission policies.
Dynamics of COVID-19 epidemics: SEIR models underestimate peak infection rates and overestimate epidemic duration
Authors: Grant Alastair
Published: April 2020

Compartment models of infectious diseases, such as SEIR, are being used extensively to model the COVID-19 epidemic. Transitions between compartments are modelled either as instantaneous rates in differential equations, or as transition probabilities in discrete time difference or matrix equations. These models give accurate estimates of the position of equilibrium points, when the rate at which individuals enter each stage is equal to the rate at which they exit from it. However, they do not accurately capture the distribution of times that an individual spends in each compartment, so do not accurately capture the transient dynamics of epidemics. Here we show how matrix models can provide a straightforward route to accurately model stage durations, and thus correctly reproduce epidemic dynamics. We apply this approach to modelling the dynamics of a COVID-19 epidemic. We show that a SEIR model underestimates peak infection rates (by a factor of three using published parameter estimates based on the progress of the epidemic in Wuhan) and substantially overestimates epidemic persistence after the peak has passed.
COVID-19 scenario modelling for the mitigation of capacity-dependent deaths in intensive care: computer simulation study
Authors: Wood Richard M , McWilliams Christopher J , Thomas Matthew J , Bourdeaux Christopher P , Vasilakis Christos
Published: April 2020

Background

Managing healthcare demand and capacity is especially difficult in the context of the COVID-19 pandemic, where limited intensive care resources can be overwhelmed by a large number of cases requiring admission in a short space of time. If patients are unable to access this specialist resource, then death is a likely outcome. The aim of this study is to estimate the extent to which such capacity-dependent deaths can be mitigated through demand-side initiatives involving non-pharmaceutical interventions and supply-side measures to increase surge capacity or reduce length of stay.

Methods

A stochastic discrete event simulation model is developed to represent the key dynamics of the intensive care admissions process for COVID-19 patients. Model inputs are aligned to levers available to planners with key outputs including duration of time at maximum capacity (to inform workforce requirements), peak daily deaths (for mortuary planning), and total deaths (as an ultimate marker of intervention efficacy). The model - freely available - is applied to the COVID-19 response at a large hospital in England for which the effect of a number of possible interventions are simulated.

Results

Capacity-dependent deaths are closely associated with both the nature and effectiveness of non-pharmaceutical interventions and availability of intensive care beds. For the hospital considered, results suggest that capacity-dependent deaths can be reduced five-fold through a combination of isolation policies, a doubling of bed capacity, and 25% reduced length of stay.

Conclusions

Without treatment or vaccination there is little that can be done to reduce deaths occurring when patients have otherwise been treated in the most appropriate hospital setting. Healthcare planners should therefore focus on minimising the capacity-dependent deaths that are within their influence.
Therapeutic Management of COVID-19 Patients: A systematic review
Authors: Tobaiqy Mansour , Qashqary Mohammed , Al-Dahery Shrooq , Mujallad Alaa , Hershan Almonther Abdullah , Kamal Mohammad Azhar , Helmi Nawal
Published: April 2020

Background

SARS-CoV-2 is the cause of the COVID-19 that has been declared a global pandemic by the WHO in 2020. The COVID-19 treatment guidelines vary in each country, and yet there is no approved therapeutic for COVID-19.

Aims of the study

this review aimed to report any evidence of therapeutics used for the management of COVID-19 patients in clinical practice since the emergence of the virus.

Methods

A systematic review protocol was developed based on PRISMA Statement. Articles for review were selected from electronic databases (Embase, Medline and Google Scholar). Readily accessible peer-reviewed full articles in English published from December 1 st, 2019 to March 26 th, 2020 were included. The search terms included combinations of: COVID, SARS-COV-2, glucocorticoids, convalescent plasma, antiviral, antibacterial. There were no restrictions on the type of study design eligible for inclusion.

Results

As of March 26, 2020, of the initial manuscripts identified (n=449) articles. Forty-one studies were included, of which clinical trials (n=3), (case reports n=7), case series (n=10), retrospective (n=11) and prospective (n=10) observational studies. Thirty-six studies were conducted in China (88%).

The most common mentioned and reported medicine in this systematic review was corticosteroids (n=25), followed by Lopinavir (n=21) and oseltamivir (n=16).

