bluuebunny/crossref_metadata_2025 huggingface dataset:
Performance and Robustness of Machine Learning-based Radiomic COVID-19 Severity Prediction
Authors: Yip Stephen S.F. , Klanecek Zan , Naganawa Shotaro , Kim John , Studen Andrej , Rivetti Luciano , Jeraj Robert
Published: September 2020

Objectives

This study investigated the performance and robustness of radiomics in predicting COVID-19 severity in a large public cohort.

Methods

A public dataset of 1110 COVID-19 patients (1 CT/patient) was used. Using CTs and clinical data, each patient was classified into mild, moderate, and severe by two observers: (1) dataset provider and (2) a board-certified radiologist. For each CT, 107 radiomic features were extracted. The dataset was randomly divided into a training (60%) and holdout validation (40%) set. During training, features were selected and combined into a logistic regression model for predicting severe cases from mild and moderate cases. The models were trained and validated on the classifications by both observers. AUC quantified the predictive power of models. To determine model robustness, the trained models was cross-validated on the inter-observer’s classifications.

Results

A single feature alone was sufficient to predict mild from severe COVID-19 with and (p<< 0.01). The most predictive features were the distribution of small size-zones (GLSZM-SmallAreaEmphasis) for provider’s classification and linear dependency of neighboring voxels (GLCM-Correlation) for radiologist’s classification. Cross-validation showed that both . In predicting moderate from severe COVID-19, first-order-Median alone had sufficient predictive power of . For radiologist’s classification, the predictive power of the model increased to as the number of features grew from 1 to 5. Cross-validation yielded and .

Conclusions

Radiomics significantly predicted different levels of COVID-19 severity. The prediction was moderately sensitive to inter-observer classifications, and thus need to be used with caution.

Key points

Interpretable radiomic features can predict different levels of COVID-19 severity

Machine Learning-based radiomic models were moderately sensitive to inter-observer classifications, and thus need to be used with caution
Electromyography recordings detect muscle activity before observable contractions in acute stroke care
Authors: Papazian Christina , Baicoianu Nick A. , Peters Keshia M. , Feldner Heather , Steele Katherine M.
Published: September 2020

Objective

To determine whether electromyography (EMG) can be used in acute stroke care to identify muscle activity in patients with no observable activity during clinical examination.

Design

Stroke survivors admitted to a level one trauma hospital with initial NIH Stroke Scale scores of two or higher for arm function were recruited within five days of stroke (average 3±1 days), including eleven stroke survivors (7 male/4 female, age 56±11) with no observable or palpable arm muscle activity (Manual Muscle Test, MMT=0) and ten stroke survivors (6 male/4 female, age 64±1) with observable muscle activity (MMT>0). We placed wireless EMG sensors on five major muscle groups (anterior deltoid, biceps, triceps, wrist extensors, and wrist flexors) of the impaired arm for 3-4 hours during standard care.

Results

We were able to identify muscle contractions in all five muscles for all participants from EMG recordings. Contractions were easily identified from 30-minutes of monitoring for participants with MMT>0, but up to three hours of monitoring was required for participants with MMT=0 to detect contractions in all five muscles during standard care. Only the wrist extensors demonstrated significantly larger amplitude contractions for participants with MMT>0 than MMT=0. Co-contraction was rare, involving less than 10% of contractions. Co-contraction of two muscles most commonly aligned with the flexor synergy pattern commonly observed after stroke. For participants with MMT=0, number of contractions and maximum amplitude in acute care were moderately correlated with MMT scores at follow-up.

Conclusion

Muscle activity can be detected with surface EMG recordings during standard care, even for stroke survivors with no observable activity by clinical exam.
Demographic Differences in US Adult Intentions to Receive a Potential Coronavirus Vaccine and Implications for Ongoing Study
Authors: Carpiano Richard M.
Published: September 2020

Abstract
Background: The coronavirus pandemic's public health and economic impacts have led to much hope in the US regarding the prospect of a safe, effective vaccine to either prevent infection or minimize symptoms and reduce mortality risk. However, recent US polls indicate a concerning level of hesitancy that will likely lead to suboptimal uptake if such a vaccine becomes available. This study investigated demographic differences regarding US adults' intent, uncertainty, and refusal to receive a potential coronavirus vaccine and specific reasons for intention to receive it.

Methods and findings: Multivariable analysis of Associated Press (AP)-NORC Center for Public Affairs Research cross-sectional survey data collected in May 2020 from a US nationally representative panel of adults (n=1000). Respondents were asked if they would receive a coronavirus vaccine (yes, unsure, no). Among those answering yes, the specific reasons were: to protect self, family, and community; chronic health condition; and having a doctor who recommends vaccines. Multinomial logistic regression models indicated numerous subgroup differences between participants who indicating (1) uncertainty versus refusal, (2) intent versus refusal, and (3) intent versus uncertainty, with the highest number of significant differences observed in the third comparison. Overall, higher likelihood of intention to receive the vaccine versus uncertainty and refusal were mostly observed among respondents with a college education or greater, White, non-Hispanic racial-ethnic identity, ages 60 or older, and more liberal (versus conservative) ideology. Despite variation in endorsement across the five reasons for wanting to receive the vaccine, subgroup differences were fairly consistent across these specific reasons when comparing respondents endorsing such intentions versus, respectively, refusal and uncertainty in separate analyses.

