bluuebunny/crossref_metadata_2025 huggingface dataset:
A secure and rapid query-software for COVID-19 test results that can easily be integrated into the clinical workflow to avoid communication overload
Authors: Völkel Gunnar , Fürstberger Axel , Schwab Julian D. , Kühlwein Silke D. , Gscheidmeier Thomas , Kraus Johann M. , Groß Alexander , Kohlmayer Florian , Kuhn Peter , Kuhn Klaus A. , Kohlbacher Oliver , Seufferlein Thomas , Kestler Hans A.
Published: April 2020

Overcoming the COVID-19 crisis requires new ideas and strategies. Rapid testing of a large number of subjects is essential to monitor, and delay, the spread of SARS-CoV-2 to mitigate the consequences of the pandemic. People not knowing that they are infected may not stay in quarantine and, thus, are a risk for infecting others. Unfortunately, the massive number of COVID-19 tests performed is challenging for both laboratories and the units that take the throat swab and have to communicate test results. Here, we present a secure tracking system (CTest) to report COVID-19 test results online as soon as they become available. The system can be integrated into the clinical workflow with very modest effort and avoids excessive load to telephone hotlines. With this open-source and browser-based online tracking system, we aim to minimize the time required to inform the tested person but also the test units, e.g. hospitals or the public healthcare system. Instead of personal calls, CTest updates the status of the test automatically when the test results are available. Test reports are published on a secured web-page enabling regular status checks also by patients not using smartphones with dedicated mobile apps which has some importance as smartphone usage diminishes with age.

The source code, as well as further information to integrate CTest into the IT environment of other clinics or test-centres, are freely available from https://github.com/sysbio-bioinf/CTest under the Eclipse Public License v2.0 (EPL2).
UV light dosage distribution over irregular respirator surfaces. Methods and implications for safety
Authors: Baluja Aurora , Arines Justo , Vilanova Ramón , Cortiñas Julio , Bao Carmen , Flores Maite
Published: April 2020

Background and Objectives

The SARS-CoV-2 pandemic has led to a global decrease in personal protective equipment (PPE), especially filtering facepiece respirators (FFRs). Ultraviolet-C wavelength is a promising way of decontamination, however adequate dosimetry is needed to ensure balance between over and underexposed areas and provide reliable results. Our study demonstrates that UVGI light irradiance varies significantly on different respirator angles and propose a method to decontaminate several masks at once ensuring appropriate dosage in shaded zones.

Methods

An UVGI irradiator was built with internal dimensions of 69.5 × 55 × 33 cm with three 15W UV lamps. Inside, a grating of 58 × 41 × 15 cm was placed to hold the masks. Two different flat fold respirator models were used to assess irradiance, four of model Aura 9322 3M of dimensions 17 × 9 × 4cm (tri-fold), and two of model SAFE 231FFP3NR (bi-fold) with dimensions 17 × 6 × 5 cm. A spectrometer STN-SilverNova was employed to verify wavelength spectrum and surface irradiance. A simulation was performed to find the irradiance pattern inside the box and the six masks placed inside. These simulations were carried out using the software DIALUX EVO 8.2.

Results

The data obtained reveal that the irradiance received inside the manufactured UVGI-irradiator depends not only on the distance between the lamps plane and the base of the respirators but also on the orientation and shape of the masks. This point becomes relevant in order to assure that all the respirators inside the chamber receive the correct dosage.

Conclusion

Irradiance over FFR surfaces depend on several factors such as distance and angle of incidence of the light source. Careful irradiance measurement and simulation can ensure reliable dosage in the whole mask surface, balancing overexposure. Closed box systems might provide a more reliable, reproducible UVGI dosage than open settings.
Can people with asymptomatic or pre-symptomatic COVID-19 infect others: a systematic review of primary data
Authors: Aguirre-Duarte Nelson
Published: April 2020

Asymptomatic but infectious people have been reported in many infectious diseases. Asymptomatic and pre-symptomatic carriers would be a hidden reservoir of COVID-19.

Aim

This review identifies primary empirical evidence about the ability of asymptomatic carriers to infect others with COVID-19 pandemic and reflects on the implications for control measures.

Methods

A systematic review is followed by a narrative report and commentary inclusion criteria were: studies reporting primary data on asymptomatic or pre-symptomatic patients, who were considered to have passed on COVID-19 infection; and published in indexed journals or in peer review between January 1 and March 31, 2020.

Results

Nine articles reported on 83 asymptomatic or pre-symptomatic persons.

Conclusions

The evidence confirms COVID-19 transmission from people who were asymptomatic at the time. A series of implications for health service response are laid out.
High-throughput extraction of SARS-CoV-2 RNA from nasopharyngeal swabs using solid-phase reverse immobilization beads
Authors: Kalikiri Mahesh K. R. , Hasan Mohammad Rubayet , Mirza Faheem , Xaba Thabisile , Tang Patrick , Lorenz Stephan
Published: April 2020

The ongoing pandemic of the novel coronavirus, SARS-CoV-2, has led to a global surge in laboratory testing for the virus. The gold standard approach to detecting an active viral infection is the use of RT-qPCR. This approach requires the isolation of viral RNA from respiratory specimens, such as nasopharyngeal swabs.

We developed a method using a widely available lysis buffer coupled with solid-phase reverse immobilization (SPRI) beads to extract viral RNA from swabs collected in viral transport medium (VTM) which can be performed manually or on a Hamilton STAR liquid-handling robot. Using a WHO recommended, laboratory-developed RT-qPCR for SARS-CoV-2, we validated this method in a CAP-accredited laboratory, against the IVD-labelled bioMérieux NucliSENS easyMAG automated extraction platform.