Conclusions

This is the first systematic review up to date related to the therapeutics used in COVID-19 patients. Only forty-one research articles on COVID-19 and therapeutics were found eligible to be included, most conducted in China, corticosteroid therapy was found to be the most used medicine in these studies.
Rapid and accurate identification of COVID-19 infection through machine learning based on clinical available blood test results
Authors: Wu Jiangpeng , Zhang Pengyi , Zhang Liting , Meng Wenbo , Li Junfeng , Tong Chongxiang , Li Yonghong , Cai Jing , Yang Zengwei , Zhu Jinhong , Zhao Meie , Huang Huirong , Xie Xiaodong , Li Shuyan
Published: April 2020

Since the sudden outbreak of coronavirus disease 2019 (COVID-19), it has rapidly evolved into a momentous global health concern. Due to the lack of constructive information on the pathogenesis of COVID-19 and specific treatment, it highlights the importance of early diagnosis and timely treatment. In this study, 11 key blood indices were extracted through random forest algorithm to build the final assistant discrimination tool from 49 clinical available blood test data which were derived by commercial blood test equipments. The method presented robust outcome to accurately identify COVID-19 from a variety of suspected patients with similar CT information or similar symptoms, with accuracy of 0.9795 and 0.9697 for the cross-validation set and test set, respectively. The tool also demonstrated its outstanding performance on an external validation set that was completely independent of the modeling process, with sensitivity, specificity, and overall accuracy of 0.9512, 0.9697, and 0.9595, respectively. Besides, 24 samples from overseas infected patients with COVID-19 were used to make an in-depth clinical assessment with accuracy of 0.9167. After multiple verification, the reliability and repeatability of the tool has been fully evaluated, and it has the potential to develop into an emerging technology to identify COVID-19 and lower the burden of global public health. The proposed tool is well-suited to carry out preliminary assessment of suspected patients and help them to get timely treatment and quarantine suggestion. The assistant tool is now available online at http://lishuyan.lzu.edu.cn/COVID2019_2/.

Funding

This work was supported by the Fundamental Research Funds for the Central Universities (lzujbky-2020-sp11) and the Gansu Provincial COVID-19 Science and Technology Major Project, China.
Building an International Consortium for Tracking Coronavirus Health Status
Authors: Segal Eran , Zhang Feng , Lin Xihong , King Gary , Shalem Ophir , Shilo Smadar , Allen William E. , Grad Yonatan H. , Greene Casey S. , Alquaddoomi Faisal , Anders Simon , Balicer Ran , Bauman Tal , Bonilla Ximena , Booman Gisel , Chan Andrew T. , Cohen Ori , Coletti Silvano , Davidson Natalie , Dor Yuval , Drew David A. , Elemento Olivier , Evans Georgina , Ewels Phil , Gale Joshua , Gavrieli Amir , Geiger Benjamin , Hajirasouliha Iman , Jerala Roman , Kahles Andre , Kallioniemi Olli , Keshet Ayya , Landua Gregory , Meir Tomer , Muller Aline , Nguyen Long H. , Oresic Matej , Ovchinnikova Svetlana , Peterson Hedi , Rajagopal Jay , Rätsch Gunnar , Rossman Hagai , Rung Johan , Sboner Andrea , Sigaras Alexandros , Spector Tim , Steinherz Ron , Stevens Irene , Vilo Jaak , Wilmes Paul ,   CCC (Coronavirus Census Collective)
Published: April 2020

Information is the most potent protective weapon we have to combat a pandemic, at both the individual and global level. For individuals, information can help us make personal decisions and provide a sense of security. For the global community, information can inform policy decisions and offer critical insights into the epidemic of COVID-19 disease. Fully leveraging the power of information, however, requires large amounts of data and access to it. To achieve this, we are making steps to form an international consortium, Coronavirus Census Collective (CCC, coronaviruscensuscollective.org), that will serve as a hub for integrating information from multiple data sources that can be utilized to understand, monitor, predict, and combat global pandemics. These sources may include self-reported health status through surveys (including mobile apps), results of diagnostic laboratory tests, and other static and real-time geospatial data. This collective effort to track and share information will be invaluable in predicting hotspots of disease outbreak, identifying which factors control the rate of spreading, informing immediate policy decisions, evaluating the effectiveness of measures taken by health organizations on pandemic control, and providing critical insight on the etiology of COVID-19. It will also help individuals stay informed on this rapidly evolving situation and contribute to other global efforts to slow the spread of disease.

In the past few weeks, several initiatives across the globe have surfaced to use daily self-reported symptoms as a means to track disease spread, predict outbreak locations, guide population measures and help in the allocation of healthcare resources. The aim of this paper is to put out a call to standardize these efforts and spark a collaborative effort to maximize the global gain while protecting participant privacy.
Rapid implementation of mobile technology for real-time epidemiology of COVID-19
Authors: Drew David A. , Nguyen Long H. , Steves Claire J. , Wolf Jonathan , Spector Tim D. , Chan Andrew T.
Published: April 2020

The rapid pace of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic (COVID-19) presents challenges to the robust collection of population-scale data to address this global health crisis. We established the COronavirus Pandemic Epidemiology (COPE) consortium to bring together scientists with expertise in big data research and epidemiology to develop a COVID-19 Symptom Tracker mobile application that we launched in the UK on March 24, 2020 and the US on March 29, 2020 garnering more than 2.25 million users to date. This mobile application offers data on risk factors, herald symptoms, clinical outcomes, and geographical hot spots. This initiative offers critical proof-of-concept for the repurposing of existing approaches to enable rapidly scalable epidemiologic data collection and analysis which is critical for a data-driven response to this public health challenge.