Conclusions: These findings suggest that the approval of a vaccine will potentially face problems with overall uptake due to uncertainty or refusal and contribute to creating significant demographic disparities in COVID-19 morbidity and mortality risk. Ongoing assessment of such attitudes are needed as Phase III trials proceed, but the findings highlight need for measuring uncertainty and its underlying reasons, as well as multiple types of education and outreach efforts for those who are uncertain as well as avoidant.
Understanding SARSCOV-2 propagation, impacting factors to derive possible scenarios and simulations
Authors: Mehl-Madrona Lewis , Bricaire François , Cuyugan Adrian , Barac Jovan , Parvaiz Asadullah , Jamil Ali Bin , Iqbal Sajid , Vally Ryan , Koliali Meryem , Sellier Mohamed Karim
Published: September 2020

Objectives

We aimed to analyze factors impacting the Covid-19 epidemic on a macro level, comparing multiple countries across the world, and verifying the occurrence at a micro level through cluster analysis.

Design

Statistical analysis of large datasets.

Methods

We used publicly available large world datasets (1-11). Data was transformed to fit parametric distributions prior to statistical analyses, which were performed with Student’s t-test, linear regression and post-hoc tests. Especially for ordinary least squares regression, natural logarithmic transformations were done to remediate normality violations in the standardized residuals.

Results

The severity of the epidemic was most strongly related to exposure to ultraviolet light and extrapolated levels of vitamin D and to the health of the population, especially with regards to obesity. We found no county with an obesity level < 8% with a severe epidemic. We also found that countries where the population benefited from sun exposure or vitamin D supplementation and spent time outside fared well. Factors related to increased propagation of the virus included the use of heating ventilation and air conditioning (HVAC), population density, poorly aerated gatherings, relative humidity, timely policies of closing clustering places until aeration was improved, and daily amount of ridership on public transportation, especially subways. Population lockdowns, masks, and blood type did not provide much explanatory power. The excess mortality observed is within the ranges of severe past influenza epidemics of 2016/2017 or 1999/2000.

Conclusions

Our study suggested that prevention measures should be directed to improving aeration systems, enhancing diets and exercise, and ensuring adequate levels of vitamin D. Further research on masking is indicated as our study could not separate policies from how well they were actually followed.

Funding

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors’

Strengths and Limitations of the Study

The Study examines large datasets across countries to look for macrotrends in management of the Covid-19 outbreak.

The Study cannot necessarily establish causation but rather correlation.

The Study raises some novel possibilities for further studies in relation to country-wide and individual-level susceptibility to Covid-19 and to other epidemics in general.

The Study raises questions about some political policies based upon country-level comparisons and suggests some areas for exploration of prevention policies.
The impact of COVID-19 on the lives and mental health of Australian adolescents
Authors: Li Sophie H. , Beames Joanne R. , Newby Jill M. , Maston Kate , Christensen Helen , Werner-Seidler Aliza
Published: September 2020

Objective

There has been significant disruption to the lives and mental health of adolescents during the COVID-19 pandemic, but the exact nature of the effects is not known. The purpose of this study was to assess the psychological and lifestyle impact of the pandemic on Australian adolescents, using an online survey, administered during and after the peak of the outbreak (June-July 2020).

Method

Self-report surveys were administered online to a sample of 760 Australian adolescents aged 12-18 years old. Surveys assessed worry about contracting COVID-19, behavioral change in response to the pandemic, impact on education, peer and family relationships, lifestyle factors including exercise, technology use and sleep, as well as mental health outcomes including psychological distress, loneliness, health anxiety and wellbeing.

Results

Overall, young people expressed significant concern and worry about contracting the virus, and most (>85%) engaged in behaviors to reduce the risk of transmission. Three quarters of the sample reported a worsening of their mental health since the pandemic began, with negative impacts reported by most respondents on learning, friendships and family relationships. More than 40% of young people reported a decrease in exercise and 70% reported an increase in technology use since the outbreak. There were high levels of uncertainty about the future reported by respondents, and their scores on validated measures indicated higher levels of sleep disturbance, psychological distress and health anxiety, and lower levels of wellbeing, relative to normative samples. Reponses on the Kessler Psychological Distress Scale indicated that 48.3% of the sample were experiencing distress consistent with a probable mental illness, which is much higher than pre-pandemic prevalence rates. Effects on mental health were worse among those who reported a previous diagnosis of depression and/or anxiety relative to those without a history of depression and/or anxiety.

Conclusion

These results indicate high levels of disruption and psychological distress experienced by adolescents during the current COVID-19 pandemic. Adolescents are already vulnerable to the onset of mental illness at this developmental stage, and the current research underscores the need to find rapid and accessible ways to support adolescent mental health during times of crisis. There is a need for longitudinal research to evaluate the enduring effects of the pandemic on adolescents.
Functionalized TiO2 nanotube-based Electrochemical Biosensor for Rapid Detection of SARS-CoV-2
Authors: Vadlamani B.S. , Uppal T. , Verma S.C. , Misra M.
Published: September 2020

