bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transgenic goats producing an improved version of cetuximab in milk
Authors: Laible Götz , Cole Sally , Brophy Brigid , Maclean Paul , Chen Li How , Pollock Dan P. , Cavacini Lisa , Fournier Nathalie , De Romeuf Christophe , Masiello Nicholas C. , Gavin William G. , Wells David N. , Meade Harry M. 
Published: June 2020

ABSTRACTTherapeutic monoclonal antibodies (mAbs) represent one of the most important classes of pharmaceutical proteins to treat human diseases. Most are produced in cultured mammalian cells which is expensive, limiting their availability. Goats, striking a good balance between a relatively short generation time and copious milk yield, present an alternative platform for the cost-effective, flexible, large-scale production of therapeutic mAbs. Here, we focused on cetuximab, a mAb against epidermal growth factor receptor, that is commercially produced under the brand name Erbitux and approved for anti-cancer treatments. We generated several transgenic goat lines that produce cetuximab in their milk. Two lines were selected for detailed characterization. Both showed stable genotypes and cetuximab production levels of up to 10g/L. The mAb could be readily purified and showed improved characteristics compared to Erbitux. The goat-produced cetuximab (gCetuximab) lacked a highly immunogenic epitope that is part of Erbitux. Moreover, it showed enhanced binding to CD16 and increased antibody-dependent cell-dependent cytotoxicity compared to Erbitux. This indicates that these goats produce an improved cetuximab version with the potential for enhanced effectiveness and better safety profile compared to treatments with Erbitux. In addition, our study validates transgenic goats as an excellent platform for large-scale production of therapeutic mAbs.
Exometabolite dynamics over stationary phase reveal strain-specific responses to nutrient limitation
Authors: Chodkowski John L. , Shade Ashley 
Published: June 2020

AbstractMicrobial exponential growth is expected to occur infrequently outside of the laboratory, in the environment. Instead, resource-limited conditions impose non-growth states for microbes. However, non-growth states are uncharacterized for the majority of environmental bacteria, especially in regard to exometabolite production. To investigate exometabolite production in response to nutrient limitation, we compared exometabolites produced over time in stationary phase across three environmental bacteria:Burkholderia thailandensisE264 (ATCC 700388),Chromobacterium violaceumATCC 31532, andPseudomonas syringaepathovartomatoDC3000 (ATCC BAA-871). We grew each strain in monoculture and investigated exometabolite dynamics over time from mid-exponential to stationary phase. We focused on exometabolites that were released into the media and accumulated over 45 hours, including approximately 20 hours of stationary phase. In concert, we analyzed transcripts (RNAseq) to inform interpretation of exometabolite output. We found that a majority of exometabolites released under these conditions were strain-specific. A subset of identified exometabolites were involved in both central and secondary metabolism. Transcript analysis supported that exometabolites were released from intact cells, as various transporters were either upregulated or consistently expressed. Interestingly, we found that all strains released succinate, and that each strain re-routed their metabolic pathways involved in succinate production during stationary phase. Overall, these results show that non-growth states can also be metabolically active and dynamic. Furthermore, they show that environmental bacteria have the capability to transform a resource-limited extracellular environment into a rich chemical milieu. This work has implications for understanding microbial community interactions via exometabolites, and within resource-limited environments.ImportanceNon-growth states are common for bacteria that live in resource-limited environments, and yet these states remain largely uncharacterized in cellular metabolism and metabolite output. Here, we investigated and compared stationary phase exometabolites and RNA transcripts for each of three environmental bacterial strains. We observed that diverse exometabolites were produced and that they collectively exhibited clear and directional dynamics over time. Additionally, each bacteria strain had a characteristic exometabolite profile and dynamic. This work affirms that stationary phase is not at all “stationary” for these bacteria, and sets the stage for understanding how individual metabolisms support interspecies interactions in resource-limited environments.
TRACKing Excess Deaths (TRACKED) – an interactive online tool to monitor excess deaths associated with COVID-19 pandemic in the United Kingdom
Authors: Poon Michael TC , Brennan Paul M , Jin Kai , Figueroa Jonine D , Sudlow Cathie LM 
Published: June 2020

