bluuebunny/crossref_metadata_2025 huggingface dataset:
MDM2 Inhibition in Combination with Endocrine Therapy and CDK4/6 Inhibition for the Treatment of ER-Positive Breast Cancer
Authors: Portman Neil , Milioli Heloisa H. , Alexandrou Sarah , Coulson Rhiannon , Yong Aliza , Fernandez Kristine J. , Chia Kee Ming , Segara Davendra , Parker Andrew , Haupt Sue , Haupt Ygal , Tilley Wayne D. , Swarbrick Alex , Caldon C. Elizabeth , Lim Elgene
Published: June 2020

Background

Resistance to endocrine therapy is a major clinical challenge in the management of estrogen receptor (ER)-positive breast cancer. In this setting p53 is frequently wildtype and its activity may be suppressed via upregulation of its key regulator MDM2. This underlies our rationale to evaluate MDM2 inhibition as a therapeutic strategy in treatment resistant ER-positive breast cancer.

Methods

We used the MDM2 inhibitor NVP-CGM097 to treatin vitroandin vivomodels alone and in combination with fulvestrant or palbociclib. We perform cell viability, cell cycle, apoptosis and senescence assays to evaluate antitumor effects in p53 wildtype and p53 mutant ER positive cell lines (MCF-7, ZR75-1, T-47D) and MCF-7 lines resistant to endocrine therapy and to CDK4/6 inhibition. We further assess the drug effects in patient-derived xenograft (PDX) models of endocrine-sensitive and -resistant ER positive breast cancer.

Results

We demonstrate that MDM2 inhibition results in cell cycle arrest and increased apoptosis in p53-wildtypein vitroandin vivobreast cancer models, leading to potent anti-tumour activity. We find that endocrine therapy or CDK4/6 inhibition synergises with MDM2 inhibition but does not further enhance apoptosis. Instead, combination treatments result in profound regulation of cell cycle-related transcriptional programmes, with synergy achieved through increased antagonism of cell cycle progression. Combination therapy pushes cell lines resistant to fulvestrant or palbociclib to become senescent and significantly reduces tumour growth in a fulvestrant resistant patient derived xenograft model.

Conclusions

We conclude that MDM2 inhibitors in combination with ER degraders or CDK4/6 inhibitors represent a rational strategy for treating advanced, endocrine resistant ER-positive breast cancer, operating through synergistic activation of cell cycle co-regulatory programs.
Extracellular DNA traps in a ctenophore demonstrate conserved immune cell behaviors in a non-bilaterian
Authors: Vandepas Lauren E. , Stefani Caroline , Domeier Phillip P. , Traylor-Knowles Nikki , Goetz Frederick W. , Browne William E. , Lacy-Hulbert Adam
Published: June 2020

The formation of extracellular DNA traps (ETosis) is a first response mechanism by specific immune cells following exposure to microbes1,2. Initially characterized in vertebrate neutrophils, cells capable of ETosis have been discovered recently in diverse non-vertebrate taxa3 4-6. To assess the conservation of ETosis between evolutionarily distant non-vertebrate phyla, we observed and quantified ETosis using the model ctenophoreMnemiopsis leidyiand the oysterCrassostrea gigas. Here we report that ctenophores – thought to have diverged very early from the metazoan stem lineage7-10– possess immune cell types capable of phagocytosis and ETosis. We demonstrate that bothMnemiopsisandCrassostreaimmune cells undergo ETosis after exposure to diverse microbes and chemical agents that stimulate ion flux. Our results support ETosis as an evolutionarily ancient metazoan defense against pathogens.
Dmp1Cre-directed knockdown of PTHrP in murine decidua is associated with increased bone width and a life-long increase in strength specific to male progeny
Authors: Ansari Niloufar , Isojima Tsuyoshi , Crimeen-Irwin Blessing , Poulton Ingrid J , McGregor Narelle E. , Ho Patricia W. M. , Kovacs Christopher S , Dimitriadis Evdokia , Gooi Jonathan H , Martin T. John , Sims Natalie A.
Published: June 2020

Parathyroid hormone related-protein (PTHrP) is a pleiotropic regulator of tissue homeostasis. In bone, knockdown in osteocytes byDmp1Cre-targeted deletion causes osteopenia and impaired strength. We report that this outcome depends on parental genotype. AdultDmp1Cre.Pthlhf/fmice from homozygous parents (Dmp1Cre.Pthlhf/f(hom)) have stronger bones, with 40% more trabecular bone mass and 30% greater femoral width than controls. At 12 days old, greater bone width was also found in male and femaleDmp1Cre.Pthlhf/f(hom)mice, but not in gene-matched mice from heterozygous parents, suggesting a maternal influence before weaning. Milk PTHrP levels were normal, but decidua from mothers ofDmp1Cre.Pthlhf/f(hom)mice were smaller, with low PTHrP levels. Moreover,Dmp1Cre.Pthlhf/f(hom)embryonic bone was more mineralized and wider than control. We conclude thatDmp1Creleads to gene recombination in decidua, and that decidual PTHrP influences decidual cell maturation and limits embryonic bone growth. This identifies a maternal-derived developmental origin of adult bone strength.
Whole Genome Sequencing of 5 Tibetan Sheep Breeds Identifies Selective Signatures to Adaptability at Different High-Altitude Areas in Qinghai-Tibetan Plateau
Authors: Li Lei-Lei , Ma Shi-Ke , Peng Wei , Fang You-Gui , Fu Hong-Yun , Jia Gong-Xue
Published: June 2020

