bluuebunny/crossref_metadata_2025 huggingface dataset:
Recent update on COVID-19 in India: Is locking down the country enough?
Authors: Virk Jitender Singh , Ali Syed Azmal , Kaur Gurjeet
Published: April 2020

Background

India is the second-largest population in the world, and it is not well equipped, hitherto, in the scenario of the global pandemic, SARS-CoV-2 could impart a devastating impact on the Indian population. Only way to respond against this critical condition is by practicing large-scale social distancing. India lock down for 21 days, however, till 7 April 2020, SARS- CoV-2 positive cases were growing exponentially, which raises the concerns if the number of reported and actual cases are similar.

Methods

We use Lasso Regression with α = 0.12 and Polynomial features of degree 2 to predict the growth factor. Also, we predicted Logistic curve using the Prophet Python. Further, using the growth rate to logistic, and carrying capacity is 20000 allowed us to calculate the maximum cases and new cases per day.

Results

We found the predicted growth factor with a standard deviation of 0.3443 for the upcoming days. When the growth factor becomes 1.0, which is known as Inflection point, it will be safe to state that the rate is no longer exponential. The estimated time to reach the inflection point is between 15-20 April. At that time, the estimated number of total positive cases will be over 12500, if lockdown remains continue.

Conclusions

Our analysis suggests that there is an urgent need to take action to extend the period of lockdown and allocate enough resources, including personnel, beds, and intensive care facilities, to manage the situation in the next few days and weeks. Otherwise, the outbreak in India can reach the level of the USA or Italy or could be worse than these countries within a few days or weeks, given the size of the population and lack of resources.
Immunoglobulin fragment F(ab’)2against RBD potently neutralizes SARS-CoV-2 in vitro
Authors: Pan Xiaoyan , Zhou Pengfei , Fan Tiejiong , Wu Yan , Zhang Jing , Shi Xiaoyue , Shang Weijuan , Fang Lijuan , Jiang Xiaming , Shi Jian , Sun Yuan , Zhao Shaojuan , Gong Rui , Chen Ze , Xiao Gengfu
Published: April 2020

COVID-19 caused by the emerging human coronavirus, SARS-CoV-2, has become a global pandemic, leading a serious threat to human health. So far, there is none vaccines or specific antiviral drugs approved for that. Therapeutic antibodies for SARS-CoV-2, was obtained from hyper immune equine plasma in this study. Herein, SARS-CoV-2 RBD with gram level were obtained through Chinese hamster ovary cells high-density fermentation. The binding of RBD to SARS-CoV-2 receptor, human ACE2, was verified and the efficacy of RBD in vivo was tested on mice and then on horses. As a result, RBD triggered high-titer neutralizing antibodies in vivo, and immunoglobulin fragment F(ab’)2was prepared from horse antisera through removing Fc. Neutralization test demonstrated that RBD-specific F(ab’)2inhibited SARS-CoV-2 with EC50at 0.07 μg/ml, showing a potent inhibitory effect on SARS-CoV-2. These results highlights as RBD-specific F(ab’)2as therapeutic candidate for SARS-CoV-2.
The spatial and cell-type distribution of SARS-CoV-2 receptor ACE2 in human and mouse brain
Authors: Chen Rongrong , Wang Keer , Yu Jie , Howard Derek , French Leon , Chen Zhong , Wen Chengping , Xu Zhenghao
Published: April 2020

By engaging angiotensin-converting enzyme 2 (ACE2 or Ace2), the novel pathogenic SARS-coronavirus 2 (SARS-CoV-2) may invade host cells in many organs, including the brain. However, the distribution of ACE2 in the brain is still obscure. Here we investigated the ACE2 expression in the brain by analyzing data from publicly available brain transcriptome databases. According to our spatial distribution analysis, ACE2 was relatively highly expressed in some brain locations, such as the choroid plexus and paraventricular nuclei of the thalamus. According to cell-type distribution analysis, nuclear expression of ACE2 was found in many neurons (both excitatory and inhibitory neurons) and some non-neuron cells (mainly astrocytes, oligodendrocytes, and endothelial cells) in human middle temporal gyrus and posterior cingulate cortex. A few ACE2-expressing nuclei were found in a hippocampal dataset, and none were detected in the prefrontal cortex. Except for the additional high expression of Ace2 in the olfactory bulb areas for spatial distribution as well as in the pericytes and endothelial cells for cell-type distribution, the distribution of Ace2 in mouse brain was similar to that in the human brain. Thus, our results reveal an outline of ACE2/Ace2 distribution in the human and mouse brain, which indicates the brain infection of SARS-CoV-2 may be capable of inducing central nervous system symptoms in coronavirus disease 2019 (COVID-19) patients. Potential species differences should be considered when using mouse models to study the neurological effects of SARS-CoV-2 infection.
Gene expression andin situprotein profiling of candidate SARS-CoV-2 receptors in human airway epithelial cells and lung tissue
Authors: Aguiar Jennifer A. , Tremblay Benjamin J-M. , Mansfield Michael J. , Woody Owen , Lobb Briallen , Banerjee Arinjay , Chandiramohan Abiram , Tiessen Nicholas , Dvorkin-Gheva Anna , Revill Spencer , Miller Matthew S. , Carlsten Christopher , Organ Louise , Joseph Chitra , John Alison , Hanson Paul , McManus Bruce M. , Jenkins Gisli , Mossman Karen , Ask Kjetil , Doxey Andrew C. , Hirota Jeremy A.
Published: April 2020

In December 2019, SARS-CoV-2 emerged causing the COVID-19 pandemic. SARS-CoV, the agent responsible for the 2003 SARS outbreak, utilizes ACE2 and TMPRSS2 host molecules for viral entry. ACE2 and TMPRSS2 have recently been implicated in SARS-CoV-2 viral infection. Additional host molecules including ADAM17, cathepsin L, CD147, and GRP78 may also function as receptors for SARS-CoV-2.