The COronaVIrus Disease (COVID-19) is a newly emerging viral disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Rapid increase in the number of COVID-19 cases worldwide led the WHO declare pandemic within a few month after the first case of infection. Due to the lack of a prophylactic measure to control the virus infection and spread, early diagnosis and quarantining of infected as well as the asymptomatic individuals are necessary for the containment of this pandemic. However, the current methods for SARS-CoV-2 diagnosis are expensive and time consuming although some promising and inexpensive technologies are coming out for emergency use. In this work, we report the synthesis of a cheap yet highly sensitive cobalt-functionalized TiO2 nanotubes (Co-TNTs)-based electrochemical biosensor and its efficacy for rapid detection of spike glycoprotein of SARS-CoV-2 by examining S-RBD protein as the reference material. A simple, low-cost, and one-step electrochemical anodization route was used to synthesize TNTs, followed by an incipient wetting method for cobalt functionalization of the TNTs platform, which is connected to a potentiostat for data collection. This sensor specifically detected the S-RBD protein of SARS-CoV-2 even at very low concentration (range of 14 nM to 1400 nM). Additionally, our sensor showed a linear response in the detection of viral protein with concentration range. In summary, our Co-TNT sensor is highly effective in detecting SARS-CoV-2 S-RBD protein in approximately 30 seconds, which can be explored for developing a point of care diagnostics for rapid detection of SARS-CoV-2 in nasal secretions and saliva samples.

AUTHOR SUMMARY

SARS-COV-2 is currently a global pandemic on a scale that has not been experienced since the Spanish flu of 1918. One of the reasons why this pandemic virus has spread so quickly is because many infected individuals with SARS-CoV-2 remain asymptomatic and involuntarily transmit the virus before they come down with the symptoms. Therefore, uniform surveillance and quarantining of infected as well as the asymptomatic individuals could provide an effective measure to contain the spread of SARS-CoV-2. However, the current methods for SARS-CoV-2 diagnosis are expensive and time consuming although some inexpensive technologies are getting approvals for emergency use. Our manuscript reports the synthesis of a cheap yet highly sensitive cobalt-functionalized TiO2 nanotubes (Co-TNTs)-based electrochemical biosensor for rapid detection of spike glycoprotein of SARS-CoV-2. Our sensor is synthesized through one-step electrochemical anodization route, followed by an incipient wetting method for cobalt functionalization of TNTs platform. The readout of this sensor is an electrochemical signal collected through a potentiostat, which can be adopted for use through smartphone applications and the development of a point of care diagnostics for COVID-19.
Histone demethylase Lsd1 is required for the differentiation of neural cells in the cnidarianNematostella vectensis
Authors: Gahan James M , Kouzel Ivan U. , Rentzsch Fabian
Published: September 2020

The evolution of multicellularity was accompanied by the emergence of processes to regulate cell fate, identity and differentiation in a robust and faithful manner. Chromatin regulation has emerged as a key process in development and yet its contribution to the evolution of such processes is largely unexplored. Chromatin is regulated by a diverse set of proteins, which themselves are tightly regulated in order to play cell/ tissue-specific functions. Using the cnidarianNematostella vectensis, a model for basal metazoans, we explore the function of one such chromatin regulator, Lysine specific demethylase 1 (Lsd1). We generated an endogenously tagged allele and show that the expression of NvLsd1 is developmentally regulated and higher in differentiated neural cells than their progenitors. We further show, using a CRISPR/Cas9 generated mutant that loss ofNvLsd1leads to several distinct developmental abnormalities. Strikingly,NvLsd1loss leads to the almost complete loss of differentiated cnidocytes, cnidarian-specific neural cells, which we show to be the result of a cell-autonomous requirement forNvLsd1. Together this suggests that complex regulation of developmental processes by chromatin modifying proteins predates the split of the cnidarian and bilaterian lineages, approximately 600 million years ago, and may constitute an ancient feature of animal development.
Visual cortex cTBS increases mixed percept duration while a-tDCS has no effect on binocular rivalry
Authors: Abuleil Dania , McCulloch Daphne , Thompson Benjamin
Published: September 2020

Neuromodulation of the primary visual cortex using anodal transcranial direct current stimulation (a-tDCS) can alter visual perception and enhance neuroplasticity. However, the mechanisms that underpin these effects are currently unknown. When applied to the motor cortex, a-tDCS reduces the concentration of the inhibitory neurotransmitter gamma aminobutyric acid (GABA), an effect that has been linked to increased neuroplasticity. The aim of this study was to assess whether a-tDCS also reduces GABA-mediated inhibition when applied to the human visual cortex. Changes in visual cortex inhibition were measured using the mixed percept duration in binocular rivalry. Binocular rivalry mixed percept duration has recently been advocated as a direct and sensitive measure of visual cortex inhibition whereby GABA agonists decrease mixed percept durations and agonists of the excitatory neurotransmitter acetylcholine increase them. Our hypothesis was that visual cortex a-tDCS would increase mixed percept duration by reducing GABA-mediated inhibition and increasing cortical excitation. In addition, we measured the effect of continuous theta-burst transcranial magnetic stimulation (cTBS) of the visual cortex on binocular rivalry dynamics. When applied to the motor or visual cortex, cTBS increases GABA concentration and we therefore hypothesized that visual cortex cTBS would decrease the mixed percept duration. Binocular rivalry dynamics were recorded before and after active and sham a-tDCS (N=15) or cTBS (N=15). Contrary to our hypotheses, a-tDCS had no effect, whereas cTBS significantly increased mixed percepts during rivalry. These results suggest that the neurochemical mechanisms of a-tDCS may differ between the motor and visual cortices.
TAZ-CAMTA1 and YAP-TFE3 modulate the basal TAZ/YAP transcriptional program by recruiting the ATAC histone acetyltransferase complex
Authors: Merritt Nicole , Garcia Keith , Rajendran Dushyandi , Lin Zhen-Yuan , Zhang Xiaomeng , Mitchell Katrina M. , Borcherding Nicholas , Fullenkamp Colleen , Chimenti Michael , Gingras Anne-Claude , Harvey Kieran F. , Tanas Munir R.
Published: September 2020