Tibetan sheep is one of primitive Chinese sheep breeds, which achieved the divergence about 2500 years ago in Qinghai plateau region. According to different geographic conditions, especially altitudes, Tibetan sheep evolved into different breeds. In this study, we performed pooled whole genome resequencing of 125 individuals from 5 representative Tibetan sheep breeds. Comparative genomic analysis showed that they can be divided into different clades with a close genetic relationship. However, some genes with common selective regions were enriched for hypoxic adaptability in different breeds living at higher altitude, includingGHR, BMP15andCPLANE1. Furthermore, breed-specific selective regions about physical characteristics, especially wool growth, were found in genes such asBSND, USP24, NCAPGandLCORL. This study could contribute to our understanding about trait formation and offer a reference for breeding of Tibetan sheep.
An SNP variant MT1-MMP with a defect in its collagenolytic activity confers the fibrotic phenotype of Dupuytren’s Disease
Authors: Itoh Yoshifumi , Ng Michael , Wiberg Akira , Inoue Katsuaki , Hirata Narumi , Paiva Katiucia Batista Silva , Ito Noriko , Dzobo Kim , Sato Nanami , Gifford Valentina , Fujita Yasuyuki , Inada Masaki , Furniss Dominic
Published: June 2020

Dupuytren’s Disease (DD) is a common fibroproliferative disease of the palmar fascia. We previously identified a strong association with a non-synonymous variant (rs1042704, pD273N) inMMP14(encoding MT1-MMP). We investigated the functional consequences of this variant, and demonstrated that the variant MT1-MMP (MT1-N273) exhibits only 17% of cell surface collagenolytic activity compared to the ancestral enzyme (MT1-D273). Cells expressing both MT1-D273and MT1-N273in a 1:1 ratio, mimicking the heterozygous state, possess 38% of the collagenolytic activity compared to the cells expressing MT1-D273, suggesting that MT1-N273acts in a dominant negative manner. Consistent with this hypothesis, patient-derived DD myofibroblasts expressing MT1-N273demonstrated around 30% of full collagenolytic activity regardless of the heterozygous or homozygous state. 3D-molecular envelope modelling using small angle X-ray scattering demonstrated altered positioning of the catalytic domain within dimeric molecules. Taken together, our data suggest that rs1042704 directly contributes to the fibrotic phenotype of DD.
Chitosan induces plant hormones and defences in tomato root exudates
Authors: Suarez-Fernandez Marta , Marhuenda-Egea Frutos Carlos , Lopez-Moya Federico , Arnao Marino B. , Cabrera-Escribano Francisca , Nueda Maria Jose , Gunsé Benet , Lopez-Llorca Luis Vicente
Published: June 2020

In this work, we use electrophysiological and metabolomic tools to determine the role of chitosan as plant defence elicitor in soil for preventing or manage root pests and diseases sustainably. Root exudates include a wide variety of molecules that plants and root microbiota use to communicate in the rhizosphere. Tomato plants were treated with chitosan. Root exudates from plants were analysed at 3, 10, 20 and 30 days after planting (dap). We found, using High Performance Liquid Chromatography (HPLC) and Excitation Emission Matrix (EEM) fluorescence, that chitosan induces plant hormones, lipid signalling and defence compounds in tomato root exudates, including phenolics. High doses of chitosan induce membrane depolarization and affect membrane integrity.1H-NMR showed the dynamic of exudation, detecting the largest number of signals in 20 dap root exudates. Root exudates from plants irrigated with chitosan inhibit ca. 2-fold growth kinetics of the tomato root parasitic fungusFusarium oxysporumf. sp. radicis-lycopersici. and reduced ca. 1.5-fold egg hatching of the root-knot nematodeMeloidogyne javanica.

One-sentence summary

Chitosan depolarizes plasma membrane of root cells, causing the secretion of hormones, lipid signalling and plant defence compounds, including phenolics. These root exudates inhibit soil-borne pathogens.
GSTU7 affects growth performance and acts as an antagonist of oxidative stress induced by methyl viologen
Authors: Ugalde José Manuel , Lamig Liliana , Herrera-Vásquez Ariel , Fuchs Philippe , Müller-Schüssele Stefanie J. , Meyer Andreas J. , Holuigue Loreto
Published: June 2020

Plant glutathioneS-transferases (GSTs) are glutathione-dependent enzymes with versatile functions, mainly related to detoxification of electrophilic xenobiotics and peroxides. The Arabidopsis genome codes for 53 GSTs, divided into seven subclasses, however understanding of their precise functions is limited. A recent study showed that class II TGA transcription factors TGA2, TGA5 and TGA6 are essential for tolerance of UV-B-induced oxidative stress and that this tolerance is associated with an antioxidative function of cytosolic tau-class GSTUs. Specifically, TGA2 controls the expression of several GSTUs under UV-B light and constitutive expression of GSTU7 in thetga256triple mutant is sufficient to revert the UV-B-susceptible phenotype oftga256. To further study the function of GSTU7, we characterized its role in mitigation of oxidative damage caused by the herbicide methyl viologen (MV). Under non-stress conditions,gstu7null mutants were smaller than wild-type (WT) plants and delayed in the onset of the MV-induced antioxidative response, which led to accumulation of hydrogen peroxide and diminished seedling survival. Complementation ofgstu7by constitutively expressedGSTU7rescued these phenotypes. Furthermore, live monitoring of the glutathione redox potential in intact cells with the fluorescent probe Grx1-roGFP2 revealed thatGSTU7overexpression completely abolished the MV-induced oxidation of the cytosolic glutathione buffer compared to WT plants. GSTU7 was found to act as a glutathione peroxidase able to complement the lack of peroxidase-type GSTs in yeast. Together, these findings show that GSTU7 is crucial in the antioxidative response by limiting oxidative damage and thus protecting cells from oxidative stress.
Humans induce differential access to prey for large African carnivores
Authors: Mills Kirby L. , Harris Nyeema C.
Published: June 2020