One Sentence Summary

COVID-19 symptom tracker for smartphones
Rapid evidence summary on SARS-CoV-2 survivorship and disinfection, and a reusable PPE protocol using a double-hit process
Authors: Derraik José G B , Anderson William A , Connelly Elisabeth A , Anderson Yvonne C
Published: April 2020

In the COVID-19 pandemic caused by SARS-CoV-2, hospitals are stretched beyond capacity. There are widespread reports of dwindling supplies of personal protective equipment (PPE), which are paramount to protect frontline medical/nursing staff and to minimize further spread of the virus. We carried out a rapid review to summarize the existing evidence on SARS-CoV-2 survivorship and methods to disinfect PPE gear, particularly N95 filtering facepiece respirators (FFR). In the absence of data on SARS-CoV-2, we focused on the sister virus SARS-CoV-1. We propose a two-step disinfection process, which is conservative in the absence of robust evidence on SARS-CoV-2. This disinfection protocol is based on an initial storage of PPE for ≥4 days, followed by ultraviolet light (UVC), dry heat treatment, or chemical disinfection. Importantly, each of the two steps is based on independent disinfection mechanisms, so that our proposed protocol is a multiplicative system, maximising the efficacy of our disinfection process. This method could be rapidly implemented in other healthcare settings, while testing of each method is undertaken, increasing the frontline supply of PPE, and avoiding many of the upstream issues of supply chain disruption currently being faced.
Chaos theory applied to the outbreak of Covid-19: an ancillary approach to decision-making in pandemic context
Authors: Mangiarotti S. , Peyre M. , Zhang Y. , Huc M. , Roger F. , Kerr Y.
Published: April 2020

Predicting the course of an epidemic is difficult, predicting the course of a pandemic from an emerging virus even more so. The validity of most predictive models relies on numerous parameters, involving biological and social characteristics often unknown or highly uncertain. Data of the COVID-19 epidemics in China, Japan, South Korea and Italy were used to build up deterministic models without strong hypothesis. These models were then applied to other countries to identify the closest scenarios in order to foresee their coming behaviour. The models enabled to predict situations that were confirmed little by little, proving that these tools can be efficient and useful for decision-making in a quickly evolving operational context.
COVID-19 Excess Deaths in the United States, New York City, and Michigan During April 2020
Authors: Wetzler Harry , Wetzler Erica
Published: April 2020

Background

It has been suggested that many of those who died from COVID-19 were older, had more comorbidities, and would have died within a short period anyway. We estimated the number and percent of excess deaths due to COVID-19 In April 2020 in the United States, New York City, and Michigan.

Methods

For each locale we calculated attributable fractions in the exposed comparing observed COVID-19 deaths and expected deaths. In addition, we estimated the number of months it would take for the excess deaths to occur without the virus and the proportions of the populations that were infected leading to the April deaths. We compared the excess deaths from the attributable fraction method to those obtained by comparing weekly deaths in 2019 and 2020.

Results

Using an assumed infection fatality rate of 1%, the percentages of excess deaths were 95%, 97%, and 95% in the US, NYC, and MI equivalent to 54,560; 14,951; and 3,338 deaths, respectively. Absent the virus these deaths would have occurred over 21.0, 29.2, and 18.4 months in the respective locations. An estimated 1.7% of the US population was infected between March 13 and April 10, 2020. Nearly 19% were infected in NYC.

Conclusions

Over 75% of COVID-19 deaths in April 2020 were excess deaths meaning they would not have occurred in April without SARS-CoV-2 but would have been spread out over the ensuing 18 to 29 months. Confirmed cases in the US under-report the actual number of infections by at least an order of magnitude. Excess death numbers calculated using the attributable fraction in the exposed are similar to those obtained from weekly mortality reports.
Molecular development of muscle spindle and Golgi tendon organ sensory afferents revealed by single proprioceptor transcriptome analysis
Authors: Oliver Katherine M. , Florez-Paz Danny M. , Badea Tudor C. , Mentis George Z. , Menon Vilas , de Nooij Joriene C.
Published: April 2020