Epithelioid hemangioendothelioma (EHE) is a vascular sarcoma that metastasizes early and lacks an effective medical therapy. The TAZ-CAMTA1 and YAP-TFE3 fusion proteins are chimeric transcription factors and initiating oncogenic drivers of EHE. A combined proteomic/genetic screen identified YEATS2 and ZZZ3, components of theAda2a-containing histone acetyltransferase (ATAC) complex, as key interactors of both TAZ-CAMTA1 and YAP-TFE3 despite the dissimilarity of the C terminal fusion partners CAMTA1 and TFE3. An integrative next generation sequencing approach showed the fusion proteins drive expression of a unique transcriptome distinct from TAZ and YAP by simultaneously hyperactivating a TEAD-based transcriptional program and modulating the chromatin environment via interaction with the ATAC complex. Interaction of the ATAC complex with both TAZ-CAMTA1 and YAP-TFE3 indicates the histone acetyltransferase complex is an oncogenic driver in EHE and potentially other sarcomas. Furthermore, the ATAC complex is an enzymatic transcriptional cofactor required for both fusion proteins in EHE, representing a unifying therapeutic target for this sarcoma. Gene fusions are the most common genetic alterations activating TAZ and YAP in cancer, and this study serves as a template for identifying epigenetic modifiers recruited by the C terminal fusion partners of other TAZ/YAP gene fusions occurring in gliomas, carcinomas, and other sarcomas.

TAZ-CAMTA1 and YAP-TFE3 alter the TAZ/YAP transcriptional program by recruiting the ATAC complex and modifying the chromatin landscape.
UVA radiation could be a significant contributor to sunlight inactivation of SARS-CoV-2
Authors: Luzzatto-Fegiz Paolo , Temprano-Coleto Fernando , Peaudecerf François J. , Landel Julien R. , Zhu Yangying , McMurry Julie A.
Published: September 2020

Past experiments demonstrated SARS-CoV-2 inactivation by simulated sunlight; models have considered exclusively mechanisms involving UVB acting directly on RNA. However, UVA inactivation has been demonstrated for other enveloped RNA viruses, through indirect mechanisms involving the suspension medium. We propose a model combining UVB and UVA inactivation for SARS-CoV-2, which improves predictions by accounting for effects associated with the medium. UVA sensitivities deduced for SARS-CoV-2 are consistent with data for SARS-CoV-1 under UVA only. This analysis calls for experiments to separately assess effects of UVA and UVB in different media, and for including UVA in inactivation models.

Lay summary

Recent experiments have demonstrated that SARS-CoV-2 is inactivated by simulated sunlight; however, there are still many unknowns, including the mechanism of action and which part of the light spectrum is principally responsible. Our analysis indicates the need for targeted experiments that can separately assess the effects of UVA and UVB on SARS-CoV-2, and that sunlight inactivation models may need to be expanded to also include the effect of UVA. A first UVA-inclusive model is also proposed here. These findings have implications for how to improve the safety of the built environment, and for the seasonality of COVID-19.
Quinolone resistance in different uropathogens isolated from urine cultures in patients with urinary tract infection
Authors: Villegas Jorge Angel Almeida , Carrillo Iris Mellolzy Estrada , Contreras Rodolfo Garcia , Peña Silvia Patricia
Published: September 2020

Objective

To identify patterns of resistance against quinolones in various uropathogens in urinary tract infections in the population of the Toluca valley, Mexico

Introduction

Quinolones are antibiotics with a spectrum of activity for both gram-positives and gram-negatives and are antibiotics used for the empirical treatment of urinary tract infections. Recently, a high index of resistance to quinolones has been reported due to different mechanisms on the part of bacteria, however the one that has taken the greatest importance is the presence of extended spectrum beta-lactamases

Methods

155 samples were collected from patients with suspected urinary tract infection without exclusion criteria such as age or gender. Automated equipment was used for the identification of the etiological agent and sensitivity tests to quinolones.

Results

The results positives were divided to evaluate which of the two antibiotics studied had greater resistance. For ciprofloxacin there are 27 resistant strains 37%, 1 strain with intermediate resistance 1% and 45 susceptible strains 62%. For levofloxacin 26 strains are resistant 36%, 41 strains are sensitive 56% and 6 strains show intermediate sensitivity 8%.

Conclusion

Different microorganisms, both gram-positive and gram-negative, were isolated and it can be observed that gram-negative strains are the ones with the greatest resistance against quinolones, mainlyEscherichia coli, which produces extended-spectrum beta-lactamases, in the case of gram-positive resistance patterns are variable with a tendency towards sensitivity.
Bacteriophage uptake by Eukaryotic cell layers represents a major sink for phages during therapy
Authors: Bichet Marion C. , Chin Wai Hoe , Richards William , Lin Yu-Wei , Avellaneda-Franco Laura , Hernandez Catherine A. , Oddo Arianna , Chernyavskiy Oleksandr , Hilsenstein Volker , Neild Adrian , Li Jian , Voelcker Nicolas Hans , Patwa Ruzeen , Barr Jeremy J.
Published: September 2020