Our method demonstrates a comparable sensitivity and specificity, making it suitable for large-scale testing and monitoring of suspected COVID-19 cases and health care workers. This is especially important as the world faces critical shortages of viral RNA extraction reagents for the existing commercial extraction systems.
A first study on the impact of current and future control measures on the spread of COVID-19 in Germany
Authors: Barbarossa Maria Vittoria , Fuhrmann Jan , Heidecke Julian , Varma Hridya Vinod , Castelletti Noemi , Meinke Jan H. , Krieg Stefan , Lippert Thomas
Published: April 2020

The novel coronavirus (SARS-CoV-2), identified in China at the end of December 2019 and causing the disease COVID-19, has meanwhile led to outbreaks all over the globe, with about 571,700 confirmed cases and about 26,500 deaths as of March 28th, 2020. We present here the preliminary results of a mathematical study directed at informing on the possible application or lifting of control measures in Germany. The developed mathematical models allow to study the spread of COVID-19 among the population in Germany and to asses the impact of non-pharmaceutical interventions.
Development of a dual-gene loop-mediated isothermal amplification (LAMP) detection assay for SARS-CoV-2: A preliminary study
Authors: Butt Azeem Mehmood , Siddique Shafiqa , An Xiaoping , Tong Yigang
Published: April 2020

Severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) has emerged as a rapidly spreading global pathogen stressing the need for development of rapid testing protocols ever than before. The aim of present study was to develop a SARS-CoV-2 detection protocol which can be performed within minimal resources and timeframe. For this purpose, we implemented the reverse transcription loop-mediated isothermal amplification (RT-LAMP) methodology for the qualitative detection of SARS-CoV-2 RNA. In order to improve the detection capability, the RT-LAMP assay was developed to simultaneously amplify two viral genes: ORF1a and N. A total of 45 SARS-CoV-2 associated coronavirus disease 2019 (COVID-19) and 25 non-COVID-19 cases were enrolled. Viral RNA was extracted from the nasopharyngeal swab samples and analyzed simultaneously using PCR and RT-LAMP protocols. Overall, our SARS-CoV-2 dual gene RT-LAMP assay was found to be 95% accurate in detecting positive cases and showed no cross-reactivity or false-positive results in non-COVID-19 samples. Further evaluation on larger and multi-centric cohorts is currently underway to establish the diagnostic accuracy and subsequent implementation into clinical practice and at point-of-care settings.
COVID-19 epidemic in Malaysia: Impact of lockdown on infection dynamics
Authors: Salim Naomie , Chan Weng Howe , Mansor Shuhaimi , Nazira Bazin Nor Erne , Amaran Safiya , Mohd Faudzi Ahmad Athif , Zainal Anazida , Huspi Sharin Hazlin , Jiun Hooi Eric Khoo , Shithil Shaekh Mohammad
Published: April 2020

COVID-19 epidemic in Malaysia started as a small wave of 22 cases in January 2020 through imported cases. It was followed by a bigger wave mainly from local transmissions resulting in 651 cases. The following wave saw unexpectedly three digit number of daily cases following a mass gathering urged the government to choose a more stringent measure. A limited lock-down approach called Movement Control Order (MCO) was immediately initiated to the whole country as a way to suppress the epidemic trajectory. The lock-down causes a major socio-economic disruption thus the ability to forecast the infection dynamic is urgently required to assist the government on timely decisions. Limited testing capacity and limited epidemiological data complicate the understanding of the future infection dynamic of the COVID-19 epidemic. Three different epidemic forecasting models was used to generate forecasts of COVID-19 cases in Malaysia using daily reported cumulative case data up until 1st April 2020 from the Malaysia Ministry of Health. The forecasts were generated using a Curve Fitting Model with Probability Density Function and Skewness Effect, the SIR Model, and a System Dynamic Model. Method one based on curve fitting with probability density function estimated that the peak will be on 19th April 2020 with an estimation of 5,637 infected persons. Method two based on SIR Model estimated that the peak will be on 20th - 31st May 2020 if Movement Contro (MCO) is in place with an estimation of 630,000 to 800,000 infected persons. Method three based on System Dynamic Model estimated that the peak will be on 17th May 2020 with an estimation of 22,421 infected persons. Forecasts from each of model suggested the epidemic may peak between middle of April to end of May 2020.
Regulation of Heart Beats by the Autonomous Nervous System in Health and Disease: Point-Process-Theory based Models and Simulation [V-I]
Authors: Emmanuel Bosco
Published: April 2020

We have advanced a point-process based framework for the regulation of heart beats by the autonomous nervous system and analyzed the model with and without feedback. The model without feedback was found amenable to several analytical results that help develop an intuition about the way the heart interacts with the nervous system. However, in reality, feedback, baroreflex and chemoreflex controls are important to model healthy and unhealthy scenarios for the heart. Based on the Hurst exponent as an index of health of the heart we show how the state of the nervous system may tune it in health and disease. Monte Carlo simulation is used to generate RR interval series of the Electrocardiogram (ECG) for different sympathetic and parasympathetic nerve excitations.
Same-Day Simultaneous Diagnosis of Bacterial and Fungal Infections in Clinical Practice by Nanopore Targeted Sequencing
Authors: Wang Ming , Fu Aisi , Hu Ben , Shen Gaigai , Liu Ran , Zhao Wanxu , Jiang Shupeng , Cai Xuan , Li Congrong , Li Juan , Wu Qing , Feng Kai , Gu Jiashuang , Chen Jia , Shu Mingyue , Zhang Binghong , Deng Zixin , Yu Lilei , Li Yan , Liu Tiangang
Published: April 2020

BACKGROUND

As approximately 19% of global deaths are attributable to infectious diseases, early diagnosis of infection is very important to reduce mortality. Traditional infection detection strategies have limited sensitivity, detection range, and turnaround times; a detection technology that can simultaneously detect bacterial and fungal infections within 24 h is urgently need in clinical settings.