AbstractBackgroundWe aimed to describe trends of excess mortality in the United Kingdom (UK) stratified by nation and cause of death, and to develop an online tool for reporting the most up to date data on excess mortality.MethodsPopulation statistics agencies in the UK including the Office for National Statistics (ONS), National Records of Scotland (NRS), and Northern Ireland Statistics and Research Agency (NISRA) publish weekly data on deaths. We used mortality data up to 22nd May in the ONS and the NISRA and 24th May in the NRS. Crude mortality for non-COVID deaths (where there is no mention of COVID-19 on the death certificate) calculated. Excess mortality defined as difference between observed mortality and expected average of mortality from previous 5 years.ResultsThere were 56,961 excess deaths and 8,986 were non-COVID excess deaths. England had the highest number of excess deaths per 100,000 population (85) and Northern Ireland the lowest (34). Non-COVID mortality increased from 23rd March and returned to the 5-year average on 10th May. In Scotland, where underlying cause mortality data besides COVID-related deaths was available, the percentage excess over the 8-week period when COVID-related mortality peaked was: dementia 49%, other causes 21%, circulatory diseases 10%, and cancer 5%. We developed an online tool (TRACKing Excess Deaths - TRACKED) to allow dynamic exploration and visualisation of the latest mortality trends (http://trackingexcessdeaths.com).ConclusionsContinuous monitoring of excess mortality trends and further integration of age- and gender-stratified and underlying cause of death data beyond COVID-19 will allow dynamic assessment of the impacts of indirect and direct mortality of the COVID-19 pandemic.
BMI and future risk for COVID-19 infection and death across sex, age and ethnicity: preliminary findings from UK biobank
Authors: Sattar Naveed , Ho Frederick K , Gill Jason MR , Ghouri Nazim , Gray Stuart R , Celis-Morales Carlos A , Katikireddi S Vittal , Berry Colin , Pell Jill P , McMurray John JV , Welsh Paul 
Published: June 2020

AbstractWe examined the link between BMI and risk of a positive test for SARS-CoV-2 and risk of COVID-19-related death among UK Biobank participants. Among 4855 participants tested for SARS-CoV-2 in hospital, 839 were positive and of these 189 died from COVID-19. Poisson models with penalised thin plate splines were run relating exposures of interest to test positivity and case-fatality, adjusting for confounding factors. BMI was associated strongly with positive test, and risk of death related to COVID-19. The gradient of risk in relation to BMI was steeper in those under 70, compared with those aged 70 years or older for COVID-19 related death (Pinteraction=0.03). BMI was more strongly related to test positivity (Pinteraction=0.010) and death (Pinteraction=0.002) in non-whites, compared with whites. These data add support for adiposity being more strongly linked to COVID-19-related deaths in younger people and non-white ethnicities. If future studies confirm causality, lifestyle interventions to improve adiposity status may be important to reduce the risk of COVID-19 in all, but perhaps particularly, non-white communities.
A systematic review of convalescent plasma treatment for COVID19
Authors: Pimenoff Ville N. , Elfström Miriam , Dillner Joakim 
Published: June 2020