For over 100 years, bacteriophages have been known as viruses that infect bacteria. Yet it is becoming increasingly apparent that bacteriophages, or phages for short, have tropisms outside their bacterial hosts. During phage therapy, high doses of phages are directly administered and disseminated throughout the body, facilitating broad interactions with eukaryotic cells. Using live cell imaging across a range of cell lines we demonstrate that cell type plays a major role in phage internalisation and that smaller phages (< 100 nm) are internalised at higher rates. Uptake rates were validated under physiological shear stress conditions using a microfluidic device that mimics the shear stress to which endothelial cells are exposed to in the human body. Phages were found to rapidly adhere to eukaryotic cell layers, with adherent phages being subsequently internalised by macropinocytosis and functional phages accumulating and stably persisting intracellularly. Finally, we incorporate these results into an established pharmacokinetic model demonstrating the potential impact of phage accumulation by these cell layers, which represents a major sink for circulating phages in the body. Understanding these interactions will have important implications on innate immune responses, phage pharmacokinetics, and the efficacy of phage therapy.
The combination of Bromelain and Acetylcysteine (BromAc) synergistically inactivates SARS-CoV-2
Authors: Akhter Javed , Quéromès Grégory , Pillai Krishna , Kepenekian Vahan , Badar Samina , Mekkawy Ahmed H. , Frobert Emilie , Valle Sarah J , Morris David L.
Published: September 2020

Background and objectives

SARS-CoV-2 infection is the cause of a worldwide pandemic, currently with limited therapeutic options. Whilst vaccines are at the forefront of the therapeutic initiative, drug repurposing remains a promising approach for SARS-CoV-2 treatment. BromAc (Bromelain & Acetylcysteine) has synergistic action against glycoproteins by the synchronous breakage of glycosidic linkages and disulfide bonds. The spike protein of SARS-CoV-2, formed of glycoprotein and disulfide bridges for stabilization, represents an attractive target as it is essential for binding to the ACE2 receptor in host cells present in nasal mucosa. We sought to determine the effect of BromAc on the Spike and Envelope proteins and its potential to reduce infectivity in host cells.

Design

Recombinant Spike and Envelope proteins were treated by single agent and combination BromAc at 50 and 100 µg/20mg/mL and analyzed by electrophoresis. Ultraviolet analysis of disulfide bond reduction was performed for both Spike and Envelope proteins after treatment with Acetylcysteine. In vitro whole virus culture inactivation of pre-treated wild type and an S1/S2 Spike mutant SARS-CoV-2 with BromAc from 25 to 250 µg/20mg/mL was measured by cytopathic effect, cell lysis assay, and replication capacity by RT-PCR.

Results

Recombinant Spike and Envelope SARS-CoV-2 proteins were fragmented by BromAc at both 50 and 100 µg/20mg/mL whilst single agents had minimal effect. Spike and Envelope protein disulfide bonds were reduced by Acetylcysteine. In vitro whole virus culture of both wild type and Spike mutant SARS-CoV-2 demonstrated a concentration-dependent inactivation from BromAc treatment but not from single agents.

Conclusion

BromAc disintegrates SARS-CoV-2 Spike and Envelope proteins. In vitro tests on whole virus support this finding with inactivation of its replication capacity most strongly at 100 and 250 µg/20mg/mL BromAc, even in Spike mutant virus. Clinical testing through nasal administration in patients with early SARS-CoV-2 infection is imminent.

Author Summary

There is currently no suitable therapeutic treatment for early SARS-CoV-2 aimed to prevent disease progression. BromAc is under clinical development by the authors for mucinous cancers due to its ability to alter complex glycoproteins structure. The potential of BromAc on SARS-CoV-2 Spike and Envelope glycoproteins stabilized by disulfide bonds was examined and found to disintegrate recombinant Spike and Envelope proteins whilst reducing disulfide stabilizer bridges. BromAc also showed an inhibitory effect on wild-type and Spike mutant SARS-CoV-2 by inactivation of its replication capacity in vitro. Hence, BromAc may be an effective therapeutic agent for early SARS-CoV-2 infection, despite mutations, and even have potential as a prophylactic in people at high risk of infection.
The role of NIH funding in vaccine readiness; foundational research and NIH funding underlying candidate SARS-CoV-2 vaccines
Authors: Kiszewski Anthony E , Cleary Ekaterina Galkina , Jackson Matthew J , Ledley Fred D
Published: September 2020

This work characterizes the NIH contribution to vaccine technologies being employed in “warp speed” development of vaccines for COVID-19, as well as the lack of sustained NIH funding for published research against recognized epidemic threats. Using quantitative methods, we examined the advance of published research on ten of the vaccine technologies incorporated in the 165 candidate vaccines entering development through July 2020 as well as the NIH funding that supported this research. Live, attenuated virus, inactivated virus, and adjuvant technologies have been used in successful products since the 1950s and continue to exhibit steady advance. Synthetic (recombinant) vaccines, viral vectors, DNA, and TLR9 agonists as adjuvants emerged since the 1980s, and exhibit a logistic, “S-curve” pattern of growth characteristic of emerging technologies that have passed an analytically-definedestablishedpoint. In contrast, mRNA, virus-like particle, and nanoparticle technologies show exponential growth characteristic of technologies short of theirestablishedpoints. The body of research and NIH funding for established and emerging vaccine technologies exhibited sustained growth through the late 2010s, supported by > 16,000 project years of NIH funding totaling over $17.2 billion (2000–2019), the majority through cooperative agreements and intramural programs. NIH funding for published research on vaccines for recognized zoonotic threats including coronavirus, Zika, Ebola, and dengue, however, has been inconsistent and reactive to disease outbreaks. These data are considered in the context of the high failure rate for candidate vaccines and evidence that technological maturity is a significant factor in the efficiency of product development. Sustained funding for both enabling technologies and vaccine development is essential to ensure a rapid response to COVID and future pandemic threats.