METHODS

We developed nanopore targeted sequencing (NTS) for same-day simultaneous Diagnosis of fungal and bacterial infections. NTS was developed by amplification of 16s rRNA gene (for bacteria), IST1/2 gene (for fungal), and rpoB (for Mycobacterium spp.) using multiple primers, and sequenced by a real-time nanopore sequencing platform. An in-house bioinformatic analyze pipeline was used to diagnose the infectious pathogens by mapping the sequencing results with the constructed databases.

RESULTS

Comparison of 1312 specimens from 1257 patients using NTS and culture method; NTS detected pathogens in 58.71% of specimens from patients, compared to 22.09% detected using the culture method. NTS showed significantly higher sensitivity than culture methods for many pathogens. Importantly, a turnaround time of <24 h for all specimens, and a pre-report within 6 h in emergency cases was possible in clinical practice. Modification of antibiotic therapy and maintenance of original anti-infection regimens in 51.52% (17/33) and 36.36% (12/33) of patients was in accordance with NTS results, and quantitative monitoring of clinical treatment effects was evaluated in four patients by continuous NTS tests.

CONCLUSIONS

Application of NTS in clinically detected pathogens can improve targeted antibiotic treatment and therapeutic monitoring.
Factors associated with hospitalization and critical illness among 4,103 patients with Covid-19 disease in New York City
Authors: Petrilli Christopher M. , Jones Simon A. , Yang Jie , Rajagopalan Harish , O’Donnell Luke , Chernyak Yelena , Tobin Katie A. , Cerfolio Robert J. , Francois Fritz , Horwitz Leora I.
Published: April 2020

Background

Little is known about factors associated with hospitalization and critical illness in Covid-19 positive patients.

Methods

We conducted a cross-sectional analysis of all patients with laboratory-confirmed Covid-19 treated at an academic health system in New York City between March 1, 2020 and April 2, 2020, with follow up through April 7, 2020. Primary outcomes were hospitalization and critical illness (intensive care, mechanical ventilation, hospice and/or death). We conducted multivariable logistic regression to identify risk factors for adverse outcomes, and maximum information gain decision tree classifications to identify key splitters.

Results

Among 4,103 Covid-19 patients, 1,999 (48.7%) were hospitalized, of whom 981/1,999 (49.1%) have been discharged, and 292/1,999 (14.6%) have died or been discharged to hospice. Of 445 patients requiring mechanical ventilation, 162/445 (36.4%) have died. Strongest hospitalization risks were age ≥75 years (OR 66.8, 95% CI, 44.7-102.6), age 65-74 (OR 10.9, 95% CI, 8.35-14.34), BMI>40 (OR 6.2, 95% CI, 4.2-9.3), and heart failure (OR 4.3 95% CI, 1.9-11.2). Strongest critical illness risks were admission oxygen saturation <88% (OR 6.99, 95% CI 4.5-11.0), d-dimer>2500 (OR 6.9, 95% CI, 3.2-15.2), ferritin >2500 (OR 6.9, 95% CI, 3.2-15.2), and C-reactive protein (CRP) >200 (OR 5.78, 95% CI, 2.6-13.8). In the decision tree for admission, the most important features were age >65 and obesity; for critical illness, the most important was SpO2<88, followed by procalcitonin >0.5, troponin <0.1 (protective), age >64 and CRP>200.

Conclusions

Age and comorbidities are powerful predictors of hospitalization; however, admission oxygen impairment and markers of inflammation are most strongly associated with critical illness.
Burden and prevalence of prognostic factors for severe covid-19 disease in sweden
Authors: Gémes Katalin , Talbäck Mats , Modig Karin , Ahlbom Anders , Berglund Anita , Feychting Maria , Matthews Anthony A.
Published: April 2020

Objectives

Describe the burden and prevalence of prognostic factors of severe COVID-19 disease at national and county level in Sweden.

Design

Cross sectional study

Setting

Sweden

Participants

9,624,428 individuals living in Sweden on 31st December 2014 and alive on 1st January 2016

Main outcome measures

Burden and prevalence of prognostic factors for severe COVID-19 based on the guidelines from the World Health Organization and European Centre for Disease Prevention and Control, which are age 70 years and older, cardiovascular disease, cancer, chronic obstructive pulmonary disease, severe asthma, and diabetes. Prognostic factors were identified based on records for three years before 1st January 2016 from the Swedish National Inpatient and Outpatient Specialist Care Register, Prescribed Drug Register, and Cancer Register.

Results

22.1% of the study population had at least one prognostic factor for severe COVID-19 (2,131,319 individuals), and 1.6% had at least three factors (154,746 individuals). The prevalence of underlying medical conditions in the whole study population ranged from 0.8% with chronic obstructive pulmonary disease (78,516 individuals) to 7.4% with cardiovascular disease (708,090 individuals), and the county specific prevalence of at least one prognostic factor ranged from 19.2% in Stockholm (416,988 individuals) to 25.9% in Kalmar (60,005 individuals).