Wildlife adaptively respond to human presence by adjusting their temporal niche, possibly modifying encounter rates among species and trophic dynamics that structure communities. Here we show that these human-induced modifications to behaviours are prolific among species and alter apex predators’ access to prey resources. We assessed human-induced changes to wildlife diel activity and consequential changes in predator-prey overlap using 11,954 detections of three apex predators and 13 ungulates across 21,430 trap-nights in West Africa. Over two-thirds of species altered their diel use in response to human presence, and ungulate nocturnal activity increased by 6.8%. Rather than traditional pairwise predator-prey comparisons, we considered spatiotemporally explicit predator access to a suite of prey resources to evaluate community-level trophic responses to human presence. Although leopard prey access was not affected, lion and hyena access to 3 prey species significantly increased when prey increased their nocturnal temporal niche to avoid humans. Ultimately, humans considerably altered the composition of available prey, with implications for prey selection, demonstrating how humans perturb ecological processes via behavioural modifications.
Navigating Chemical Space By Interfacing Generative Artificial Intelligence and Molecular Docking
Authors: Xu Ziqiao , Wauchope Orrette , Frank Aaron T.
Published: June 2020

Here we report the testing and application of a simple, structure-aware framework to design target-specific screening libraries for drug development. Our approach combines advances in generative artificial intelligence (AI) with conventional molecular docking to rapidly explore chemical spaceconditionedon the unique physiochemical properties of the active site of a biomolecular target. As a proof-of-concept, we used our framework to construct a focused library for cyclin-dependent kinase type-2 (CDK2). We then used it to rapidly generate a library specific to the active site of the main protease (Mpro) of the SARS-CoV-2 virus, which causes COVID-19. By comparing approved and experimental drugs to compounds in our library, we also identified six drugs, namely, Naratriptan, Etryptamine, Panobinostat, Procainamide, Sertraline, and Lidamidine, as possible SARS-CoV-2 Mprotargeting compounds and, as such, potential drug repurposing candidates. To complement the open-science COVID-19 drug discovery initiatives, we make our SARS-CoV-2 Mprolibrary fully accessible to the research community (https://github.com/atfrank/SARS-CoV-2).
Reovirus σ1 conformational flexibility modulates the efficiency of host cell attachment
Authors: Diller Julia R. , Halloran Sean R. , Koehler Melanie , dos Santos Natividade Rita , Alsteens David , Stehle Thilo , Dermody Terence S. , Ogden Kristen M.
Published: June 2020

Reovirus attachment protein σ1 is a trimeric molecule containing tail, body, and head domains. During infection, σ1 engages sialylated glycans and junctional adhesion molecule-A (JAM-A), triggering uptake into the endocytic compartment, where virions are proteolytically converted to infectious subvirion particles (ISVPs). Further disassembly allows σ1 release and escape of transcriptionally active reovirus cores into the cytosol. Electron microscopy has revealed a distinct conformational change in σ1 from a compact form on virions to an extended form on ISVPs. To determine the importance of σ1 conformational mobility, we used reverse genetics to introduce cysteine mutations that can crosslink σ1 by establishing disulfide bonds between structurally adjacent sites in the tail, body, and head domains. We detected phenotypic differences among the engineered viruses. A mutant with a cysteine pair in the head domain replicates with enhanced kinetics, forms large plaques, and displays increased avidity for JAM-A relative to the parental virus, mimicking properties of ISVPs. However, unlike ISVPs, particles containing cysteine mutations that crosslink the head domain uncoat and transcribe viral positive-sense RNA with kinetics similar to the parental virus and are sensitive to ammonium chloride. Together, these data suggest that σ1 conformational flexibility modulates the efficiency of reovirus host cell attachment.

IMPORTANCE

Nonenveloped virus entry is an incompletely understood process. For reovirus, the functional significance of conformational rearrangements in the attachment protein, σ1, that occur during entry and particle uncoating are unknown. We engineered and characterized reoviruses containing cysteine mutations that crosslink σ1 monomers in non-reducing conditions. We found that the introduction of a cysteine pair in the receptor-binding domain of σ1 yielded a virus that replicates with faster kinetics than the parental virus and forms larger plaques. Using functional assays, we found that crosslinking the σ1 receptor-binding domain modulates reovirus attachment but not uncoating or transcription. These data suggest that σ1 conformational rearrangements mediate the efficiency of reovirus host cell attachment.
Prevalence and Predictors of General Psychiatric Disorders and Loneliness during COVID-19 in the United Kingdom: Results from the Understanding Society UKHLS
Authors: Li Lambert Zixin , Wang Senhu
Published: June 2020