To determine the expression andin situlocalization of candidate SARS-CoV-2 receptors in the respiratory mucosa, we analyzed gene expression datasets from airway epithelial cells of 515 healthy subjects, gene promoter activity analysis using the FANTOM5 dataset containing 120 distinct sample types, single cell RNA sequencing (scRNAseq) of 10 healthy subjects, immunoblots on multiple airway epithelial cell types, and immunohistochemistry on 98 human lung samples.

We demonstrate absent to low ACE2 promoter activity in a variety of lung epithelial cell samples and lowACE2gene expression in both microarray and scRNAseq datasets of epithelial cell populations. Consistent with gene expression, rare ACE2 protein expression was observed in the airway epithelium and alveoli of human lung. We present confirmatory evidence for the presence of TMPRSS2, CD147, and GRP78 proteinin vitroin airway epithelial cells and confirm broadin situprotein expression of CD147 in the respiratory mucosa.

Collectively, our data suggest the presence of a mechanism dynamically regulating ACE2 expression in human lung, perhaps in periods of SARS-CoV-2 infection, and also suggest that alternate receptors for SARS-CoV-2 exist to facilitate initial host cell infection.
Prediction of SARS-CoV interaction with host proteins during lung aging reveals a potential role for TRIB3 in COVID-19
Authors: de Moraes Diogo , Paiva Brunno Vivone Buquete , Cury Sarah Santiloni , Junior João Pessoa Araújo , da Silva Mori Marcelo Alves , Carvalho Robson Francisco
Published: April 2020

COVID-19 is prevalent in the elderly. Old individuals are more likely to develop pneumonia and respiratory failure due to alveolar damage, suggesting that lung senescence may increase the susceptibility to SARS-CoV-2 infection and replication. Considering that human coronavirus (HCoVs; SARS-CoV-2 and SARS-CoV) require host cellular factors for infection and replication, we analyzed Genotype-Tissue Expression (GTEx) data to test whether lung aging is associated with transcriptional changes in human protein-coding genes that potentially interact with these viruses. We found decreased expression of the gene tribbles homolog 3 (TRIB3) during aging in male individuals, and its protein was predicted to interact with HCoVs nucleocapsid protein and RNA-dependent RNA polymerase. Using publicly available lung single-cell data, we foundTRIB3expressed mainly in alveolar epithelial cells that express SARS-CoV-2 receptor ACE2. Functional enrichment analysis of age-related genes, in common with SARS-CoV-induced perturbations, revealed genes associated with the mitotic cell cycle and surfactant metabolism. Given that TRIB3 was previously reported to decrease virus infection and replication, the decreased expression ofTRIB3in aged lungs may help explain why older male patients are related to more severe cases of the COVID-19. Thus, drugs that stimulate TRIB3 expression should be evaluated as a potential therapy for the disease.
RevisitingOrthotospovirusPhylogeny Using Whole Genomic Data and a Hypothesis for their Geographic Origin and Diversification
Authors: Butković Anamarija , González Rubén , Elena Santiago F.
Published: April 2020

The familyTospoviridae, a member of theBunyaviralesorder, is constituted of tri-segmented negative-sense single-stranded RNA viruses that infect plants and are also able of replicating in their insect vectors in a persistent manner. The family is composed of a single genus, theOrthotospovirus, whose type species isTomato spotted wilt virus(TSWV). Previous studies assessing the phylogenetic relationships within this genus were based upon partial genomic sequences, thus resulting in unresolved clades and a poor assessment of the roles of recombination and genome shuffling during mixed infections. Complete genomic data for mostOrthotospovirusspecies are now available at NCBI genome database. In this study we have used 62 complete genomes from 20 species. Our study confirms the existence of four phylogroups (A to D), grouped in two major clades (A-B and C-D), within the genus. We have estimated the split between the two major clades ∼3,100 years ago shortly followed by the split between the A and B phylogroups ∼2,860 years ago. The split between the C and D phylogroups happened more recently, ∼1,465 years ago. Segment reassortment has been shown to be important in the generation of novel viruses. Likewise, within-segment recombination events have been involved in the origin of new viral species. Finally, phylogeographic analyses of representative viruses suggests the Australasian ecozone as the possible origin of the genus, followed by complex patterns of migration, with rapid global spread and numerous reintroduction events.