Conclusions

The prevalence of prognostic factors for severe COVID-19 disease will aid authorities in optimally planning healthcare resources during the ongoing pandemic. Results can also be applied to underlying assumptions of disease burden in modelling efforts to support COVID-19 planning. This information is crucial when deciding appropriate strategies to mitigate the pandemic and reduce both the direct mortality burden from the disease itself, and the indirect mortality burden from potentially overwhelmed health systems.
Increased gametocyte production and mosquito infectivity in chronic versus incident Plasmodium falciparum infections
Authors: Barry Aissata , Bradley John , Stone Will , Guelbeogo Moussa W. , Lanke Kjerstin , Ouedraogo Alphonse , Soulama Issiaka , Nébié Ouedraogo Issa , Serme Samuel S. , Grignard Lynn , Patterson Katie , Awandu Shehu S. , Ouedraogo Mireille , Tarama Casimire W. , Kargougou Désiré , Zoumanaba Zongo , Sirima Sodiomon B. , Marti Matthias , Drakeley Chris , Tiono Alfred B. , Bousema Teun
Published: April 2020

We longitudinally assessed P. falciparum parasite kinetics, gametocyte production and infectivity in incident infections that were naturally acquired following infection clearance and in chronic asymptomatic infections in Burkina Faso. 92% (44/48) of the incident cohort developed symptoms and were treated within 35 days, compared to 23% (14/60) of the chronic cohort. All but two individuals with chronic infection were gametocytaemic at enrollment, whereas only 35% (17/48) in the incident cohort developed gametocytes within 35 days. The relative abundance of ap2-g transcripts was positively associated with conversion to gametocyte production (i.e. the ratio of gametocytes at day 14 to ring stage parasites at baseline) and was higher in chronic infections. Parasite multiplication rate, assessed by daily molecular parasite quantification, was positively associated with prospective gametocyte production. Most incident infections were cleared before gametocyte density was sufficiently high to infect mosquitoes. In contrast, chronic, asymptomatic infections represented a significant source of mosquito infections. If present, gametocytes were significantly less infectious if concurrent with malaria symptoms. Our observations support the notion that malaria transmission reduction may be expediated by enhanced case management, involving both symptom-screening and infection detection.
Estimating the Growth Rate and Doubling Time for Short-Term Prediction and Monitoring Trend During the COVID-19 Pandemic with a SAS Macro
Authors: Xu Stanley , Clarke Christina , Shetterly Susan , Narwaney Komal
Published: April 2020

Coronavirus disease (COVID-19) has spread around the world causing tremendous stress to the US health care system. Knowing the trend of the COVID-19 pandemic is critical for the federal and local governments and health care system to prepare plans. Our aim was to develop an approach and create a SAS macro to estimate the growth rate and doubling time in days if growth rate is positive or half time in days if growth rate is negative. We fit a series of growth curves using a rolling approach. This approach was applied to the hospitalization data of Colorado State during March 13th and April 13th. The growth rate was 0.18 (95% CI=(0.11, 0.24)) and the doubling time was 5 days (95% CI= (4, 7)) for the period of March 13th-March 19th; the growth rate reached to the minimum −0.19 (95% CI= (−0.29, −0.10)) and the half time was 4 days (95% CI= (2, 6)) for the period of April 2nd – April 8th. This approach can be used for regional short-term prediction and monitoring the regional trend of the COVID-19 pandemic.
Characterizing key attributes of the epidemiology of COVID-19 in China: Model-based estimations
Authors: Ayoub Houssein H. , Chemaitelly Hiam , Mumtaz Ghina R , Seedat Shaheen , Awad Susanne F. , Makhoul Monia , Abu-Raddad Laith J.
Published: April 2020

Background

A novel coronavirus strain, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in China in late 2019. The resulting disease, Coronavirus Disease 2019 (COVID-2019), soon became a pandemic. This study aims to characterize key attributes of the epidemiology of this infection in China.

Methods

An age-stratified mathematical model was constructed to describe the transmission dynamics and estimate the age-specific differences in the biological susceptibility to the infection, age-assortativeness in transmission mixing, case fatality rate (CFR), and transition in rate of infectious contacts (and reproduction number R0) following introduction of mass interventions.

Results

The model estimated the infectious contact rate in early epidemic at 0.59 contacts per day (95% uncertainty interval (UI)=0.48-0.71). Relative to those 60-69 years of age, susceptibility to the infection was only 0.06 in those ≤19 years, 0.34 in 20-29 years, 0.57 in 30-39 years, 0.69 in 40-49 years, 0.79 in 50-59 years, 0.94 in 70-79 years, and 0.88 in ≥80 years. The assortativeness in transmission mixing by age was very limited at 0.004 (95% UI=0.002-0.008). Final CFR was 5.1% (95% UI=4.8-5.4%). R0 rapidly declined from 2.1 (95% UI=1.8-2.4) to 0.06 (95% UI=0.05-0.07) following onset of interventions.