SIGNIFICANCE STATEMENT

This work examines the advance of research and NIH funding for technologies being employed in “warp speed” development of COVID-19 vaccines in the context of evidence that mature technologies have a greater likelihood of generating successful products. We show that candidate vaccines for COVID-19 employ a variety of established and still-emerging technologies, and identify $17.2 billion in NIH funding for this research from 2000–2019. In contrast, NIH funding for published research for vaccines on recognized pandemic threats has been inconsistent. This work highlights the significance and scale of the NIH contribution to vaccine technologies and the lack of sustained initiatives for vaccine development.
Sweetspot mapping in deep brain stimulation: Strengths and limitations of current approaches
Authors: Dembek Till A. , Baldermann Juan Carlos , Petry-Schmelzer Jan-Niklas , Jergas Hannah , Treuer Harald , Visser-Vandewalle Veerle , Dafsari Haidar S. , Barbe Michael T.
Published: September 2020

Objective

Open questions remain regarding the optimal target, or sweetspot, for deep brain stimulation (DBS) in e.g. Parkinson’s Disease. Previous studies introduced different methods of mapping DBS effects to determine sweetspots. While having a direct impact on surgical targeting and postoperative programming in DBS, these methods so far have not been investigated in ground-truth data.

Materials & Methods

This study investigated five previously published DBS mapping methods regarding their potential to correctly identify a ground-truth sweetspot. Methods were investigated in silico in eight different use-case scenarios, which incorporated different types of clinical data, noise, and differences in underlying neuroanatomy. Dice-coefficients were calculated to determine the overlap between identified sweetspots and the ground-truth. Additionally, out-of-sample predictive capabilities were assessed using the amount of explained variance R2.

Results

The five investigated methods resulted in highly variable sweetspots. Methods based on voxel-wise statistics against average outcomes showed the best performance overall. While predictive capabilities were high, even in the best of cases Dice-coefficients remained limited to values around 0.5, highlighting the overall limitations of sweetspot identification.

Conclusions

This study highlights the strengths and limitations of current approaches to DBS sweetspot mapping. Those limitations need to be taken into account when considering the clinical implications. All future approaches should be investigated in silico before being applied to clinical data.
Patterns of age disparities in colon and lung cancer survival: a systematic narrative literature review
Authors: Pilleron Sophie , Gower Helen , Janssen-Heijnen Maryska , Signal Virginia , Gurney Jason , Morris Eva JA , Cunningham Ruth , Sarfati Diana
Published: September 2020

Objective

To identify patterns of age disparities in cancer survival, using colon and lung cancer as exemplars.

Methods

We conducted a systematic review of literature published in EMBASE, MEDLINE, Scopus, and Web of Science according to PRISMA guidelines. We included population-based studies in patients with colon or lung cancer. We assessed the quality of included studies against selected evaluation domains from the QUIPS Tool, and items concerning statistical reporting. We evaluated age disparities using the absolute difference in survival or mortality rates between middle-aged group and the oldest age group, or by describing survival curves.

Results

Out of 2,162 references reviewed, we retained 35 studies (15 for colon, 18 for lung, 2 for both sites). Regardless of the cancer site, included studies were highly heterogeneous and often of poor quality. The magnitude of age disparities in survival varied greatly by sex, ethnicity, socio-economic status, stage at diagnosis, cancer site and morphology, the number of nodes examined, and by treatment strategy. Although results were inconsistent for most characteristics, we consistently observed greater age disparities for females with lung cancer compared to males. Also, age disparities increased with more advanced stages for colon cancer, and decreased with more advanced stages for lung cancer.

Conclusions

Although age is one of the most important prognostic factors in cancer survival, age disparities in colon and lung cancer survival have so far been understudied in population-based research. Further studies are needed to better understand age disparities in colon and lung cancer survival. (PROSPERO registration number: CRD42020151402).

Article Summary

Strengths and limitations of this study

For the first time, we conducted a systematic review of population-based studies relating to differences in cancer survival between middle-aged and older patients, using colon and lung cancer as exemplar cancers.

We limited our search to peer-reviewed original articles and letters to Editors published in English up until 30 September 2019.

We excluded clinical studies and trials because of the strict selection of patients and the common underrepresentation of older patients in these studies.

We could not conduct any quantitative analysis (such as meta-analysis) because of the vast heterogeneity of studies included, which prevented us from quantifying the relationship between increasing age and cancer survival.
Comparative evaluation of six immunoassays for the detection of antibodies against SARS-CoV-2
Authors: Pérez-García Felipe , Pérez-Tanoira Ramón , Esther Iglesias María , Romanyk Juan , Arroyo Teresa , Gómez-Herruz Peña , González Rosa , Cuadros-González Juan
Published: September 2020

Objectives:

Serologic techniques can serve as a complement to diagnose SARS-CoV-2 infection. The objective of our study was to compare the diagnostic performance of six immunoassays to detect antibodies against SARS-CoV-2: three lateral flow immunoassays (LFAs), one ELISA and two chemiluminescence assays (CLIAs).