Despite ample research on the prevalence of specific psychiatric disorders during COVID-19, we know little about how the pandemic affects the general wellbeing of a wider population. The study investigates the prevalence and predictors of general psychiatric disorders measured by the 12-item General Health Questionnaire (GHQ-12) and frequency of loneliness during COVID-19 in the United Kingdom, a country heavily hit by the pandemic. We analyzed 15,530 respondents of the first large-scale, nationally representative survey of COVID-19 in a developed country, the first wave of Understanding Society COVID-19 Study. Results show that 29.2% of the respondents score 4 or more, the caseness threshold, on the general psychiatric disorder measure, and 35.86% of the respondents sometimes or often feel lonely. Regression analyses show that those who have or had COVID-19-related symptoms are more likely to develop general psychiatric disorders and are lonelier. Women and people in their 20s have higher risks of general psychiatric disorders and loneliness, while having a job and living with a partner are protective factors. This study showcases the general psychiatric disorders and loneliness of broader members of the society during COVID-19 and the underlying social disparities.
Cross-state variation in opioid use disorder among a privately insured nonelderly population in the United States
Authors: Jiang Bibo , Wang Li , Leslie Douglas
Published: June 2020

Background

Although cross-state variation of the opioid epidemic in the United States are well documented in general, little are known about the epidemic in privately insured individuals.

Objectives

To describe cross-state variation in Opioid Use Disorder (OUD) among privately insured individuals in the US for the years 2005-2015 and investigate demographic differences of OUD patients between a group of hard-hit states and the rest states.

Methods

The MarketScan® Commercial Claims and Encounters database was used to calculate prevalence of opioid use disorder for the 50 states in the US, respectively. We analyzed level and change of OUD prevalence in each state from 2005 to 2015 and identified the states which were affected most by the epidemic. One-sided exact fisher test was used to analyze demographic difference of the epidemic in the hard-hit states and the remaining states.

Results

Cross-state variations of the opioid epidemic among privately insured population were substantial, both in terms of severity and acceleration of the epidemic. Demographic patterns of the epidemic were similar across states. The 18-34 age group was the most affected group with the highest prevalence. The 55-64 group experienced the most rapid increase of OUD prevalence, especially in states that suffered most in the epidemic.

Conclusions

Results can assist policy makers to design better clinical and policy interventions on the opioid epidemic, especially on privately insured individuals. Drastic increase of OUD prevalence among the 55-64 group might indicate the need to improve prescription drug monitoring programs for chronic pain, especially in states more affected by the epidemic.
Group-level patterns emerge from individual speed as revealed by an extremely social robotic fish
Authors: Jolles Jolle W. , Weimar Nils , Landgraf Tim , Romanczuk Pawel , Krause Jens , Bierbach David
Published: June 2020

Understanding the emergence of collective behaviour has long been a key research focus in the natural sciences. Besides the fundamental role of social interaction rules, a combination of theoretical and empirical work indicates individual speed may be a key process that drives the collective behaviour of animal groups. Socially-induced changes in speed by interacting animals make it difficult to isolate the effects of individual speed on group-level behaviours. Here we tackled this issue by pairing guppies with a biomimetic robot. We used a closed-loop tracking and feedback system to let a robotic fish naturally interact with a live partner in real time, and programmed it to strongly copy and follow its partner’s movements while lacking any preferred movement speed or directionality of its own. We show that individual differences in guppies’ movement speed were highly repeatable and shaped key collective patterns: higher individual speeds resulted in stronger leadership, lower cohesion, higher alignment, and better temporal coordination in the pairs. By combining the strengths of individual-based models and observational work with state-of-the-art robotics, we provide novel evidence that individual speed is a key, fundamental process in the emergence of collective behaviour.
Medial entorhinal spike clusters carry more finely tuned spatial information than single spikes
Authors: Quinlan Leo. Richard , Tyree Susan. Margot , Munn Robert. Gordon. Keith.
Published: June 2020

Many cells within the entorhinal cortex (EC) fire relatively infrequently, with the majority of their spikes separated by many hundreds of milliseconds. However, most cells are seen to occasionally fire two, three, or more spikes in quick succession. Recent evidence has shown that, in EC grid cells, “burstier” cells; cells that fire more of their spikes in bursts, have more well defined spatial characteristics than cells that fire fewer bursts. However, there is evidence that the window for considering related spikes in MEC could be as long as 100ms. Here, we divide the spikes fired by single cells into single spikes and “clusters” of spikes occuring within 100ms. We show that these burst “clusters” of spikes fired by cells in MEC convey more finely tuned spatial and directional information than the numerically more common single spikes. In addition, we find that introducing environmental uncertainty decreases the ratio of clusters fired to single spikes. Most crucially, we find that although single spikes are less spatially precise than clusters, they are more temporally precise – these spikes are more closely entrained to LFP theta than clusters. These findings demonstrate that clusters of spikes in EC convey more specific information about space than single spikes, may reflect “certainty” about spatial position and direction, and may represent a different firing “mode” in which intraregional communication is less relevant than interregional traffic.
Intraspecific diversity loss in a predator species alters prey community structure and ecosystem functions
Authors: Raffard Allan , Cucherousset Julien , Montoya José M. , Richard Murielle , Acoca-Pidolle Samson , Poésy Camille , Garreau Alexandre , Santoul Frédéric , Blanchet Simon
Published: June 2020