Conclusion

Age appears to be a principal factor in explaining the patterns of COVID-19 transmission dynamics in China. The biological susceptibility to the infection seems limited among children, intermediate among young to mid-age adults, but high among those >50 years of age. There was no evidence for differential contact mixing by age, consistent with most transmission occurring in households rather than in schools or workplaces.
Accounting for incomplete testing in the estimation of epidemic parameters
Authors: Betensky R.A. , Feng Y.
Published: April 2020

As the COVID-19 pandemic spreads across the world, it is important to understand its features and responses to public health interventions in real-time. The field of infectious diseases epidemiology has highly advanced modeling strategies that yield relevant estimates. These include the doubling time of the epidemic and various other representations of the numbers of cases identified over time. Crude estimates of these quantities suffer from dependence on the underlying testing strategies within communities. We clarify the functional relationship between testing and the epidemic parameters, and thereby derive sensitivity analyses that explore the range of possible truths under various testing dynamics. We derive the required adjustment to the estimates of interest for New York City. We demonstrate that crude estimates that assume stable testing or complete testing can be biased.
Modeling layered non-pharmaceutical interventions against SARS-CoV-2 in the United States with Corvid
Authors: Chao Dennis L. , Oron Assaf P. , Srikrishna Devabhaktuni , Famulare Michael
Published: April 2020

Abstract

Background

The novel coronavirus SARS-CoV-2 has rapidly spread across the globe and is poised to cause millions of deaths worldwide. There are currently no proven pharmaceutical treatments, and vaccines are likely over a year away. At present, non-pharmaceutical interventions (NPIs) are the only effective option to reduce transmission of the virus, but it is not clear how to deploy these potentially expensive and disruptive measures. Modeling can be used to understand the potential effectiveness of NPIs for both suppression and mitigation efforts.

Methods and Findings

We developed Corvid, an adaptation of the agent-based influenza model called FluTE to SARS-CoV-2 transmission. To demonstrate features of the model relevant for studying the effects of NPIs, we simulated transmission of SARS-CoV-2 in a synthetic population representing a metropolitan area in the United States. Transmission in the model occurs in several settings, including at home, at work, and in schools. We simulated several combinations of NPIs that targeted transmission in these settings, such as school closures and work-from-home policies. We also simulated three strategies for testing and isolating symptomatic cases. For our demonstration parameters, we show that testing followed by home isolation of ascertained cases reduced transmission by a modest amount. We also show how further reductions may follow by isolating cases in safe facilities away from susceptible family members or by quarantining all family members to prevent transmission from likely infections that have yet to manifest.

Conclusions

Models that explicitly include settings where individuals interact such as the home, work, and school are useful for studying the effectiveness of NPIs, as these are more dependent on community structure than pharmaceutical interventions such as vaccination. Corvid can be used to help evaluate complex combinations of interventions, although there is no substitute for real-world observations. Our results on NPI effectiveness summarize the behavior of the model for an assumed set of parameters for demonstration purposes. Model results can be sensitive to the assumptions made about disease transmission and the natural history of the disease, both of which are not yet sufficiently characterized for SARS-CoV-2 for quantitative modeling. Models of SARS-CoV-2 transmission will need to be updated as the pathogen becomes better-understood.
A stochastic model for COVID-19 spread and the effects of Alert Level 4 in Aotearoa New Zealand
Authors: Plank Michael J. , Binny Rachelle N. , Hendy Shaun C. , Lustig Audrey , James Alex , Steyn Nicholas
Published: April 2020

While case numbers remain low, population-wide control methods combined with efficient tracing, testing, and case isolation, offer the opportunity for New Zealand to contain and eliminate COVID-19. We use a stochastic model to investigate containment and elimination scenarios for COVID-19 in New Zealand, as the country considers the exit from its four week period of strong Level 4 population-wide control measures. In particular we consider how the effectiveness of its case isolation operations influence the outcome of lifting these strong population-wide controls. The model is parameterised for New Zealand and is initialised using current case data, although we do not make use of information concerning the geographic dispersion of cases and the model is not stratified for age or co-morbidities.

We find that fast tracing and case isolation (i.e. operations that are sustained at rates comparable to that at the early stages of New Zealand’s response) can lead to containment or elimination, as long as strong population-wide controls remain in place. Slow case isolation can lead to containment (but not elimination) as long as strong Level 4 population-wide controls remain in place. However, we find that relaxing strong population-wide controls after four weeks will most likely lead to a further outbreak, although the speed of growth of this outbreak can be reduced by fast case isolation, by tracing, testing, or otherwise. We find that elimination is only likely if case isolation is combined with strong population-wide controls that are maintained for longer than four weeks.

Further versions of this model will include an age-structured population as well as considering the effects of geographic dispersion and contact network structure, the possibility of regional containment combined with inter-regional travel restrictions, and the potential for harm to at risk communities and essential workers.

Executive Summary

While New Zealand case numbers remain low, tracing, testing, and rapid case isolation, combined with population-wide control methods, offer an opportunity for the country to contain and eliminate COVID-19.

Simulations using our model suggest that the current population-wide controls (Alert Level 4) have already had a significant effect on new case numbers (see figure below).

We also find that fast case isolation, whether as a result of contact tracing, rapid testing, or otherwise, can lead to containment and possibly even elimination, when combined with strong population-wide controls.