IMPORTANCE

Members of theOrthotospovirusgenus infect a large number of plant families, including food crops and ornamentals, resulting in multimillionaire economical losses. Despite this importance, phylogenetic relationships within the genus were established years ago based in partial genomic sequences. A peculiarity of orthotospoviruses is their tri-segmented negative sense genomes, which makes segment reassortment and within-segment recombination, two forms of viral sex, potential evolutionary forces. Using full genomes from all described orthotospovirus species, we revisited their phylogeny and confirmed the existence of four major phylogroups with uneven geographic distribution. We have also shown a pervasive role of sex in the origin of new viral species. Finally, using Bayesian phylogeographic methods, we assessed the possible geographic origin and historical dispersal of representative viruses from the different phylogroups.
The respiratory sound features of COVID-19 patients fill gaps between clinical data and screening methods
Authors: Huang Yinghui , Meng Sijun , Zhang Yi , Wu Shuisheng , Zhang Yu , Zhang Yawei , Ye Yixiang , Wei Qifeng , Zhao Niangui , Jiang Jianping , Ji Xiaoying , Zhou Chunxia , Zheng Chao , Zhang Wen , Xie Lizhong , Hu Yongchao , He Jianquan , Chen Jian , Wang Wangyue , Cao Liming , Xu Wen , Lei Yunhong , Jiang Zhenghua , Hu Weiping , Qin Wenjuan , Wang Wanyu , He Yulong , Xiao Hang , Zheng Xiaofang , Hu Yiqun , Pan Wensheng , Zhang Changhua , Cai Jianfeng
Published: April 2020

Background

The 2019 novel coronavirus (COVID-19) has continuous outbreaks around the world. Lung is the main organ that be involved. There is a lack of clinical data on the respiratory sounds of COVID-19 infected pneumonia, which includes invaluable information concerning physiology and pathology. The medical resources are insufficient, which are now mainly supplied for the severe patients. The development of a convenient and effective screening method for mild or asymptomatic suspicious patients is highly demanded.

Methods

This is a retrospective case series study. 10 patients with positive results of nucleic acid were enrolled in this study. Lung auscultation was performed by the same physician on admission using a hand-held portable electronic stethoscope delivered in real time via Bluetooth. The recorded audio was exported, and was analyzed by six physicians. Each physician individually described the abnormal breathing sounds that he heard. The results were analyzed in combination with clinical data. Signal analysis was used to quantitatively describe the most common abnormal respiratory sounds.

Results

All patients were found abnormal breath sounds at least by 3 physicians, and one patient by all physicians. Cackles, asymmetrical vocal resonance and indistinguishable murmurs are the most common abnormal breath sounds. One asymptomatic patient was found vocal resonance, and the result was correspondence with radiographic computed tomography. Signal analysis verified the credibility of the above abnormal breath sounds.

Conclusions

This study describes respiratory sounds of patients with COVID-19, which fills up for the lack of clinical data and provides a simple screening method for suspected patients.
How does spinal movement variability change in people with low back pain?: protocol for a systematic review
Authors: Saito Hiroki , takasaki Hiroshi , Watanabe Yoshiteru , Kutsuna Toshiki , Futohashi Toshihiro , Kubo Masayoshi , Kusumoto Yasuaki , Tiba Hiroki
Published: April 2020

Low back pain(LBP) is the number one cause of disability worldwide. One factor which might potentially contribute to ongoing pain is impaired spinal movement variability. It is uncertain how movement variability changes during trunk movements in the presence of LBP. In this protocol, we will systematically investigate and compare both the amount and structure of spinal movement variability during repeated trunk motions between people with and without LBP. The results will be reported in line with the PRISMA(Preferred Reporting Items for Systematic Review and Meta-Analysis). Searches will be conducted on CENTRAL, PubMed, MEDLINE, EMBASE, and CINAHL databases, along with a comprehensive review of grey literature and key journals.Three pairs of two independent reviewers will screen potential studies and two independent reviewers assess the risk of bias within studies which meet the inclusion criteria. The Newcastle-Ottawa risk of bias tool will be used to assess the quality of the data.
ADNC-RS, a clinical-genetic risk score, predicts Alzheimer’s pathology in autopsy-confirmed Parkinson’s Disease and Dementia with Lewy Bodies
Authors: Dai David L , Tropea Thomas F , Robinson John L , Suh Eunran , Hurtig Howard , Weintraub Daniel , Van Deerlin Vivianna , Lee Edward B. , Trojanowski John Q , Chen-Plotkin Alice S
Published: April 2020

Growing evidence suggests overlap between Alzheimer’s disease (AD) and Parkinson’s disease (PD) pathophysiology in a subset of patients. Indeed, 50-80% of autopsy cases with a primary clinicopathological diagnosis of Lewy body disease (LBD) – most commonly manifesting during life as PD – have concomitant amyloid-beta and tau pathology, the defining pathologies of AD. Here we evaluated common genetic variants in genome-wide association with AD as predictors of concomitant AD pathology in the brains of people with a primary clinicopathological diagnosis of PD or Dementia with Lewy Bodies (DLB), diseases both characterized by neuronal Lewy bodies. 208 consecutive autopsy-confirmed cases of PD or DLB were assessed for AD neuropathological change (ADNC), and these same cases were genotyped at 20 single nucleotide polymorphisms (SNPs) found by genome-wide association study to associate with risk for AD. In a training set of the first 127 individuals, we developed a logistic regression model predicting the presence of ADNC, using backward stepwise regression for model selection and 10-fold cross-validation to estimate performance. We then assessed model performance in a separate test set of the next 81 individuals. The best-fit model generated a risk score for ADNC (ADNC-RS) based on age at disease onset and genotype at three SNPs (APOE, BIN1, and SORL1 loci). In the training set, the area under the receiver operating curve (AUC) for this model was 0.751. In the test set, the AUC was 0.781. Individuals with ADNC-RS in the top quintile had four-fold likelihood of having AD pathology at autopsy compared with those in each of the lowest two quintiles. In patients with autopsy-confirmed PD or DLB a simple model incorporating three AD-risk SNPs and age at disease onset substantially enriches for concomitant AD pathology at autopsy, with implications for identifying LBD patients in which targeting amyloid-beta or tau is a therapeutic strategy.
Effects of latency on estimates of the COVID-19 replication number
Authors: Sadun Lorenzo
Published: April 2020