Anatomical and physiological analyses have long revealed differences between proprioceptive groups Ia, II, and Ib sensory neurons, yet the molecular correlates of these three muscle afferent subtypes remain unknown. We performed single cell RNA sequencing of genetically identified adult proprioceptors and, using unbiased bioinformatics approaches, detected five molecularly distinct neuronal clusters. Validation of cluster-specific transcripts in dorsal root ganglia (DRG) and skeletal muscle provides evidence these clusters correspond to functionally distinct muscle spindle (MS) or Golgi tendon organ (GTO) afferent proprioceptors. Remarkably, while we uncovered just one type of GTO afferents, four of the five clusters represent MS afferents, thus demonstrating a previously unappreciated diversity among these muscle proprioceptors.In vitroelectrophysiological recordings reveal just two broadly distinct proprioceptor types, and suggest that the refinement of functional subtype diversity may occur along multiple axes of maturation. Lineage analysis between proprioceptor transcriptomes at different developmental stages show little or no correlation for transcripts that define adult MS or GTO afferents, supporting the idea that proprioceptor subtype identity emerges late in development. Together, our data provide the first comprehensive molecular signature for groups Ia and II MS afferents and group Ib GTO afferents, and offer new strategies for genetic interrogation of the role of these individual proprioceptor subtypes in regulating voluntary motor behavior.
Neuronal kinase SGK1.1 protects against brain damage after status epilepticus
Authors: Martin-Batista Elva , Maglio Laura E. , Armas-Capote Natalia , Hernandez Guadalberto , de la Rosa Diego Alvarez , Giraldez Teresa
Published: April 2020

Epilepsy is a neurological condition associated to significant brain damage produced bystatus epilepticus(SE) including neurodegeneration, gliosis and ectopic neurogenesis. Reduction of these processes constitutes a useful strategy to improve recovery and ameliorate negative outcomes after an initial insult. SGK1.1, the neuronal isoform of the serum and glucocorticoids-regulated kinase 1 (SGK1), has been shown to increase M-current density in neurons, leading to reduced excitability and protection against seizures. We now show that SGK1.1 activation potently reduces levels of neuronal death and gliosis after SE induced by kainate, even in the context of high seizure activity. This neuroprotective effect is not exclusively a secondary effect of M-current activation but is also directly linked to decreased apoptosis levels through regulation of Bim and Bcl-xLcellular levels. Our results demonstrate that this newly described antiapoptotic role of SGK1.1 activation acts synergistically with the regulation of cellular excitability, resulting in a significant reduction of SE-induced brain damage. The protective role of SGK1.1 occurs without altering basal neurogenesis in brain areas relevant to epileptogenesis.

SIGNIFICANCE STATEMENT

Approaches to control neuronal death and inflammation are of increasing interest in managing epilepsy, one of the most important idiopathic brain diseases. We have previously shown that activation of SGK1.1 reduces neuronal excitability by increasing M-current levels, significantly reducing seizure severity. We now describe a potent neuroprotective role of SGK1.1, which dramatically reduces neuronal death and gliosis after status epilepticus. This effect is partially dependent on M-current activation and includes an additional anti-apoptotic role of SGK1.1. Our data strongly support the relevance of this kinase as a potential target for epilepsy treatment.
Characterization Of Yellow Root Cassava And Food Products: Investigation Of Cyanogenic Glycosides And Pro-Vitamin A
Authors: Odoemelam Chiemela S. , Percival Benita , Ahmad Zeeshan , Chang Ming-Wei , Scholey Dawn , Burton Emily , Okafor Polycarp N. , Wilson Philippe B.
Published: April 2020

Objective

Cyanide is a highly toxic compound, and the consumption of products containing cyanide is of singificant public health concern. In contrast,β-carotene possesses essential nutritional attributes related to human health, therefore the characterisation and quanfication of both compounds in food products is both fundamental and necessary. This investigation sought to identify the cyanide and β-carotene levels in two flours produced from the roots of two varieties of cassava (Manihot esculenta crantz), namely UMUCASS-38 (TMS 01/1371) and NR 8082, and their associated food products.