Slow case isolation can also lead to containment, but only as long as strong population wide controls remain in place. It is unlikely to lead to elimination.
A loss-of-function mutation in IL-17F enhances susceptibility of mice to oropharyngeal candidiasis
Authors: Zhou Chunsheng , Monin Leticia , Gordon Rachael , Aggor Felix E.Y. , Bechara Rami , Edwards Tara N. , Kaplan Daniel H. , Gingras Sebastien , Gaffen Sarah L.
Published: April 2020

Oropharyngeal candidiasis (OPC) is an opportunistic infection of the oral mucosa caused by the commensal fungusC. albicans. IL-17 receptor signaling is essential to prevent OPC in mice and humans, but the individual roles of its ligands, IL-17A, IL-17F and IL-17AF, are less clear. A homozygous IL-17F deficiency in mice does not cause OPC susceptibility, whereas mice lacking IL-17A are moderately susceptible. In humans, a rare heterozygous mutation in IL-17F (IL-17F.S65L) was identified that causes chronic mucocutaneous candidiasis, suggesting the existence of essential antifungal pathways mediated by IL-17F and/or IL-17AF. To investigate the role of IL-17F and IL-17AF in more detail, we exploited this ‘experiment of nature’ by creating a mouse line bearing the homologous mutation in IL-17F (Ser65Leu) by CRISPR/Cas9.The resultingIl17fS65L/S65Lmice showed increased susceptibility to OPC, but only in homozygous, not heterozygous, mutant mice. The mutation was linked to impaired CXC chemokine expression and neutrophil recruitment to the infected tongue but not to alterations in antimicrobial peptide expression. These findings suggest mechanisms by which the enigmatic cytokine IL-17F contributes to host defense against fungi.
In-depth Bioinformatic Analyses of Human SARS-CoV-2, SARS-CoV, MERS-CoV, and OtherNidoviralesSuggest Important Roles of Noncanonical Nucleic Acid Structures in Their Lifecycles
Authors: Bartas Martin , Brázda Václav , Bohálová Natália , Cantara Alessio , Volná Adriana , Stachurová Tereza , Malachová Kateřina , Jagelská Eva B. , Porubiaková Otília , Červeň Jiří , Pečinka Petr
Published: April 2020

Noncanonical nucleic acid structures play important roles in the regulation of molecular processes. Considering the importance of the ongoing coronavirus crisis, we decided to evaluate genomes of all coronaviruses sequenced to date (stated more broadly, the orderNidovirales) to determine if they contain noncanonical nucleic acid structures. We discovered much evidence of putative G-quadruplex sites and even much more of inverted repeats (IRs) loci, which in fact are ubiquitous along the whole genomic sequence and indicate a possible mechanism for genomic RNA packaging. The most notable enrichment of IRs was found inside 5′UTR for IRs of size 12+ nucleotides, and the most notable enrichment of putative quadruplex sites (PQSs) was located before 3′UTR, inside 5′UTR, and before mRNA. This indicates crucial regulatory roles for both IRs and PQSs. Moreover, we found multiple G-quadruplex binding motifs in human proteins having potential for binding of SARS-CoV-2 RNA. Noncanonical nucleic acids structures inNidoviralesand in novel SARS-CoV-2 are therefore promising druggable structures that can be targeted and utilized in the future.
LADON, a natural antisense transcript ofNODAL, promotes an invasive behaviour in melanoma cells
Authors: Annie Dutriaux , Serena Diazzi , Sandrine Caburet , Chiara Bresesti , Sylvie Hardouin , Frédérique Deshayes , Jérôme Collignon , Domenico Flagiello
Published: April 2020

The TGFβ family member NODAL, known for its role during embryonic development, has also been associated with tumor progression in several cancers. Some of the evidence supporting its involvement in melanoma appeared contradictory, suggesting that NODAL in this context might rely on a non-canonical signalling mode. We found that NODAL inactivation in a metastatic melanoma cell line prevents the cells from acquiring invasive behaviour. However, we show that this phenotype does not result from the absence of NODAL, but from a defect in the expression of a natural antisense transcript of NODAL, here called LADON. We found that LADON promotes the mesenchymal to amoeboid transition that is critical to melanoma cell invasiveness, and that a WNT/β-CATENIN signalling-dependent increase in LADON expression is required to complete this transition. LADON’s downstream effectors include, among others, the proto-oncogene MYCN. These results identify LADON as a player in the regulatory network that governs tumor progression in melanoma, and possibly in other types of cancer.
Distinct evolutionary paths in chronic lymphocytic leukemia during resistance to graft-versus-leukemia
Authors: Bachireddy Pavan , Ennis Christina , Nguyen Vinhkhang N. , Clement Kendell , Gohil Satyen H. , Shukla Sachet A. , Forman Juliet , Barkas Nikolas , Freeman Samuel , Bavli Natalie , Elagina Liudmila , Leshchiner Ignaty , Mohammad Arman W. , Rassenti Laura Z , Kipps Thomas J , Brown Jennifer R. , Getz Gad A. , Ho Vincent T. , Gnirke Andreas , Neuberg Donna , Soiffer Robert J. , Ritz Jerome , Alyea Edwin P. , Kharchenko Peter V. , Wu Catherine J.
Published: April 2020

Resistance to the graft-versus-leukemia (GvL) effect remains the major barrier to successful allogeneic hematopoietic stem cell transplantation (allo-HSCT) for aggressive hematologic malignancies. The basis of GvL resistance for advanced lymphoid malignancies remains incompletely understood. We hypothesized that for patients with chronic lymphocytic leukemia (CLL) treated with allo-HSCT, leukemic cell-intrinsic features shape GvL outcomes by directing the evolutionary trajectories of CLL cells. Integrated genetic, transcriptomic and epigenetic analyses of CLL cells from 10 patients revealed that the clinical kinetics of post- HSCT relapse are shaped by distinct molecular dynamics and suggest that the selection pressures of the GvL bottleneck are unlike those imposed by chemotherapy. No selective advantage for HLA loss was observed, even when present in pre-transplant subpopulations. Regardless of post-transplant relapse kinetics, gain of stem cell modules was a common signature associated with leukemia relapse. These data elucidate the biological pathways that underlie GvL resistance and post-transplant relapse.