It is not currently known how long it takes a person infected by the COVID-19 virus to become infectious. Models of the spread of COVID-19 use very different lengths for this latency period, leading to very different estimates of the replication number R, even when models work from the same underlying data sets. In this paper we quantify how much varying the length of the latency period affects estimates of R, and thus the fraction of the population that is predicted to be infected in the first wave of the pandemic. This variation underscores the uncertainty in our understanding of R and raises the possibility that R may be considerably greater than has been assumed by those shaping public policy.
A simple method to quantify country-specific effects of COVID-19 containment measures
Authors: Pedersen Morten Gram , Meneghini Matteo
Published: April 2020

Most of the world is currently fighting to limit the impact of the COVID-19 pandemic. Italy, the Western country with most COVID-19 related deaths, was the first to implement drastic containment measures in early March, 2020. Since then most other European countries, the USA, Canada and Australia, have implemented similar restrictions, ranging from school closures, banning of recreational activities and large events, to complete lockdown. Such limitations, and softer promotion of social distancing, may be more effective in one society than in another due to cultural or political differences. It is therefore important to evaluate the effectiveness of these initiatives by analyzing country-specific COVID-19 data. We propose to model COVID-19 dynamics with a SIQR (susceptible – infectious – quarantined – recovered) model, since confirmed positive cases are isolated and do not transmit the disease. We provide an explicit formula that is easily implemented and permits us to fit official COVID-19 data in a series of Western countries. We found excellent agreement with data-driven estimation of the day-of-change in disease dynamics and the dates when official interventions were introduced. Our analysis predicts that for most countries only the more drastic restrictions have reduced virus spreading. Further, we predict that the number of unidentified COVID-19-positive individuals at the beginning of the epidemic is ∼10 times the number of confirmed cases. Our results provide important insight for future planning of non-pharmacological interventions aiming to contain spreading of COVID-19 and similar diseases.
Systematic review of distribution models for Amblyomma ticks and Rickettsial group pathogens
Authors: Lippi Catherine A. , Gaff Holly D. , White Alexis L. , Ryan Sadie J.
Published: April 2020

The rising prevalence of tick-borne diseases in humans in recent decades has called attention to the need for more information on geographic risk for public health planning. Species distribution models (SDMs) are an increasingly utilized method of constructing potential geographic ranges.There are many knowledge gaps in our understanding of risk of exposure to tick-borne pathogens, particularly for those in the rickettsial group. Here, we conducted a systematic review of the SDM literature for rickettsial pathogens and tick vectors in the genus Amblyomma. Of the 174 reviewed papers, only 24 studies used SDMs to estimate the potential extent of vector and/or pathogen ranges. The majority of studies (79%) estimated only tick distributions using vector presence as a proxy for pathogen exposure. Studies were conducted at different scales and across multiple continents. Few studies undertook original data collection, and SDMs were mostly built with presence-only datasets from public database or surveillance sources. While we identify agap in knowledge, this may simply reflect a lag in new data acquisition and a thorough understanding of the tick-pathogen ecology involved.
Exploring gendered patterns of interaction within an inter-professional health care network
Authors: Aguirre Nelson , Carswell Peter , Kenealy Tim
Published: April 2020

Background

Numerous studies have shown gender-based similarity affects interactions in organizational contexts. However, studies in the health care arena have shown contradictory findings.

Objective

To explore gender homophily in an inter-professional network comprising doctors and nurses across the primary and secondary care interface in diabetes care.

Methods

A Social Network Analysis was conducted with primary and secondary care clinicians responsible for diabetes care in Auckland New Zealand. Three different methods were used to test gender affinity in 40 health professionals (GPs, endocrinologist and specialist nurses). First, a metric analysis of homophily ranking corrected for potential differences in gender proportions was conducted. Homophily ranking is scored between −1 (perfect heterophily) and 1 (perfect homophily). We also examined the ego-net composition and measured the density of interactions among men and women in the network.

Results

Gender homophily was close to 0, indicated that network members were likely to interact with males and females without preferences, a result that was confirmed through ego-net composition.

Conclusions

This study in diabetes managed care network found little evidence to support the impact of gender homophily on communication exchange. This contrasts with other studies in the health care context. Other influences need to be explored at this context.
Appropriate intensification of diabetes-related therapy by general practitioners: cross sectional study
Authors: Aguirre Nelson , Carswell Peter , Kenealy Tim
Published: April 2020

Aim

To measure intensification of therapy (the inverse of clinical inertia) by general practitioners in the management of hyperglycaemia, hypertension and dyslipidaemia in patients with diabetes.

Methods

We analysed clinical practices results for Hb1c, blood pressure, lipids and pharmacy records for prescriptions according to the guidelines. We identified whether medication was increased at each patient visit when the goals for glycosylated haemoglobin (<= 64 mmol/mol), systolic blood pressure (<=130 mmHg) and LDL cholesterol (<=3.5 mmol/L) had not been reached at the time of the visit. The study was conducted between January 2009 and December 2011 in South Auckland, New Zealand.