Abstract

Loss in intraspecific diversity can alter ecosystem functions, but the underlying mechanisms are still elusive, and intraspecific biodiversity-ecosystem function relationships (iBEF) have been restrained to primary producers. Here, we manipulated genetic and functional richness of a fish consumer (Phoxinus phoxinus), to test whether iBEF relationships exist in consumer species, and whether they are more likely sustained by genetic or functional richness. We found that both genotypic and functional richness affected ecosystem functioning, either independently or in interaction. Loss in genotypic richness reduced benthic invertebrate diversity consistently across functional richness treatments, whereas it reduced zooplankton diversity only when functional richness was high. Finally, both losses in genotypic and functional richness altered essential functions (e.g. decomposition) through trophic cascades. We concluded that iBEF relationships lead to substantial top-down effects on entire food chains. The loss of genotypic richness impacted ecological properties as much as the loss of functional richness, probably because it sustains “cryptic” functional diversity.
Hijacking SARS-Cov-2/ACE2 receptor interaction by natural and semi-synthetic steroidal agents acting on functional pockets on receptor binding region
Authors: Carino Adriana , Moraca Federica , Fiorillo Bianca , Marchianò Silvia , Sepe Valentina , Biagioli Michele , Finamore Claudia , Bozza Silvia , Francisci Daniela , Distrutti Eleonora , Catalanotti Bruno , Zampella Angela , Fiorucci Stefano
Published: June 2020

The coronavirus disease 2019 (COVID-19) is a respiratory tract infection caused by the severe acute respiratory syndrome coronavirus (SARS)-CoV-2. In the light of the urgent need to identify novel approaches to be used in the emergency phase, a largely explored strategy has been the repurpose of clinically available drugs as new antivirals, by targeting different viral proteins. In this paper, we describe a drug repurposing strategy based on a virtual screening of druggable pockets located in the central β-sheet core of the SARS-CoV-2 Spike protein RBD supported by in vitro tests identifying several steroidal derivatives as SARS-CoV-2 entry inhibitors. Our results demonstrate that several potential binding sites exist in the SARS CoV-2 S protein, and that the occupancy of these pockets reduces the ability of the S protein RBD to bind to the ACE2 consensus in vitro. In particular, natural occurring and clinically available steroids as glycyrrhetinic and oleanolic acids, as well as the bile acids derivatives glyco-UDCA and obeticholic acid have been shown to be effective in preventing virus entry in the case of low viral load. All together, these results might help to define novel approaches to reduce the viral load by using SARS-CoV-2 entry inhibitors.
Evaluation of 30-day mortality for 500 patients undergoing non-emergency surgery in a COVID-19 cold site within a multicentre regional surgical network during the COVID-19 pandemic
Authors: Kasivisvanathan Veeru , Lindsay Jamie , Rakshani-Moghadam Sara , Elhamshary Ahmed , Kapriniotis Konstantinos , Kazantzis Georgios , Syed Bilal , Hines John , Bex Axel , Ho Daniel Heffernan , Hayward Martin , Bhan Chetan , MacDonald Nicola , Clarke Simon , Walker David , Bellingan Geoff , Moore James , Rohn Jennifer , Muneer Asif , Roberts Lois , Haddad Fares , Kelly John D ,   UCLH study group collaborators
Published: June 2020

Background

Two million non-emergency surgeries are being cancelled globally every week due to the COVID-19 pandemic, which will have a major impact on patients and healthcare systems.

Objective

To determine whether it is feasible and safe to continue non-emergency surgery in the COVID-19 pandemic

Design, setting and participants

This is a cohort study of 500 consecutive patients undergoing non-emergency surgery in a dedicated COVID-19 cold site following the first case of COVID-19 that was reported in the institution. The study was carried out during the peak of the pandemic in the United Kingdom, which currently has one of the highest number of cases and deaths from COVID-19 globally.

We set up a hub-and-spoke surgical network amongst 14 National Health Service institutions during the pandemic. The hub was a cancer centre, which was converted into a COVID-19 cold site, performing urological, thoracic, gynaecological and general surgical operations.

Outcomes

The primary outcome was 30-day mortality from COVID-19. Secondary outcomes included all-cause mortality and post-operative complications at 30-days.

Results

500 patients underwent surgery with median age 62.5 (IQR 51-71). 65% were male and 60% had a known diagnosis of cancer. 44% of surgeries were performed with robotic or laparoscopic assistance and 61% were considered complex or major operations.

None of the 500 patients undergoing surgery died from COVID-19 at 30-days. 30-day allcause mortality was 3/500 (1%). 10 (2%) patients were diagnosed with COVID-19, 4 (1%) with confirmed laboratory diagnosis and 6 (1%) with probable COVID-19. 33/500 (7%) of patients developed Clavien-Dindo grade 3 or higher complications, with 1/33 (3%) occurring in a patient with COVID-19.

Conclusion

It is safe to continue non-emergency surgery during the COVID-19 pandemic with appropriate service reconfiguration.