Methods:

We evaluated three LFAs (Alltest, One Step and SeroFlash), one ELISA (Dia.Pro) and 34 two CLIAs (Elecsys and COV2T). To assess the specificity, 60 pre-pandemic sera were 35 used. To evaluate the sensitivity, we used 80 serum samples from patients with 36 positive PCR for SARS-CoV-2. Agreement between techniques was evaluated using the kappa score (k).

Results

All immunoassays showed a specificity of 100% except for SeroFlash (96.7%). Overall sensitivity was 61.3%, 73.8%, 67.5%, 85.9%, 88.0% and 92.0% for Alltest, One Step, SeroFlash, Dia.Pro, Elecsys and COV2T, respectively. Sensitivity increased throughout the first two weeks from the onset of symptoms, reaching sensitivities over 85% from 14 days for all LFAs, being One Step the most sensitive (97.6%), followed by SeroFlash (95.1%). Dia.Pro, Elecsys and COV2T showed sensitivities over 97% from 14 days, being 100% for COV2T. One Step showed the best agreement results among LFAs, showing excellent agreement with Dia.Pro (agreement=94.2%, k=0.884), COV2T (99.1%, k=0.981) and Elecsys (97.3%, k=0.943). Dia.Pro, COV2T and Elecsys also showed excellent agreement between them.

Conclusion

One Step, Dia.Pro, Elecsys and COV2T obtained the best diagnostic performanc e results. All these techniques showed a specificity of 100% and sensitivities over 97% from 14 days after the onset of symptoms, as well as excellent levels of agreement.
Systematic profiling of SARS-CoV-2 specific IgG epitopes at single amino acid resolution
Authors: Qi Huan , Ma Ming-liang , Jiang He-wei , Ling Jian-ya , Chen Ling-yun , Zhang Hai-nan , Lai Dan-yun , Li Yang , Guo Zi-wen , Hu Chuan-sheng , Guo Shu-Juan , Meng Qing-feng , Ren Yan , Wang Wei , Yang Xiao , Zhou Jie , Zhao Xiao-dong , Li Hua , Tao Sheng-ce
Published: September 2020

SARS-CoV-2 specific IgG responses play critical roles for patients to recover from COVID-19, in-depth dissecting of the IgG responses on systems level is of great interest. Herein, we adopted a newly developed high-throughput epitope mapping technology (AbMap), analyzed 55 COVID-19 convalescent sera and 226 antibody samples enriched by specific proteins or peptides from these sera. We revealed three areas that are rich of IgG epitopes, two are on Spike protein but outside of RBD, and one is on Nucleocapsid protein. We identified 29 significant epitopes on Spike protein, from two of these significant epitopes, two critical epitope residues were found,i. e., D936 and P1263, which are highly related to the infectivity of SARS-CoV-2 In summary, we provided the first global map of IgG binding epitopes for SARS-CoV-2 at single amino acid resolution. This map will facilitate the precise development of therapeutic antibodies and vaccines.

HIGHLIGHTS

A map of SARS-CoV-2 specific IgG binding epitopes at single amino acid resolution

Two areas outside of RBD that are rich of significant epitopes were identified

One area rich of significant epitopes was determined on Nucleocapsid protein

Two critical epitope residues (D936 and P1263) on Spike protein are highly related to the infectivity of SARS-CoV-2
First report on the Latvian SARS-CoV-2 isolate genetic diversity
Authors: Zrelovs Nikita , Ustinova Monta , Silamiķelis Ivars , Birzniece Līga , Megnis Kaspars , Rovīte Vita , Freimane Lauma , Silamiķele Laila , Ansone Laura , Pjalkovskis Jānis , Fridmanis Dāvids , Vilne Baiba , Priedīte Marta , Caica Anastasija , Gavars Mikus , Perminovs Dmitrijs , Storoženko Jeļena , Savicka Oksana , Dimiņa Elīna , Dumpis Uga , Kloviņš Jānis
Published: September 2020

Remaining a major healthcare concern with nearly 29 million confirmed cases worldwide at the time of writing, novel severe acute respiratory syndrome coronavirus - 2 (SARS-CoV-2) has caused more than 920 thousand deaths since its outbreak in China, December 2019. First case of a person testing positive for SARS-CoV-2 infection within the territory of the Republic of Latvia was registered on 2ndof March 2020, nine days prior to the pandemic declaration by WHO. Since then, more than 277 000 tests were carried out confirming a total of 1464 cases of COVID-19 in the country as of 12thof September 2020. Rapidly reacting to the spread of the infection, an ongoing sequencing campaign was started mid-March in collaboration with the local testing laboratories, with an ultimate goal in sequencing as much local viral isolates as possible, resulting in first full-length SARS-CoV-2 isolate genome sequences from the Baltics region being made publicly available in early April. With 133 viral isolates representing ∼9.1% of the total COVID-19 cases in the country being completely sequenced as of today, here we provide a first report on the genetic diversity of Latvian SARS-CoV-2 isolates.
COVID-19 Transmission Dynamics and Effectiveness of Public Health Interventions in New York City during the 2020 Spring Pandemic Wave
Authors: Yang Wan , Shaff Jaimie , Shaman Jeffrey
Published: September 2020