Results

Data from 314 patients with diabetes included 2398 prescriptions. Appropriate intensification of therapy was seen in 31% of 457 visits when HbA1c was raised, 11% of 375 visits when systolic blood pressure was raised and 2% of 51 visits when LDL cholesterol was raised.

Conclusions

There are clear differences in intensification therapy in terms of the co-morbidity addressed. Clinical inertia may be one important and changeable contributor to diabetes complications. New Zealand has replaced “get Checked” programme for Diabetes Care Improvement Package, which is a primary care based programme seeking to improve outcomes for people with diabetes. This new programme is based on coordination of diabetes care, therefore a further analysis measuring clinical inertia may show improvements in quality, consistency and direction of care for people with diabetes in New Zealand.

Highlights

We measure intensification of therapy by general practitioners.

Management of hyperglycaemia, hypertension and dyslipidaemia were tested.

There are differences in intensification therapy in terms of each co-morbidity.

Clinical inertia may be one changeable contributor to diabetes complications.
BioLaboro: A bioinformatics system for detecting molecular assay signature erosion and designing new assays in response to emerging and reemerging pathogens
Authors: Holland Mitchell , Negrón Daniel , Mitchell Shane , Dellinger Nate , Ivancich Mychal , Barrus Tyler , Thomas Sterling , Jennings Katharine W. , Goodwin Bruce , Sozhamannan Shanmuga
Published: April 2020

Background

Emerging and reemerging infectious diseases such as the novel Coronavirus disease, COVID-19 and Ebola pose a significant threat to global society and test the public health community’s preparedness to rapidly respond to an outbreak with effective diagnostics and therapeutics. Recent advances in next generation sequencing technologies enable rapid generation of pathogen genome sequence data, within 24 hours of obtaining a sample in some instances. With these data, one can quickly evaluate the effectiveness of existing diagnostics and therapeutics usingin silicoapproaches. The propensity of some viruses to rapidly accumulate mutations can lead to the failure of molecular detection assays creating the need for redesigned or newly designed assays.

Results

Here we describe a bioinformatics system named BioLaboro to identify signature regions in a given pathogen genome, design PCR assays targeting those regions, and then test the PCR assaysin silicoto determine their sensitivity and specificity. We demonstrate BioLaboro with two use cases: Bombali Ebolavirus (BOMV) and the novel Coronavirus 2019 (SARS-CoV-2). For the BOMV, we analyzed 30 currently available real-time reverse transcription-PCR assays against the three available complete genome sequences of BOMV. Only two met ourin silicocriteria for successful detection and neither had perfect matches to the primer/probe sequences. We designed five new primer sets against BOMV signatures and all had true positive hits to the three BOMV genomes and no false positive hits to any other sequence. Four assays are closely clustered in the nucleoprotein gene and one is located in the glycoprotein gene. Similarly, for the SARS-CoV-2, we designed five highly specific primer sets that hit all 145 whole genomes (available as of February 28, 2020) and none of the near neighbors.

Conclusions

Here we applied BioLaboro in two real-world use cases to demonstrate its capability; 1) to identify signature regions, 2) to assess the efficacy of existing PCR assays to detect pathogens as they evolve over time, and 3) to design new assays with perfectin silicodetection accuracy, all within hours, for further development and deployment. BioLaboro is designed with a user-friendly graphical user interface for biologists with limited bioinformatics experience.
Access to routinely collected health data for clinical trials – review of successful data requests to UK registries
Authors: Lensen Sarah , Macnair Archie , Love Sharon B , Yorke-Edwards Victoria , Noor Nurulamin M , Martyn Meredith , Blenkinsop Alexandra , Diaz-Montana Carlos , Powell Graham , Williamson Elizabeth , Carpenter James , Sydes Matthew R
Published: April 2020

Background

Clinical trials generally each collect their own data despite routinely-collected health data (RCHD) increasing in quality and breadth. Our aim is to quantify UK-based randomised controlled trials (RCTs) accessing RCHD for participant data, characterise how these data are used and thereby recommend how more trials could use RCHD.

Methods

We conducted a systematic review of RCTs accessing RCHD from at least one registry in the UK between 2013-2018, for the purposes of informing or supplementing participant data. A list of all registries holding RCHD in the UK was compiled. In cases where registries published release registers, these were searched for RCTs accessing RCHD. Where no release register was available, registries were contacted to request a list of RCTs. For each identified RCT, information was collected from all publicly available sources (release registers, websites, protocol etc.). The search and data extraction was undertaken between Jan-2019 and May-2019.

Results

We identified 160 RCTs accessing RCHD between 2013 and 2018 from a total of 22 registries; this corresponds to only a very small proportion of all UK RCTs (approximately 3%). RCTs accessing RCHD were generally large (median sample size 1590), commonly evaluating treatments for cancer or cardiovascular disease. Most of the included RCTs accessed RCHD from NHS Digital (68%), and the most frequently accessed datasets were mortality (76%) and hospital visits (55%). RCHD was used to inform the primary trial (82%) and long-term follow-up (57%). There was substantial variation in how RCTs used RCHD to inform participant outcome measures. A limitation was the lack of information and transparency from registries and RCTs with respect to which datasets have been accessed and for what purposes.

Conclusions

In the last five years, only a small minority of UK-based RCTs have accessed RCHD to inform participant data. We ask for improved accessibility, confirmed data quality and joined up thinking between the registries and the regulatory authorities.