Results

The fresh tuber, raw flour and food products were analysed for levels of residual cyanide andβ-carotene using standard analytical methods. The cyanide content of NR 8082 (18.01±0.01 ppm) and UMUCASS 38 (17.02±0.02 ppm) flours were significantly higher (p< 0.05) than the residual cyanide levels determined in the cookies (10.00±0.00 ppm) and cake (7.10±0.14 ppm). The levels of β-carotene determined in the sample varied significantly (p< 0.05). The highest levels of β-carotene (6.53±0.02 µg/g) were determined in raw roots of UMUCASS 38 while NR 8082 levels of β-carotene were 1.12±0.02 µg/g. Processing the roots into flour reduced the β-carotene content to 4.78±0.01 µg/g and 0.76±0.02 µg/g in UMUCASS 38 and NR8082 flours, respectively. Cookies and cake produced from flour derived from the UMUCASS 38 variety had 2.15±0.01 µg/g and 2.84±0.04 µg/g of β-carotene, respectively.
SARS-CoV-2 and SARS-CoV differ in their cell tropism and drug sensitivity profiles
Authors: Bojkova Denisa , McGreig Jake E. , McLaughlin Katie-May , Masterson Stuart G. , Widera Marek , Krähling Verena , Ciesek Sandra , Wass Mark N. , Michaelis Martin , Cinatl Jindrich
Published: April 2020

SARS-CoV-2 is a novel coronavirus currently causing a pandemic. We show that the majority of amino acid positions, which differ between SARS-CoV-2 and the closely related SARS-CoV, are differentially conserved suggesting differences in biological behaviour. In agreement, novel cell culture models revealed differences between the tropism of SARS-CoV-2 and SARS-CoV. Moreover, cellular ACE2 (SARS-CoV-2 receptor) and TMPRSS2 (enables virus entry via S protein cleavage) levels did not reliably indicate cell susceptibility to SARS-CoV-2. SARS-CoV-2 and SARS-CoV further differed in their drug sensitivity profiles. Thus, only drug testing using SARS-CoV-2 reliably identifies therapy candidates. Therapeutic concentrations of the approved protease inhibitor aprotinin displayed anti-SARS-CoV-2 activity. The efficacy of aprotinin and of remdesivir (currently under clinical investigation against SARS-CoV-2) were further enhanced by therapeutic concentrations of the proton pump inhibitor omeprazole (aprotinin 2.7-fold, remdesivir 10-fold). Hence, our study has also identified anti-SARS-CoV-2 therapy candidates that can be readily tested in patients.
Achieving high-quality ddRAD-like reference catalogs for non-model species: the power of overlapping paired-end reads
Authors: Driller Maximilian , Arantes Larissa Souza , Vilaça Sibelle Torres , Carrasco-Valenzuela Tomás , Heeger Felix , Mbedi Susan , Chevallier Damien , De Thoisy Benoit , Mazzoni Camila J
Published: April 2020

Reduced representation libraries (RRS) allow large scale studies on non-model species to be performed without the need for a reference genome, by building a pseudo-reference locus catalog directly from the data. However, using closely-related high-quality genomes can help maximize nucleotide variation identified from RRS libraries. While chromosome-level genomes remain unavailable for most species, researchers can still invest in building high-quality and project-specificde novolocus catalogs. Among methods that use restriction enzymes (RADSeq), those including fragment size selection to help obtain the desired number of loci - such as double-digest RAD (ddRAD) - are highly flexible but can present important technical issues. Inconsistent size selection reproducibility across libraries and variable coverage across fragment lengths can affect genotyping confidence, number of identified single nucleotide polymorphisms (SNPs), and quality and completeness of thede novoreference catalog. We have developed a strategy to optimize locus catalog building from ddRAD-like data by sequencing overlapping reads that recreate original fragments and add information about coverage per fragment size. Furtherin silicosize selection and digestion steps limit the filtered dataset to well-covered sets of loci and identity thresholds are estimated based on sequence pairwise comparisons. We have developed a full workflow that identifies a set of reduced-representation single-copy orthologs (R2SCOs) for any given species and that includes estimating and evaluating allelic variation in comparison with SNP calling results. We also show how to use our concept in an established RADSeq pipeline - Stacks - and confirm that our approach increases average coverage and number of SNPs called per locus in the final catalog. We have demonstrated our full workflow using newly generated data from five sea turtle species and provided further proof-of-principle using published hybrid sea turtle and primate datasets. Finally, we showed that a project-specific set of R2SCOs perform better than a draft genome as a reference.
Dopaminergic modulation of reward discounting in healthy rats: a systematic review and meta-analysis
Authors: Castrellon Jaime J. , Meade James , Greenwald Lucy , Hurst Katlyn , Samanez-Larkin Gregory R.
Published: April 2020