One Sentence Summary

We find that the clinical kinetics of chronic lymphocytic leukemia relapse after stem cell transplant are underwritten by distinct genetic and epigenetic evolutionary trajectories and suggest that the selection pressures of the post-transplant, immunologic bottleneck are unlike those imposed by chemotherapy.
The Development of Cognitive Control in Children with Autism Spectrum Disorders or Obsessive-Compulsive Disorder: A Longitudinal fMRI study
Authors: Gooskens Bram , Bos Dienke J. , Naaijen Jilly , Akkermans Sophie E.A. , Kaiser Anna , Hohmann Sarah , Bruchhage Muriel M.K. , Banaschewski Tobias , Brandeis Daniel , Williams Steven C.R. , Lythgoe David J. , Buitelaar Jan K. , Oranje Bob , Durston Sarah ,   the TACTICS consortium
Published: April 2020

Repetitive behavior is a core symptom of Autism Spectrum Disorder (ASD) and Obsessive-Compulsive Disorder (OCD), and has been associated with impairments in cognitive control. However, it is unclear how cognitive control and associated neural circuitry relate to the development of repetitive behavior in children with these disorders. In a multicenter, longitudinal study (TACTICS; Translational Adolescent and Childhood Therapeutic Interventions in Compulsive Syndromes), the development of cognitive control was assessed during late childhood using a longitudinal fMRI design with a modified stop-signal task in children with ASD or OCD, and typically developing (TD) children (baseline: N=122 (8-12y), follow-up: N=72 (10-14y), average interval: 1.2y). Stop-signal reaction time (SSRT) decreased over development, regardless of diagnosis. Repetitive behavior in children with ASD and OCD was not associated with performance on the stop-signal task. There were no whole-brain between-group differences in brain activity, but ROI-analyses showed increases in activity in right precentral gyrus over development for children with OCD. In sum, even though subtle differences were observed in the development of brain activity in children with OCD, the findings overall suggest that the development of cognitive control, as assessed by the stop signal task, is similar in children with and without ASD or OCD.
DivIVA is essential inDeinococcus radioduransand its C terminal domain regulates new septum orientation during cell division
Authors: Chaudhary Reema , Kota Swathi , Misra Hari S
Published: April 2020

FtsZ assembly at mid cell position in rod shaped bacteria is regulated by gradient of MinCDE complex across the poles. In round shaped bacteria, which lack predefined poles and the next plane of cell division is perpendicular to previous plane, the determination of site for FtsZ assembly is intriguing.Deinococcus radioduransa coccus shaped bacterium, is characterized for its extraordinary resistance to DNA damage. Here we report that DivIVA a putative component of Min system in this bacterium (drDivIVA) interacts with cognate cell division and genome segregation proteins. The deletion of full length drDivIVA was found to be indispensable while its C-terminal deletion (ΔdivIVAC) was dispensable but produced distinguishable phenotypes like slow growth, altered plane for new septum formation and angular septum. Both wild type and mutant showed FtsZ foci formation and their gamma radiation responses were nearly identical. But unlike in wild type, the FtsZ localization in mutant cells was found to be away from orthogonal axis with respect to plane of previous septum. Notably, DivIVA-RFP localizes to membrane during cell division and then perpendicular to previous plane of cell division.In transexpression of drDivIVA in ΔdivIVACbackground could restore the wild type pattern of septum formation perpendicular to previous septum. These results suggested that DivIVA is an essential protein inD. radioduransand the C-terminal domain that contributes to its interaction with MinC determines the plane of new septum formation, possibly by controlling MinC oscillation through orthogonal axis in the cells.
A 63-bp insertion in exon 2 of the porcineKIF21Agene is associated with arthrogryposis multiplex congenita
Authors: Fang Zih-Hua , Nosková Adéla , Crysnanto Danang , Neuenschwander Stefan , Vögeli Peter , Pausch Hubert
Published: April 2020

Arthrogryposis multiplex congenita (AMC) is a recessively inherited fatal disease detected almost 20 years ago in the Swiss Large White pig population. A diagnostic marker test enabled the identification of carrier animals, but the underlying causal mutation remains unknown. To identify the mutation underlying AMC, we collected whole-genome genotyping and sequencing data for 11 affected piglets and 23 healthy pigs. Haplotype-based case-control association testing using 47,829 SNPs confirmed that AMC maps to SSC5 (P= 9.4 ×10−13). Subsequent autozygosity mapping revealed a common 6.06 Mb region (from 66,757,970 to 72,815,151 bp) of extended homozygosity in 11 piglets affected by AMC. We detected a 63-bp insertion in the second exon ofKIF21Agene encoding Kinesin Family Member 21A using whole-genome sequences of a carrier boar, two of its affected and two heterozygous piglets. This insertion was compatible with the recessive inheritance of AMC. The 63-bp insertion likely represents a loss-of-function allele because it is predicted to introduce a premature stop codon inKIF21Agene (p.Val41_Phe42insTer) that truncates 1,614 amino acids (∼ 97%) from the protein. Lack of KIF21A protein is lethal in mice, thus providing additional evidence that a loss-of function allele ofKIF21Amight cause fatal AMC in pigs. We found that this deleterious allele still segregates at low frequency in the Swiss Large White pig population. The unambiguous detection of carrier animals can now facilitate the eradication of the deleterious allele from the population.
Zebrafish IL-4-like cytokines and IL-10 suppress inflammation but only IL-10 is essential for gill homeostasis
Authors: Bottiglione Federica , Dee Christopher T. , Lea Robert , Zeef Leo , Badrock Andrew P. , Wane Madina , Bugeon Laurence , Dallman Margaret J. , Allen Judith , Hurlstone Adam F. L.
Published: April 2020