Registration

PROSPERO CRD42019123088
Artificial intelligence applied on chest X-ray can aid in the diagnosis of COVID-19 infection: a first experience from Lombardy, Italy
Authors: Castiglioni Isabella , Ippolito Davide , Interlenghi Matteo , Monti Caterina Beatrice , Salvatore Christian , Schiaffino Simone , Polidori Annalisa , Gandola Davide , Messa Cristina , Sardanelli Francesco
Published: April 2020

Objectives

We tested artificial intelligence (AI) to support the diagnosis of COVID-19 using chest X-ray (CXR). Diagnostic performance was computed for a system trained on CXRs of Italian subjects from two hospitals in Lombardy, Italy.

Methods

We used for training and internal testing an ensemble of ten convolutional neural networks (CNNs) with mainly bedside CXRs of 250 COVID-19 and 250 non-COVID-19 subjects from two hospitals. We then tested such system on bedside CXRs of an independent group of 110 patients (74 COVID-19, 36 non-COVID-19) from one of the two hospitals. A retrospective reading was performed by two radiologists in the absence of any clinical information, with the aim to differentiate COVID-19 from non-COVID-19 patients. Real-time polymerase chain reaction served as reference standard.

Results

At 10-fold cross-validation, our AI model classified COVID-19 and non COVID-19 patients with 0.78 sensitivity (95% confidence interval [CI] 0.74–0.81), 0.82 specificity (95% CI 0.78–0.85) and 0.89 area under the curve (AUC) (95% CI 0.86–0.91). For the independent dataset, AI showed 0.80 sensitivity (95% CI 0.72–0.86) (59/74), 0.81 specificity (29/36) (95% CI 0.73–0.87), and 0.81 AUC (95% CI 0.73– 0.87). Radiologists’ reading obtained 0.63 sensitivity (95% CI 0.52–0.74) and 0.78 specificity (95% CI 0.61–0.90) in one centre and 0.64 sensitivity (95% CI 0.52–0.74) and 0.86 specificity (95% CI 0.71–0.95) in the other.

Conclusions

This preliminary experience based on ten CNNs trained on a limited training dataset shows an interesting potential of AI for COVID-19 diagnosis. Such tool is in training with new CXRs to further increase its performance.

Key points

Artificial intelligence based on convolutional neural networks was preliminary applied to chest-X-rays of patients suspected to be infected by COVID-19.

Convolutional neural networks trained on a limited dataset of 250 COVID-19 and 250 non-COVID-19 were tested on an independent dataset of 110 patients suspected for COVID-19 infection and provided a balanced performance with 0.80 sensitivity and 0.81 specificity.

Training on larger multi-institutional datasets may allow this tool to increase its performance.
Anticipating the novel coronavirus disease (COVID-19) pandemic
Authors: Kaur Taranjot , Sarkar Sukanta , Chowdhury Sourangsu , Sinha Sudipta Kumar , Jolly Mohit Kumar , Dutta Partha Sharathi
Published: April 2020

COVID-19 outbreak has been declared as a public health emergency of international concern, and later as a pandemic. In most countries, the COVID-19 incidence curve rises sharply in a short period, suggesting a transition from a disease-free (or low-burden disease) equilibrium state to a sustained infected (or high-burden disease) state. Such a transition is often known to exhibit characteristics of ‘critical slowing down’. Critical slowing down can be, in general, successfully detected using many statistical measures such as variance, lag-1 autocorrelation, density ratio, and skewness. Here, we report an empirical test of this phenomena on the COVID-19 data sets for nine countries, including India, China, and the United States. For most of the data sets, increase in variance and autocorrelation predict the onset of a critical transition. Our analysis suggests two key features in predicting the COVID-19 incidence curve for a specific country: a) the timing of strict social distancing and/or lockdown interventions implemented, and b) the fraction of a nation’s population being affected by COVID-19 at that time. Further, using satellite data of nitrogen dioxide, as an indicator of lockdown efficacy, we find that in countries where the lockdown was implemented early and firmly have been successful in reducing the COVID-19 spread. These results are essential for designing effective strategies to control the spread/resurgence of infectious pandemics.
Purely data-driven exploration of COVID-19 pandemic after three months of the outbreak
Authors: Kadyrov Shirali , Saydaliev Hayot Berk
Published: April 2020

It has been three months since the novel coronavirus (COVID-19) pandemic outbreak. Many research studies were carried to understand its epidemiological characteristics in the early phase of the disease outbreak. The current study is yet another contribution to better understand the disease properties by parameter estimation of mathematical SIR epidemic modeling. The authors use Johns Hopkins University’s dataset to estimate the basic reproduction number of COVID-19 for representative countries (Japan, Germany, Italy, France, and Netherlands) selected using cluster analysis. As a by-product, the authors estimate transmission, recovery, and death rates for each selected country and carry statistical tests to see if there are any significant differences.
Hydroxychloroquine (HCQ): an observational cohort study in primary and secondary prevention of pneumonia in an at-risk population
Authors: Vanasse Alain , Courteau Josiane , Chiu Yohann , Cantin André , Leduc Richard
Published: April 2020

Background

Recent studies suggest that hydroxychloroquine (HCQ) could be effective against COVID-19. It is reasonable to expect that if HCQ can prevent or reduce the adverse effects of influenza, it may also reduce the effects of COVID-19 in humans. The objective of this study was to test whether HCQ can prevent or reduce the risk and severity of influenza.