Although numerous studies have suggested that pharmacological alteration of the dopamine (DA) system modulates reward discounting, these studies have produced inconsistent findings. Here, we conducted a systematic review and pre-registered meta-analysis to evaluate DA drug-mediated effects on reward discounting of time, probability, and effort costs in studies of healthy rats. This produced a total of 1,343 articles to screen for inclusion/exclusion. From the literature, we identified 117 effects from approximately 1,549 individual rats. Using random-effects with maximum-likelihood estimation, we meta-analyzed placebo-controlled drug effects for (1) DA D1-like receptor agonists and (2) antagonists, (3) D2-like agonists and (4) antagonists, and (5) DA transporter-modulating drugs. Meta-analytic effects showed that DAT-modulating drugs decreased reward discounting. While D1-like and D2-like antagonists both increased discounting, agonist drugs for those receptors had no significant effect on discounting behavior. A number of these effects appear contingent on study design features like cost type, rat strain, and microinfusion location. These findings suggest a nuanced relationship between DA and discounting behavior and urge caution when drawing generalizations about the effects of pharmacologically manipulating dopamine on reward-based decision making.
Activation of SnRK2 by the Raf-like kinase ARK represents a common mechanism of ABA response in embryophytes
Authors: Islam Mousona , Inoue Takumi , Hiraide Mayuka , Khatun Nobiza , Jahan Akida , Kuwata Keiko , Umezawa Taishi , Yotsui Izumi , Sakata Yoichi , Takezawa Daisuke
Published: April 2020

The Raf-like protein kinase ARK previously identified in the mossPhyscomitrella patensacts as an upstream regulator of subgroup III SnRK2, the key regulator of abscisic acid (ABA) and abiotic stress responses. However, the mechanisms underlying activation of ARK by ABA and abiotic stress for the regulation of SnRK2 including the role of ABA receptor-associated group A PP2C (PP2C-A) are not understood. We identified Ser1029 as the phosphorylation site in the activation loop of ARK, which provided a possible mechanism for regulation of its activity. Analysis of transgenicarklines expressing ARK-GFP with Ser1029-to-Ala mutation indicated that this replacement causes reductions in ABA-induced gene expression, stress tolerance and SnRK2 activity. Immunoblot analysis using an anti-phosphopeptide antibody indicated that ABA treatments rapidly stimulate Ser1029 phosphorylation in wild type. The phosphorylation profile of Ser1029 in ABA-hypersensitiveppabi1lacking PP2C-A was similar to that in wild type, whereas little Ser1029 phosphorylation was observed in ABA-insensitivearkmissense lines. Furthermore, newly isolatedppabi1 arklines showed ABA-insensitive phenotypes similar to those ofarklines. These results indicate that ARK is a primary activator of SnRK2, preceding negative regulation by PP2C-A in bryophytes, which provides a prototypal mechanism for ABA and abiotic stress-responses in embryophytes.

One sentence summary

Physiological characterization of various moss mutants revealed a common mechanism for phytohormone responses under water deficit in all land plants.
Functional and Pharmacological Evaluation of a NovelSCN2AVariant Linked to Early-onset Epilepsy
Authors: Adney Scott K. , Millichap John J. , DeKeyser Jean-Marc , Abramova Tatiana , Thompson Christopher H. , George Alfred L.
Published: April 2020

Objective

We identified a novelde novo SCN2Avariant (M1879T) associated with infantile-onset epilepsy that responded dramatically to sodium channel blocker antiepileptic drugs. We analyzed the functional and pharmacological consequences of this variant to establish pathogenicity, and to correlate genotype with phenotype and clinical drug response.

Methods

The clinical and genetic features of an infant boy with epilepsy are presented. We investigated the effect of the variant using heterologously expressed recombinant human NaV1.2 channels. We performed whole-cell patch clamp recording to determine the functional consequences and response to carbamazepine.

Results

The M1879T variant caused disturbances in channel inactivation including substantially depolarized voltage-dependence of inactivation, slower time course of inactivation, and enhanced resurgent current that collectively represent a gain-of-function. Carbamazepine partially normalized the voltage-dependence of inactivation and produced use-dependent block of the variant channel at high pulsing frequencies. Carbamazepine also suppresses resurgent current conducted by M1879T channels, but this effect was explained primarily by reducing the peak transient current. Molecular modeling suggests that the M1879T variant disrupts contacts with nearby residues in the C-terminal domain of the channel.

Interpretation

Our study demonstrates the value of conducting functional analyses ofSCN2Avariants of unknown significance to establish pathogenicity and genotype-phenotype correlations. We also show concordance ofin vitropharmacology using heterologous cells with the drug response observed clinically in a case of SCN2A-associated epilepsy.
The importance of the immunodominant CD8+ T cell epitope ofPlasmodium bergheicircumsporozoite protein in parasite- and vaccine-induced protection
Authors: Gibbins Matthew P. , Müller Katja , Glover Maya , Liu Jasmine , Putrianti Elyzana D. , Bauza Karolis , Reyes-Sandoval Arturo , Matuschewski Kai , Silvie Olivier , Hafalla Julius Clemence R.
Published: April 2020