Healthy fish stocks are central to global food security. Key to fish health is robust immunity at mucosal surfaces, and especially at the gills. However, a balance must be struck between tolerating commensal microorganisms and reacting appropriately toward pathogens. In mammals, IL-4 and IL-13 in concert with IL-10 are essential for balancing immune response to pathogens and suppressing inflammation. Whether their fish counterparts perform similar roles is an open question. Here, we have generated IL-4/13A and IL-4/13B mutant zebrafish and, together with existing IL-10 mutants, characterized the consequences of loss-of-function of these cytokines. We demonstrate that these cytokines are required to suppress inflammation. Further, IL-4/13A and IL-4/13B are required for the maintenance of a Th2-like phenotype in the gills. As in mammals, IL-10 appears to have a more striking anti-inflammatory function than IL-4-like cytokines. Thus, both IL-10 and IL-4/13 paralogues in zebrafish exhibit aspects of conserved function with their mammalian counterparts.
Kill and cure: genomic phylogeny and bioactivity of a diverse collection ofBurkholderia gladiolibacteria capable of pathogenic and beneficial lifestyles
Authors: Jones Cerith , Webster Gordon , Mullins Alex J. , Jenner Matthew , Bull Matthew J. , Dashti Yousef , Spilker Theodore , Parkhill Julian , Connor Thomas R. , LiPuma John J. , Challis Gregory L. , Mahenthiralingam Eshwar
Published: April 2020

Burkholderia gladioliis one of few bacteria with a broad ecology spanning disease in humans, animals, and plants, and encompassing beneficial interactions with multiple eukaryotic hosts. It is a plant pathogen, a bongkrekic acid toxin producing food-poisoning agent, and a lung pathogen in people with cystic fibrosis (CF). Contrasting beneficial traits include antifungal production exploited by insects to protect their eggs, plant protective abilities and antibiotic biosynthesis. We explored the ecological diversity and specialized metabolite biosynthesis of 206B. gladiolistrains, phylogenomically defining 5 evolutionary clades. Historical disease pathovars (pv)B. gladiolipv.allicolaandB. gladiolipv.cocovenenanswere phylogenetically distinct, whileB. gladiolipv.gladioliandB. gladiolipv.agaricicolawere indistinguishable. Soft-rot disease and CF infection pathogenicity traits were conserved across all pathovars. Biosynthetic gene clusters for toxoflavin, caryoynencin and enacyloxin were dispersed acrossB. gladioli, but bongkrekic acid and gladiolin production were clade specific. Strikingly, 13% of CF-infection strains characterised (n=194) were bongkrekic acid toxin positive, uniquely linking this food-poisoning risk factor to chronic lung disease. Toxin production was suppressed by exposing strains to the antibiotic trimethoprim, providing a potential therapeutic strategy to minimise poisoning risk in CF.
Dynamics of viral index infections in novel hosts
Authors: Mollentze Nardus , Streicker Daniel G. , Murcia Pablo R. , Hampson Katie , Biek Roman
Published: April 2020

Whether a pathogen entering a new host species results in a single infection or in onward transmission, and potentially an outbreak, depends upon the progression of infection in the index case. Although index infections are rarely observable in nature, experimental inoculations of pathogens into novel host species have a long history in biomedical research. This provides a rich and largely unexploited data source for meta-analyses to identify the host and pathogen determinants of variability in infection outcomes. Here, we analysed the progressions of 514 experimental cross-species inoculations of rabies virus, a widespread zoonotic pathogen which in nature exhibits both dead end infections and varying levels of sustained transmission in novel hosts. Inoculations originating from bats rather than carnivores, and from warmer to cooler-bodied species caused infections with shorter incubation periods that were associated with diminished virus excretion. Inoculations between distantly related hosts tended to result in shorter clinical disease periods, which will also impede transmission. All effects were modulated by infection dose and together suggest that increased virulence as host species become more dissimilar is the limiting factor preventing onward transmission. These results explain observed constraints on rabies virus host shifts, allow us to evaluate the risk of novel reservoirs establishing, and give mechanistic insights into why host shifts are less likely between genetically distant species. More generally, our study highlights meta-analyses of experimental infections as a tractable approach to quantify the complex interactions between virus, reservoir, and novel host that shape the outcome of cross-species transmission.

Significance statement

Emerging disease epidemics often result from a pathogen establishing transmission in a novel host species. However, most cross-species transmissions fail to establish in the newly infected species for reasons that remain poorly understood. Examining cross-species inoculations involving rabies, a widespread viral zoonosis, we show that mismatches in virulence, which are predictable from host and viral factors, make sustained transmission in the novel host less likely. In particular, disease progression was accelerated and virus excretion decreased when the reservoir and novel host were physiologically or genetically more dissimilar. These mechanistic insights help to explain and predict host shift events and highlight meta-analyses of existing experimental inoculation data as a powerful and generalisable approach for understanding the dynamics of index infections in novel species.