Methods

This is an observational cohort study using medico-administrative data from Québec. Patients included had at least one emergency department (ED) visit in 2012 or 2013, with a prior diagnosis of chronic conditions, and were admissible to the public drug insurance plan. Two sub-cohorts were considered depending on reasons for ED visit: other than influenza or pneumonia (primary prevention) and influenza or pneumonia (secondary prevention).

Results

In the primary prevention analysis (n=417,353), patients taking HCQ (n=3,659) had an increased risk of hospitalization for pneumonia in the following year compared to those who did not (5.2% vs. 2.9%; adjusted OR=1.25, p=0.0079). In the secondary prevention analysis (n=27,152), patients taking HCQ (n=392), compared to those who did not had a modest and non-significant increased risk of hospitalization for pneumonia after 30 days (25.8% vs. 22.6%; adjusted OR=1.14, p=0.3177).

Interpretation

Based on the assumption that HCQ has similar effects on the COVID-19 as those observed on influenza, we can infer that it will not have positive effects on COVID-19. We should therefore act cautiously before initiating prospective interventional studies on the use of HCQ to reduce adverse effects of COVID-19.
Phosphorylation of Threonine 107 by Calcium/Calmodulin dependent Kinase II δ Regulates the Detoxification Efficiency and Proteomic Integrity of Glyoxalase 1
Authors: Morgenstern Jakob , Katz Sylvia , Krebs-Haupenthal Jutta , Chen Jessy , Saadatmand Alireza , Cortizo Fabiola Garcia , Moraru Alexandra , Zemva Johanna , Campos Marta Campos , Teleman Aurelio , Backs Johannes , Nawroth Peter , Fleming Thomas
Published: April 2020

The glyoxalase system is a ubiquitously expressed enzyme system with narrow substrate specificity and is responsible for the detoxification of harmful methylglyoxal (MG), a spontaneous by-product of energy metabolism. Glyoxalase 1 (Glo1) is the first and therefore rate limiting enzyme of this protective system. In this study we were able to show that a phosphorylation of threonine-107 in the Glo1 protein, mediated by Ca2+/Calmodulin-dependent Kinase II delta (CamKIIδ), is associated with elevated catalytic efficiency of Glo1. In fact, Michaelis-Menten kinetics of Glo1 mutants revealed that a permanent phosphorylation of Glo1 was associated with increased Vmax(1.23 µmol/min/mg) and decreased Km(0.19 mM HTA), whereas the non-phosphorylatable Glo1 showed significantly lower Vmax(0.66 µmol/min/mg) and increased Km(0.31 mM HTA). This was also confirmed with human recombinant Glo1 (Vmax(Glo1phos) = 999 µmol/min/mg; Km(Glo1phos) = 0.09 mM HTA vs. Vmax(Glo1red) = 497 µmol/min/mg; Km(Glo1red) = 0.12 mM HTA). Additionally, proteasomal degradation of non-phosphorylated Glo1 via ubiquitination occurred more rapidly as compared to native Glo1. The absence of the responsible kinase CamKIIδ was associated with poor MG detoxification capacity and decreased protein content of Glo1 in a murine CamKIIδ knock-out model. Furthermore, this regulatory mechanism is also related to an altered Glo1 status in cancer, diabetes and during aging. In summary, phosphorylation of threonine-107 in the Glo1 protein by CamKIIδ is a quick and precise mechanism regulating Glo1 activity.
Structural basis for the inhibition of SARS-CoV-2 main protease by antineoplastic drug Carmofur
Authors: Jin Zhenming , Zhao Yao , Sun Yuan , Zhang Bing , Wang Haofeng , Wu Yan , Zhu Yan , Zhu Chen , Hu Tianyu , Du Xiaoyu , Duan Yinkai , Yu Jing , Yang Xiaobao , Yang Xiuna , Yang Kailin , Liu Xiang , Guddat Luke W. , Xiao Gengfu , Zhang Leike , Yang Haitao , Rao Zihe
Published: April 2020

The antineoplastic drug Carmofur was shown to inhibit SARS-CoV-2 main protease (Mpro). Here the X-ray crystal structure of Mproin complex with Carmofur reveals that the carbonyl reactive group of Carmofur is covalently bound to catalytic Cys145, whereas its fatty acid tail occupies the hydrophobic S2 subsite. Carmofur inhibits viral replication in cells (EC50= 24.30 μM) and it is a promising lead compound to develop new antiviral treatment for COVID-19.
Metabolite plasticity drives carbon-nitrogen resource budgeting to enable division of labor in a clonal community
Authors: Varahan Sriram , Sinha Vaibhhav , Walvekar Adhish , Krishna Sandeep , Laxman Sunil
Published: April 2020

Previously, we discovered that in glucose-limited yeast colonies, metabolic constraints drive cells into groups exhibiting gluconeogenic and glycolytic metabolic states. Here, threshold amounts of trehalose - a limiting, produced resource, controls the emergence and self-organization of the cells exhibiting the glycolytic state, by acting as a carbon source to fuel these metabolic demands (Varahan et al., 2019). We now discover that the plasticity of use of a non-limiting resource, aspartate, controls both resource production and the emergence of heterogeneous cell states, based on differential cellular metabolic budgeting. In gluconeogenic cells, aspartate provides carbon for trehalose production, while in glycolytic cells using trehalose for carbon, aspartate supplies nitrogen to drive nucleotide synthesis. This metabolic plasticity of aspartate enables carbon-nitrogen budgeting, thereby driving the biochemical self-organization of distinct cell states. Through this organization, cells in each state exhibit true division of labor, providing bet-hedging and growth/survival advantages for the whole community.
The initiation knot is a signaling center required for molar tooth development
Authors: Mogollón Isabel , Moustakas-Verho Jacqueline E , Niittykoski Minna , Ahtiainen Laura
Published: April 2020