ABSTRACTBackgroundTransfusion of convalescent immune plasma (CP) is commonly used in epidemics. Several articles now describe clinical report data of CP for treatment of SARS-CoV-2-induced COVID-19 disease.MethodsA systematic literature review was conducted using the NCBI curated COVID-19 related open-resource literature database LitCovid to identify studies using CP as treatment for COVID-19 patients. We retrieved and curated all COVID-19 related patient and treatment characteristics from previously reported studies. A Poisson model was developed to evaluate the association between age of the patients, older age being the most common risk factor for COVID-19 mortality, and recovery time since CP treatment using data extracted from the literature.ResultsFrom 18,293 identified COVID-19 related articles, we included ten studies reporting results of CP treatment for COVID-19 from a total of 61 patients. Decreased symptoms of severe COVID-19 and clearance of SARS-CoV-2 RNA were the most direct observations. We found that patients over the age of sixty who received CP treatment for COVID-19 had a significantly prolonged recovery estimated by viral clearance (from 10 to 29 days since first dose of CP) compared to younger patients, who recovered from the infection in less than a week after receiving CP treatment.ConclusionsLimited published results on plasma transfusion treatment for COVID-19 disease with concomitant treatments suggest that CP therapy for COVID-19 is well tolerated and effective. First randomized clinical trial results, however, revealed no improvements in recovery time for elderly patients with severe COVID-19 between standard treatment alone and added with convalescent plasma. Accordingly, we argue that older patients may need a significantly longer time for recovery. Further randomized clinical trial data for COVID-19 with rigorous ethical standards is urgently needed.
Association between complement component 4A expression, cognitive performance and brain imaging measures in UK Biobank
Authors: O’Connell Kevin S , Sønderby Ida E. , Frei Oleksandr , van der Meer Dennis , Athanasiu Lavinia , Smeland Olav B. , Alnæs Dag , Kaufmann Tobias , Westlye Lars T. , Steen Vidar M. , Andreassen Ole A. , Hughes Timothy , Djurovic Srdjan 
Published: June 2020

ABSTRACTAltered expression of the complement componentC4Agene is a known risk factor for schizophrenia. Further, predicted brainC4Aexpression has also been associated with memory function highlighting that altered C4A expression in the brain may be relevant for cognitive and behavioral traits. We investigated if predicted brainC4Aexpression was associated with cognitive performance and brain imaging measures in the UK Biobank. We identified significant negative associations between predictedC4Aexpression and performance on select cognitive tests, and significant associations with MRI-based cortical thickness and surface area in select regions. Finally, we observed significant inconsistent partial mediation of the effects of predictedC4Aexpression on cognitive performance, by specific brain structure measures. These results demonstrate that theC4risk locus is associated with the central endophenotypes of cognitive performance and brain morphology, even when considered independently of other genetic risk factors and in individuals without mental or neurological disorders.
Is the psychological well-being of a population associated with COVID-19 related survival?
Authors: Feys Frederik 
Published: June 2020

AbstractOBJECTIVEImmunological mind-body research suggests mental health may also be important in the COVID-19 pandemic. This study aimed to investigate the potential influence of mental health as a protective factor for COVID-19 related mortality in the general population. The second goal was to examine this among populations of countries most affected by COVID-19 related mortality.METHODSData sources were the Global Burden of Disease report 2017 and publicly reported situational reports of COVID-19. We described variables; calculated the spearman’s correlation coefficient, calculated the percentage of the variability of the data that is explained by the association. We explored inter-relationships among other variables: aged 70 or older, cardiovascular disease, obesity and diabetes. A correlation matrix with plotted scatter matrix diagrams was produced.RESULTSAcross 181 countries, the mean total COVID-19 related survivors per million was 999,949 (sd = 125), median = 999,993. The variable had a lognormal distribution; the mean mentally healthy per 100,000 was 85,411 (sd = 1,871), median = 85,634. The test of normality resulted in p-value < 0.001. Correlation of mentally healthy per 100,0000 and totals of COVID-19 related survivors wasϱs= 0.29 (n = 181, 95% CI 0.16–0.43). The variance explained by the relation between mental healthy and totals of COVID-19 related survivors was 8.4% (2.6–18.5%). Across countries most affected by COVID-19 related mortalityϱs= 0.49 (n = 45, 0.28–0.70), explaining 24.2% (7.7–49.3%).CONCLUSIONA weak association was found between the psychological well-being of a population and COVID-19 related survival. This relationship explained between 2.6 and 18.5% of COVID-19 related survival. For countries most affected by COVID-19 related death, this association was moderate and explained between 7.7 and 49.3%. Confirmation of these important observational findings is needed with future individual patient data research.
Epigenetic and transcriptional regulation of osteoclastogenesis in the pathogenesis of skeletal diseases: a protocol for a systematic review
Authors: Sharma Siddhartha , Mittal Anupam , Mahajan Aditi , Gohil Riddhi 
Published: June 2020