Patient summary

No patients died from COVID-19 when undergoing non-emergency surgery during the pandemic in one of the worst affected world regions.
Estimating Lower Bounds for COVID-19 Mortality from Northern Italian Towns
Authors: Coleman Thomas S.
Published: June 2020

For COVID-19 the Infection Fatality Rate or IFR – a crucial variable in epidemiological modeling – is difficult to estimate because many cases are asymptomatic and the overall infection rate is generally not known. Circumstances in the Italian provinces of Milano, Bergamo, Brescia, and Lodi allow estimation of lower bounds for age- and sex-specific all-cause excess mortality (a proxy for IFR) since anecdotal reports indicate some towns were close to fully infected. Using data from ISTAT on mortality from January 1 through April 15 for 2020 and the three preceding years, I estimate excess mortality by sex and age categories (0-14, 15-54, 55-64, 65-74, and 75+ years) while controlling for town-specific mortality that proxies for town-specific infection rate. The 99th percentile from the tail of the town distribution gives a lower-bound estimate for COVID-19 mortality. The overall population-weighted mortality at the 99th percentile is 1.09 percent (95% CI 1.06-1.14). The age- and sex-specific rates vary considerably: for men age 65-74 the estimate is 2.10 percent (95% CI 1.94-2.28) which is 3.5-times higher than men 55-64 and 2.7-times higher than women 65-74.
A Sleep Disorder Detection Model based on EEG Cross-Frequency Coupling and Random Forest
Authors: Dimitriadis Stavros I. , Salis Christos I. , Liparas Dimitris
Published: June 2020

Sleep disorders are medical disorders of a subject’s sleep architecture and based on their severity, they can interfere with mental, emotional and physical functioning. The most common ones are insomnia, narcolepsy, sleep apnea, bruxism, etc. There is an increased risk of developing sleep disorders in elderly like insomnia, periodic leg movements, rapid eye movement (REM) behaviour disorders, sleep disorder breathing, etc. Consequently, their accurate diagnosis and classification are important steps towards an early stage treatment that could save the life of a patient. The Electroencephalographic (EEG) signal is the most sensitive and important biosignal, which is able to capture the brain sleep activity that is sensitive to sleep. In this study, we attempt to analyse EEG sleep activity via complementary cross-frequency coupling (CFC) estimates, which further feed a classifier, aiming to discriminate sleep disorders. We adopted an open EEG Database with recordings that were grouped into seven sleep disorders and a healthy control. The EEG brain activity from common sensors has been analysed with two basic types of cross-frequency coupling (CFC). Finally, a Random Forest (RF) classification model was built on CFC patterns, which were extracted from non-cyclic alternating pattern (CAP) epochs. Our RFCFC model achieved a 74% multiclass accuracy. Both types of CFC, phase-to-amplitude (PAC) and amplitude-amplitude coupling (AAC) patterns contribute to the accuracy of the RF model, thus supporting their complementary information. CFC patterns, in conjunction with the RF classifier proved a valuable biomarker for the classification of sleep disorders.
Meso-scale modeling of COVID-19 spatio-temporal outbreak dynamics in Germany
Authors: Kergaßner A. , Burkhardt C. , Lippold D. , Nistler S. , Kergaßner M. , Steinmann P. , Budday D. , Budday S.
Published: June 2020

The COVID-19 pandemic has kept the world in suspense for the past months. In most federal countries such as Germany, locally varying conditions demand for state- or county-level decisions. However, this requires a deep understanding of the meso-scale outbreak dynamics between micro-scale agent models and macro-scale global models. Here, we introduce a reparameterized SIQRD network model that accounts for local political decisions to predict the spatio-temporal evolution of the pandemic in Germany at county and city resolution. Our optimized model reproduces state-wise cumulative infections and deaths as reported by the Robert-Koch Institute, and predicts development for individual counties at convincing accuracy. We demonstrate the dominating effect of local infection seeds, and identify effective measures to attenuate the rapid spread. Our model has great potential to support decision makers on a state and community politics level to individually strategize their best way forward.
Identifying and Ranking Common COVID-19 Symptoms from Arabic Twitter
Authors: Alanazi Eisa , Alashaikh Abdulaziz , Alqurashi Sarah , Alanazi Aued
Published: June 2020

Background

Massive amount of covid-19 related data is generated everyday by Twitter users. Self-reports of covid-19 symptoms on Twitter can reveal a great deal about the disease and its prevalence in the community. In particular, self-reports can be used as a valuable resource to learn more about the common symptoms and whether their order of appearance differs among different groups in the community. With sufficient available data, this has the potential of developing a covid-19 risk-assessment system that is tailored toward specific group of people.

Objective

The aim of this study is to identify the most common symptoms reported by covid-19 patients in the Arabic language and order the symptoms appearance based on the collected data.

Methods

We search the Arabic content of Twitter for personal reports of covid-19 symptoms from March 1st to May 27th, 2020. We identify 463 Arabic users who tweeted testing positive for covid-19 and extract the symptoms they publicly associate with covid-19. Furthermore, we ask them directly through personal messages to opt in and rank the appearance of the first three symptoms they experienced right before (or after) diagnosed with covid-19. Finally, we track their Twitter timeline to identify additional symptoms that were mentioned within ±5 days from the day of tweeting having covid-19. In summary, a list of 270 covid-19 reports were collected and symptoms were (at least partially) ranked from early to late.

Results

The collected reports contained roughly 900 symptoms originated from 74% (n=201) male and 26% (n=69) female Twitter users. The majority (82%) of the tracked users were living in Saudi Arabia (46%) and Kuwait (36%). Furthermore, 13% (n=36) of the collected reports were asymptomatic. Out of the users with symptoms (n=234), 66% (n=180) provided a chronological order of appearance for at least three symptoms.