Signaling centers, or organizers, regulate many aspects of embryonic morphogenesis. In the mammalian molar tooth, reiterative signaling in specialized centers called enamel knots (EKs) determine tooth patterning. Preceding the first, primary EK, a transient epithelial thickening appears whose significance remains debated. Using tissue confocal fluorescence imaging with laser ablation experiments, we show that this transient thickening is an earlier signaling center, the molar initiation knot (IK), required for the progression of tooth development. IK cell dynamics manifest signaling center hallmarks; cell cycle exit, condensation, and eventual apoptotic silencing. IK initiation and maturation are defined by the juxtaposition of high Wnt activity cells toShh-expressing non-proliferating cells, the combination of which drives the growth of the tooth bud, leading to the formation of the primary EK as an independent cell cluster. Overall, the whole development of the tooth, from initiation to patterning, is driven by the iterative use of signaling centers.
Transcriptome analysis of the zebrafishatoh7−/−mutant,lakritz, highlights Atoh7-dependent genetic networks with potential implications for human eye diseases
Authors: Covello Giuseppina , Rossello Fernando J. , Filosi Michele , Gajardo Felipe , Duchemin Anne-Laure , Tremonti Beatrice F. , Eichenlaub Michael , Polo Jose M. , Powell David , Ngai John , Allende Miguel L. , Domenici Enrico , Ramialison Mirana , Poggi Lucia
Published: April 2020

Expression of the bHLH transcription protein Atoh7 is a crucial factor conferring competence to retinal progenitor cells for the development of retinal ganglion cells. A number of studies have emerged establishingATOH7as a retinal disease gene. Remarkably, such studies uncoveredATOH7variants associated with global eye defects including optic nerve hypoplasia, microphthalmia, retinal vascular disorders and glaucoma. The complex genetic networks and cellular decisions arising downstream ofatoh7expression, and how their dysregulation cause development of such disease traits remains unknown. To begin to understand such Atoh7-dependent eventsin vivowe performed transcriptome analysis of wild type andatoh7mutant (lakritz) zebrafish embryos at the onset of retinal ganglion cell differentiation. We investigatedin silicointerplays ofatoh7and other disease-related genes and pathways. By network reconstruction analysis of differentially expressed genes we identified gene clusters enriched in retinal development, cell cycle, chromatin remodelling, stress response and Wnt pathways. By weighted gene coexpression network we identified coexpression modules affected by the mutation and enriched in retina development genes tightly connected toatoh7. We established the groundwork whereby Atoh7-linked cellular and molecular processes can be investigated in the dynamic multi-tissue environment of the developing normal and diseased vertebrate eye.
Metagenomic Analysis of Bacterial Community Associated with Rhizosphere and Phyllosphere of Basmati Rice
Authors: rasul maria , Yasmin Sumera , Hakim Sughra , Zaheer Ahmad , Mirza Babur , Mirza M Sajjad
Published: April 2020

Rice is one of the most important crops for feeding about more than half of the world's population. Yield of rice crop is significantly hampered by various biotic and abiotic factors. Application of cost-effective and environment-friendly bioinoculant is a common practice to combat the yield losses of rice in this era. The rhizosphere and phyllosphere of rice plants provide specific habitats for various micro-organisms. In the present study, the bacterial population dwelling the rhizosphere and phyllosphere of Basmati rice were explored using metagenomic approach from rice growing areas of Punjab, Pakistan. The bacterial communities associated with the rice rhizosphere of different rice growing areas as well as phyllosphere/rhizosphere were compared. Out of 20,069 16S rRNA gene sequences retreived from rhizosphere soil, 6485 were originated from Faisalabad, 5174 from Gujranwala and 8410 from Sheikhupura. Data analyses revelead that Proteobactria was dominant phylum at all three sites. Choloflexi was second abundant phylum at Sheikhupura, while Actinobacteria and Firmicutes at Gujranwala and Faisalabad. In addition to dominant culturable PGPB Bacillus genus at all three sites, Nitrosospira , Gaiella , Marmoricola , Clostridium sensu stricto . Maximum geners were detected from Faisalabad (159), followed by Sheikhupura (146) and Gujranwala (131). Comparison of the common sequences at the genus-level revealed that maximum number of shared genera (101) were observed in Sheikhupura and Gujranwala. 50 genera were specifically related to Faisalabad, while 27 and 21 genera were detected for Sheikhupura and Gujranwala. In the phyllosphere, Proteobacteria (79.6%) was detected as dominant phylum followed by Firmicutes (9.8%), Bacteroidetes (8.6%), Chloroflexi (4.3%) and Actinobacteria (0.9%). Comparison of phyllosphere and rhizosphere showed less bacterial diversity in the phyllosphere but Bradyrhizobium , Sphingomonas , GP6, Pseudomonas , Bacillus are abuundant. Fifteen genera were detected at both compartments. Furthermore, we may select these strains for development of compatible inocula for application in the rhizosphere and phyllosphere of rice.