The circumsporozoite protein (CSP) builds up the surface coat of sporozoites and is the leading malaria pre-erythrocytic-stage vaccine candidate. CSP has been shown to induce robust CD8+ T cell responses that are capable of eliminating developing parasites in hepatocytes resulting in protective immunity. In this study, we characterised the importance of the immunodominant CSP-derived epitope, SYIPSAEKI, ofPlasmodium bergheiin both sporozoite- and vaccine-induced protection in murine infection models. In BALB/c mice, where SYIPSAEKI is efficiently presented in the context of the major histocompatibility complex class I (MHC-I) molecule H-2-Kd, we established that epitope-specific CD8+ T cell responses contribute to parasite killing following sporozoite immunisation. Yet, sterile protection was achieved in the absence of this epitope substantiating the concept that other antigens can be sufficient for parasite-induced protective immunity. Furthermore, we demonstrated that SYIPSAEKI-specific CD8+ T cell responses elicited by viral-vectored CSP-expressing vaccines effectively targeted parasites in hepatocytes. The resulting sterile protection strictly relied on the expression of SYIPSAEKI. In C57BL/6 mice, which are unable to present the immunodominant epitope, CSP-based vaccines did not confer complete protection, despite the induction of high levels of CSP-specific antibodies. These findings underscore the significance of CSP in protection against malaria pre-erythrocytic stages and demonstrate that a significant proportion of the protection against the parasite is mediated by CD8+ T cells specific for the immunodominant CSP-derived epitope.
Factors required for adhesion ofSalmonella entericaserovar Typhimurium to lettuce (Lactuca sativa)
Authors: Elpers Laura , Hensel Michael
Published: April 2020

Salmonella entericaserovar Typhimurium (STM) is a major cause of food-borne gastroenteritis. Recent outbreaks of infections by STM are often associated with non-animal related food, i.e. vegetables, fruits, herbs, sprouts and nuts. One main problem related to consumption of fresh produce is the minimal processing, especially for leafy salads such as corn salad, rocket salad, or lettuce. In this study, we focused on lettuce (Lactuca sativa) which is contaminated by STM at higher rates compared to corn salad, resulting in prolonged persistence. We previously described the contribution of Saf fimbriae, type 1 secretion system (T1SS)-secreted BapA, intact LPS, and flagella-mediated motility to adhesion to corn salad leaves. We systematically analyzed factors contributing to adhesion of STM to lettuce leaves. We used the previously established reductionist, synthetic approach to identify factors that contribute to the surface binding of STM to leaves of lettuce by expressing all known adhesive structure by the Tet-on system. The analyses revealed contributions of Lpf fimbriae, Sti fimbriae, autotransported adhesin MisL, T1SS-secreted BapA, intact LPS, and flagella-mediated motility to adhesion of STM to lettuce leaves. In addition, we identified BapA is a potential adhesin involved in binding to corn salad and lettuce leaf surfaces.

Importance

Gastrointestinal pathogens can be transmitted by animal products, as well as by fresh produce of non-animal origin. The numbers of outbreaks by fresh produce contaminated with gastrointestinal pathogens are increasing, and underline the relevance to human health. The mechanisms involved in the colonization of, persistence on, and transmission by fresh produce are poorly understood and have to be part of further research. Here, we investigated the contribution of adhesive factors of STM in the initial phase of plant colonization, i.e. the binding to the plant surface. Usage of a reductionist, synthetic approach including the controlled surface expression of specific adhesive structures of STM, one at a time, allowed the determination of relevant fimbrial and non-fimbrial adhesins, the O-antigen of lipopolysaccharide, the flagella, and chemotaxis to binding to lettuce leaves.
No indications for overt innate immune suppression in critically ill COVID-19 patients
Authors: Kox Matthijs , Frenzel Tim , Schouten Jeroen , van de Veerdonk Frank L. , Koenen Hans J.P.M. , Pickkers Peter
Published: April 2020

At the end of March 2020, there were in excess of 800.000 confirmed cases of coronavirus disease 2019 (COVID-19) worldwide. Several reports suggest that, in severe cases, COVID-19 may cause a hyperinflammatory “cytokine storm”. However, unlike SARS-CoV infection, high levels of anti-inflammatory mediators have also been reported in COVID-19 patients. One study reported that 16% of COVID-19 patients who died developed secondary infection, which might indicate an immune-suppressed state. We explored kinetics of mHLA-DR expression, the most widely used marker of innate immune suppression in critically ill patients, in COVID-19 patients admitted to the ICU.