Fever 59% (n=139), Headache 43% (n=101), and Anosmia 39% (n=91) were found to be the top three symptoms mentioned by the reports. They count also for the top-3 common first symptoms in a way that 28% (n=65) said their covid journey started with a Fever, 15% (n=34) with a Headache and 12% (n=28) with Anosmia. Out of the Saudi symptomatic reported cases (n=110), the most common three symptoms were Fever 59% (n=65), Anosmia 42% (n=46), and Headache 38% (n=42).

Conclusions

This study demonstrates that Twitter is a valuable resource to analyze and identify COVID-19 early symptoms within the Arabic content of Twitter. It also suggests the possibility of developing a real-time covid-19 risk estimator based on the users’ tweets.
On the sensitivity of non-pharmaceutical intervention models for SARS-CoV-2 spread estimation
Authors: Soltesz Kristian , Gustafsson Fredrik , Timpka Toomas , Jaldén Joakim , Jidling Carl , Heimerson Albin , Schön Thomas B. , Spreco Armin , Ekberg Joakim , Dahlström Örjan , Carlson Fredrik Bagge , Jöud Anna , Bernhardsson Bo
Published: June 2020

Introduction

A series of modelling reports that quantify the effect of non-pharmaceutical interventions (NPIs) on the spread of the SARS-CoV-2 virus have been made available prior to external scientific peer-review. The aim of this study was to investigate the method used by the Imperial College COVID-19 Research Team (ICCRT) for estimation of NPI effects from the system theoretical viewpoint of model identifiability.

Methods

An input-sensitivity analysis was performed by running the original software code of the systems model that was devised to estimate the impact of NPIs on the reproduction number of the SARS-CoV-2 infection and presented online by ICCRT in Report 13 on March 30 2020. An empirical investigation was complemented by an analysis of practical parameter identifiability, using an estimation theoretical framework.

Results

Despite being simplistic with few free parameters, the system model was found to suffer from severe input sensitivities. Our analysis indicated that the model lacks practical parameter identifiability from data. The analysis also showed that this limitation is fundamental, and not something readily resolved should the model be driven with data of higher reliability.

Discussion

Reports based on system models have been instrumental to policymaking during the SARS-CoV-2 pandemic. With much at stake during all phases of a pandemic, we conclude that it is crucial to thoroughly scrutinise any SARS-CoV-2 effect analysis or prediction model prior to considering its use as decision support in policymaking. The enclosed example illustrates what such a review might reveal.
A unified activities-based approach to the modelling of viral epidemics and COVID-19 as an illustrative example
Authors: Shikhmurzaev Yulii D. , Shikhmurzaev Vladislav D.
Published: June 2020

A new approach to formulating mathematical models of increasing complexity to describe the dynamics of viral epidemics is proposed. The approach utilizes a map of social interactions characterizing the population and its activities and, unifying the compartmental and the stochastic viewpoints, offers a framework for incorporating both the patterns of behaviour studied by sociological surveys and the clinical picture of a particular infection, both for the virus itself and the complications it causes. The approach is illustrated by taking a simple mathematical model developed in its framework and applying it to the ongoing pandemic of SARS-CoV-2 (COVID-19), with the UK as a representative country, to assess the impact of the measures of social distancing imposed to control its course.
Sex-based differences in clearance of chronicPlasmodium falciparuminfection
Authors: Briggs Jessica , Teyssier Noam , Nankabirwa Joaniter I. , Rek John , Jagannathan Prasanna , Arinatiwe Emmanuel , Bousema Teun , Drakeley Chris , Murray Margaret , Crawford Emily , Hathaway Nicholas , Staedke Sarah G. , Smith David , Rosenthal Phillip J. , Kamya Moses , Dorsey Grant , Rodriguez-Barraquer Isabel , Greenhouse Bryan
Published: June 2020

Multiple studies have reported a male bias in incidence and/or prevalence of malaria infection in males compared to females. To test the hypothesis that sex-based differences in host-parasite interactions affect the epidemiology of malaria, we intensively followedPlasmodium falciparuminfections in a cohort in a malaria endemic area of eastern Uganda and estimated both force of infection (FOI) and rate of clearance using amplicon deep-sequencing. We found no evidence of differences in behavioral risk factors, incidence of malaria, or FOI by sex. In contrast, females cleared asymptomatic infections at a faster rate than males (hazard ratio [HR] = 1.82, 95% CI 1.20 to 2.75 by clone and HR = 2.07, 95% CI 1.24 to 3.47 by infection event) in multivariate models adjusted for age, timing of infection onset, and parasite density. These findings implicate biological sex-based differences as an important factor in the host response to this globally important pathogen.
Deep brain electrical neurofeedback allows Parkinson patients to control pathological oscillations and quicken movements
Authors: Bichsel Oliver , Stieglitz Lennart H. , Oertel Markus F. , Baumann Christian R. , Gassert Roger , Imbach Lukas L.
Published: June 2020