New York City experienced a large COVID-19 pandemic wave during March – May 2020. We model the transmission dynamics of COVID-19 in the city during the pandemic and estimate the effectiveness of public health interventions (overall and for each major intervention separately) for the entire population and by age group. We estimate that the overall effective reproductive number was 2.99 at the beginning of the pandemic wave and reduced to 0.93 one week after the stay-at-home mandate. Most age groups experienced similar reductions in transmission. Interventions reducing contact rates were associated with a 70.7% (95% CI: 65.0 – 76.4%) reduction of transmission overall and > 50% for all age groups during the pandemic. Face covering was associated with a 6.6% (95% CI: 0.8 – 12.4%) reduction of transmission overall and up to 20% for 65+ year-olds during the first month of implementation. Accounting for the amount of time masks are in use (i.e. mainly outside homes), these findings indicate universal masking could reduce transmission by up to 28-32% when lockdown-like measures are lifted, if the high effectiveness estimated for older adults were achieved for all ages. These estimates are verified by out-of-fit projections and support the need for implementing multiple interventions simultaneously in order to effectively mitigate the spread of COVID-19.
A prefusion SARS-CoV-2 spike RNA vaccine is highly immunogenic and prevents lung infection in non-human primates
Authors: Vogel Annette B. , Kanevsky Isis , Che Ye , Swanson Kena A. , Muik Alexander , Vormehr Mathias , Kranz Lena M. , Walzer Kerstin C. , Hein Stephanie , Güler Alptekin , Loschko Jakob , Maddur Mohan S. , Tompkins Kristin , Cole Journey , Lui Bonny G. , Ziegenhals Thomas , Plaschke Arianne , Eisel David , Dany Sarah C. , Fesser Stephanie , Erbar Stephanie , Bates Ferdia , Schneider Diana , Jesionek Bernadette , Sänger Bianca , Wallisch Ann-Kathrin , Feuchter Yvonne , Junginger Hanna , Krumm Stefanie A. , Heinen André P. , Adams-Quack Petra , Schlereth Julia , Kröner Christoph , Hall-Ursone Shannan , Brasky Kathleen , Griffor Matthew C. , Han Seungil , Lees Joshua A. , Mashalidis Ellene H. , Sahasrabudhe Parag V. , Tan Charles Y. , Pavliakova Danka , Singh Guy , Fontes-Garfias Camila , Pride Michael , Scully Ingrid L. , Ciolino Tara , Obregon Jennifer , Gazi Michal , Carrion Ricardo , Alfson Kendra J. , Kalina Warren V. , Kaushal Deepak , Shi Pei-Yong , Klamp Thorsten , Rosenbaum Corinna , Kuhn Andreas N. , Türeci Özlem , Dormitzer Philip R. , Jansen Kathrin U. , Sahin Ugur
Published: September 2020

To contain the coronavirus disease 2019 (COVID-19) pandemic, a safe and effective vaccine against the new severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is urgently needed in quantities sufficient to immunise large populations. In this study, we report the design, preclinical development, immunogenicity and anti-viral protective effect in rhesus macaques of the BNT162b2 vaccine candidate. BNT162b2 contains an LNP-formulated nucleoside-modified mRNA that encodes the spike glycoprotein captured in its prefusion conformation. After expression of the BNT162b2 coding sequence in cells, approximately 20% of the spike molecules are in the one-RBD ‘up’, two-RBD ‘down’ state. Immunisation of mice with a single dose of BNT162b2 induced dose level-dependent increases in pseudovirus neutralisation titers. Prime-boost vaccination of rhesus macaques elicited authentic SARS-CoV-2 neutralising geometric mean titers 10.2 to 18.0 times that of a SARS-CoV-2 convalescent human serum panel. BNT162b2 generated strong TH1 type CD4+and IFNγ+CD8+T-cell responses in mice and rhesus macaques. The BNT162b2 vaccine candidate fully protected the lungs of immunised rhesus macaques from infectious SARS-CoV-2 challenge. BNT162b2 is currently being evaluated in a global, pivotal Phase 2/3 trial (NCT04368728).
CTCF knockout in zebrafish induces alterations in regulatory landscapes and developmental gene expression
Authors: Franke Martin , De la Calle-Mustienes Elisa , Neto Ana , Acemel Rafael D. , Tena Juan J. , Santos-Pereira José M. , Gómez-Skarmeta José L.
Published: September 2020

CTCF is an 11-zinc-finger DNA-binding protein that acts as a transcriptional repressor and insulator as well as an architectural protein required for 3D genome folding1–5. CTCF mediates long-range chromatin looping and is enriched at the boundaries of topologically associating domains, which are sub-megabase chromatin structures that are believed to facilitate enhancer-promoter interactions within regulatory landscapes6–12. Although CTCF is essential for cycling cells and developing embryos13,14, itsin vitroremoval has only modest effects over gene expression5,15, challenging the concept that CTCF-mediated chromatin interactions and topologically associated domains are a fundamental requirement for gene regulation16–18. Here we link the loss of chromatin structure and gene regulation in anin vivomodel and during animal development. We generated actcfknockout mutant in zebrafish that allows us to monitor the effect of CTCF loss of function during embryo patterning and organogenesis. CTCF absence leads to loss of chromatin structure in zebrafish embryos and affects the expression of thousands of genes, including many developmental genes. In addition, chromatin accessibility, both at CTCF binding sites andcis-regulatory elements, is severely compromised inctcfmutants. Probing chromatin interactions from developmental genes at high resolution, we further demonstrate that promoters fail to fully establish long-range contacts with their associated regulatory landscapes, leading to altered gene expression patterns and disruption of developmental programs. Our results demonstrate that CTCF and topologically associating domains are essential to regulate gene expression during embryonic development, providing the structural basis for the establishment of developmental gene regulatory landscapes.