Twenty-four confirmed COVID-19 patients were included, of which 75% was male and 79% had comorbidities. All patients were mechanically ventilated and exhibited large high levels of inflammatory parameters such as CRP and PCT. mHLA-DR expression levels were mostly within the normal range of 15000-45000 mAb/cell and showed no change over time. COVID-19 patients displayed notably higher mHLA-DR expression levels compared with bacterial septic shock patients. None of the COVID-19 patients developed a secondary infection.

In conclusion, despite a pronounced inflammatory response, mHLA-DR expression kinetics indicate no overt innate immune suppression in COVID-19 patients. These data signify that innate immune suppression as a negative feedback mechanism following PAMP-induced inflammation appears not to be present in COVID-19.
Polygenic score for body mass index is associated with disordered eating in a general population cohort
Authors: Abdulkadir Mohamed , Herle Moritz , De Stavola Bianca , Hübel Christopher , Ferreira Diana Santos , Loos Ruth J F , Bryant-Waugh Rachel , Bulik Cynthia M. , Micali Nadia
Published: April 2020

Background

Disordered eating (DE) is common and is associated with body mass index (BMI). We aimed to investigate if genetic variants for BMI were associated with DE.

Methods

BMI polygenic scores (PGS) were calculated for participants of the Avon Longitudinal Study of Parents and Children (ALSPAC; N= 8,654) and their association with DE tested. Data on DE behaviors (e.g. binge eating, and compensatory behaviors) were collected at ages 14, 16, 18 years, and DE cognitions (e.g. body dissatisfaction) at 14 years. Mediation analyses determined whether BMI mediated the association between the BMI-PGS and DE.

Results

The BMI-PGS was positively associated with fasting (OR= 1.42, 95% CI=1.25, 1.61), binge eating (OR=1.28, 95% CI= 1.12, 1.46), purging (OR= 1.20, 95% CI= 1.02, 1.42), body dissatisfaction (Beta= 0.99, 95% CI= 0.77, 1.22), restrained eating (Beta=0.14, 95% CI= 0.10, 1.17), emotional eating (Beta= 0.21, 95% CI= 0.052, 0.38), and negatively associated with thin ideal internalization (Beta= −0.15, 95% CI= −0.23, −0.07) and external eating (Beta= −0.19, 95% CI= −0.30, −0.09). These associations were mainly mediated by BMI.

Conclusions

Genetic variants associated with BMI are also associated with DE. This association was mediated through BMI suggesting that weight potentially sits on the pathway from genetic liability to DE.
Risk of aortic aneurysm in patients with psoriasis: a systematic review and meta-analysis
Authors: Yu Xinyu , Feng Xin , Xia Liangtao , Cao Shiyi , Wei Xiang
Published: April 2020

Objective

Psoriasis is a chronic inflammatory disease that may play a role in the pathogenesis of atherosclerotic vascular diseases. We conducted this systematic review to investigate the association between psoriasis and the risk of aortic aneurysm.

Methods

Pubmed, Embase, and Scopus were searched up to July 20, 2019. We included cohort studies if they reported estimate effects assessing the association between having psoriasis and aortic aneurysm. We used Newcastle-Ottawa Scale to evaluate methodology quality of eligible studies. Random-effect meta-analyses were used to pool individual estimates. Subgroup analyses were conducted to find heterogeneity source.

Results

After a view of 2207 citations, we included three large cohort studies enrolling 5,706,525 participants in this systematic review. Psoriasis patients have an increased risk of development of aortic aneurysm (hazard ratio [HR]: 1.30, 95%confidence intervals [CI], 1.10 to 1.55,I2= 53.1%). However, the risk of AA was not significantly increased in female psoriasis patients (HR, 1.55, 95%CI, 0.65 to 3.72), patients with hypertension (HR, 1.44, 95%CI, 0.85 to 2.42), patients with hyperlipidemia (HR, 1.69, 95%CI, 1.15 to 2.48) and patients with diabetes (HR, 1.15, 95%CI 0.46 to 2.87).

Conclusions

Current evidence from observational studies suggests that psoriasis may increase the risk of aortic aneurysm, and screening of aortic aneurysm might be considered among psoriasis patients.

Key questions

What is already known on this subject?

Patients with psoriasis have an increased prevalence of cardiovascular diseases, including ischemic heart disease, heart failure, peripheral vascular disease and stroke. The increased risk of cardiovascular events is believed to be associated with the systematic inflammatory pathophysiological mechanisms of psoriasis.

What might this study add?

This systematic review and meta-analysis summarized epidemiological evidence investigating the relationship between psoriasis and aortic aneurysm, and we found psoriasis patients have an increased risk of aortic aneurysm.

How might this impact on clinical practice?

Screening for aortic aneurysm could be conducted among psoriasis patients, and the anti-inflammatory therapy may be helpful for the treatment of aortic aneurysm.