Parkinsonian motor symptoms are linked to pathologically increased beta-oscillations in the basal ganglia. While pharmacological treatment and deep brain stimulation (DBS) reduce these pathological oscillations concomitantly with improving motor performance, we set out to explore neurofeedback as an endogenous modulatory method. We implemented deep brain electrical neurofeedback to provide real-time visual neurofeedback of pathological subthalamic oscillations measured through implanted DBS electrodes. All 8 patients volitionally controlled ongoing beta-oscillatory activity within minutes of training. During a single one-hour training session, the reduction of beta-oscillatory activity became gradually stronger and accelerated hand movements. Lastly, endogenous control over deep brain activity was possible even after removing visual neurofeedback, suggesting that neurofeedback-acquired strategies were retained in the short-term. We observed a similar motor improvement when the learnt mental strategies were applied 2 days later. Further improvement of deep brain neurofeedback might benefit Parkinson patients by improving symptom control, even in the absence of real-time neurofeedback.
Mortality Attributed to COVID-19 in High-Altitude Populations
Authors: Woolcott Orison O. , Bergman Richard N.
Published: June 2020

Background

Since partial oxygen pressure decreases as altitude increases, environmental hypoxia could worsen COVID-19 patient’s hypoxemia. We compared COVID-19 mortality at different altitudes.

Methods

Retrospective analysis of population-level data on COVID-19 deaths in the U.S. (1,016 counties) and Mexico (567 municipalities). Mixed-model Poisson regression analysis of the association between altitude and COVID-19 mortality using individual-level data from 40,168 Mexican subjects with COVID-19, adjusting for multiple covariates.

Results

Between January 20 and April 13, 2020, mortality rates were higher in U.S. counties located at ≥2,000 m elevation vs. those located below 1,500 m (12.3 vs. 3.2 per 100,000; P<0.001). In Mexico, between March 13 and May 13, 2020, mortality rates were higher in municipalities located at ≥2,000 m vs. <1,500 m (5.3 vs. 3.9 per 100,000; P<0.001). Among Mexican subjects <65 years old, the risk of death was 36% higher in those living at ≥2,000 m vs. <1,500 m (adjusted incidence rate ratio: 1.36; 95% CI, 1.05-1.78; P=0.022). Among men, the risk of death was 31% higher at ≥2,000 m vs. <1,500 m (adjusted IRR: 1.31; 95% CI, 1.03-1.66; P=0.025). No association was found among women.

Conclusion

Altitude is associated with COVID-19 mortality in men younger than 65 years.
Effects of auditory reliability and ambiguous visual stimuli on auditory spatial discrimination
Authors: Cappelloni Madeline S. , Shivkumar Sabyasachi , Haefner Ralf M. , Maddox Ross K.
Published: June 2020

The brain combines information from multiple sensory modalities to interpret the environment. Multisensory integration is often modeled by ideal Bayesian causal inference, a model proposing that perceptual decisions arise from a statistical weighting of information from each sensory modality based on its reliability and relevance to the observer’s task. However, ideal Bayesian causal inference fails to describe human behavior in a simultaneous auditory spatial discrimination task in which spatially aligned visual stimuli improve performance despite providing no information about the correct response. This work tests the hypothesis that humans weight auditory and visual information in this task based on their relative reliabilities, even though the visual stimuli are task-uninformative, carrying no information about the correct response, and should be given zero weight. Listeners perform an auditory spatial discrimination task with relative reliabilities modulated by the stimulus durations. By comparing conditions in which task-uninformative visual stimuli are spatially aligned with auditory stimuli or centrally located (control condition), listeners are shown to have a larger multisensory effect when their auditory thresholds are worse. Even in cases in which visual stimuli are not task-informative, the brain combines sensory information that is scene-relevant, especially when the task is difficult due to unreliable auditory information.
Beyond Shielding: The Roles of Glycans in SARS-CoV-2 Spike Protein
Authors: Casalino Lorenzo , Gaieb Zied , Goldsmith Jory A. , Hjorth Christy K. , Dommer Abigail C. , Harbison Aoife M. , Fogarty Carl A. , Barros Emilia P. , Taylor Bryn C. , McLellan Jason S. , Fadda Elisa , Amaro Rommie E.
Published: June 2020

The ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in more than 15,000,000 infections and 600,000 deaths worldwide to date. Antibody development efforts mainly revolve around the extensively glycosylated SARS-CoV-2 spike (S) protein, which mediates the host cell entry by binding to the angiotensin-converting enzyme 2 (ACE2). Similar to many other viruses, the SARS-CoV-2 spike utilizes a glycan shield to thwart the host immune response. Here, we built a full-length model of glycosylated SARS-CoV-2 S protein, both in the open and closed states, augmenting the available structural and biological data. Multiple microsecond-long, all-atom molecular dynamics simulations were used to provide an atomistic perspective on the roles of glycans, and the protein structure and dynamics. We reveal an essential structural role of N-glycans at sites N165 and N234 in modulating the conformational dynamics of the spike’s receptor binding domain (RBD), which is responsible for ACE2 recognition. This finding is corroborated by biolayer interferometry experiments, which show that deletion of these glycans through N165A and N234A mutations significantly reduces binding to ACE2 as a result of the RBD conformational shift towards the “down” state. Additionally, end-to-end accessibility analyses outline a complete overview of the vulnerabilities of the glycan shield of SARS-CoV-2 S protein, which may be exploited by therapeutic efforts targeting this molecular machine. Overall, this work presents hitherto unseen functional and structural insights into the SARS-CoV-2 S protein and its glycan coat, providing a strategy to control the conformational plasticity of the RBD that could be harnessed for vaccine development.