AbstractOsteoclastogenesis (OCG) is a multi-stage process that involves formation of activated osteoclasts from bone marrow macrophages. The progression of each stage of OCG is governed by a set of transcription factors and gene regulators, which are genetically and epigenetically regulated at both transcription and post-transcription levels. Epigenetic changes are used to denote interactions between genetic material and environment leading to phenotypic alterations that can be inherited, without any variations in DNA sequence. Epigenetic and transcription regulatory events have profound effects on osteoclast formation and activation; these have been implicated in numerous disorders including osteoporosis, osteopetrosis, rheumatoid arthritis, spondyloarthritis, gout and bone metastasis. We aim to conduct a systematic review to assess possible relationship between key epigenetic and transcriptional regulators of osteoclastogenesis, and their role in specific bone disorders. This is a protocol for the proposed review.
Serology confirms SARS-CoV-2 infection in PCR-negative children presenting with Paediatric Inflammatory Multi-System Syndrome
Authors: Perez-Toledo Marisol , Faustini Sian E. , Jossi Sian E. , Shields Adrian M. , Kanthimathinathan Hari Krishnan , Allen Joel D. , Watanabe Yasunori , Goodall Margaret , Wraith David C. , Veenith Tonny V. , Drayson Mark T. , Jyothish Deepthi , Al-Abadi Eslam , Chikermane Ashish , Welch Steven B. , Masilamani Kavitha , Hackett Scott , Crispin Max , Scholefield Barnaby R , Cunningham Adam F. , Richter Alex G. 
Published: June 2020

BackgroundDuring the COVID-19 outbreak, reports have surfaced of children who present with features of a multisystem inflammatory syndrome with overlapping features of Kawasaki disease and toxic shock syndrome – Paediatric Inflammatory Multisystem Syndrome-temporally associated with SARS-CoV-2 pandemic (PIMS-TS). Initial reports find that many of the children are PCR-negative for SARS-CoV-2, so it is difficult to confirm whether this syndrome is a late complication of viral infection in an age group largely spared the worst consequences of this infection, or if this syndrome reflects enhanced surveillance.MethodsChildren hospitalised for symptoms consistent with PIMS-TS between 28 April and 8 May 2020, and who were PCR-negative for SARS-CoV-2, were tested for antibodies to viral spike glycoprotein using an ELISA test.ResultsEight patients (age range 7–14 years, 63% male) fulfilled case-definition for PIMS-TS during the study period. Six of the eight patients required admission to intensive care. All patients exhibited significant IgG and IgA responses to viral spike glycoprotein. Further assessment showed that the IgG isotypes detected in children with PIMS-TS were of the IgGl and lgG3 subclasses, a distribution similar to that observed in samples from hospitalised adult COVID-19 patients. In contrast, lgG2 and lgG4 were not detected in children or adults. IgM was not detected in children, which contrasts with adult hospitalised adult COVID-19 patients of whom all had positive IgM responses.ConclusionsStrong IgG antibody responses can be detected in PCR-negative children with PIMS-TS. The low detection rate of IgM in these patients is consistent with infection having occurred weeks previously and that the syndrome onset occurs well after the control of SARS-CoV-2 viral load. This implies that the disease is largely immune-mediated. Lastly, this indicates that serology can be an appropriate diagnostic tool in select patient groups.
Heterogeneity is essential for contact tracing
Authors: Nielsen Bjarke Frost , Sneppen Kim , Simonsen Lone , Mathiesen Joachim 
Published: June 2020

Background(Dated: June 5, 2020)The COVID-19 pandemic is most often modelled by well-mixed models, sometimes stratified by age and work. People are, however, different from one another in terms of interaction frequency as well as in formation of social groups. This contact heterogeneity especially challenges models of contact tracing (CT), but also predictions of epidemic severity generally. We explore how heterogeneity affects CT effectiveness and overall epidemic severity, using a real-world contact network.MethodsUtilizing smartphone proximity data from Danish university students, we simulate the spread of COVID-19 on a network with realistic contact structure. Two modes of network homogenization are implemented to probe effects of heterogeneity. We then simulate a CT scheme on the network and explore the impact of heterogeneity, testing probability and contact threshold for quarantining.ResultsMeasuring contact heterogeneity, we find an exponential distribution which persists on a timescale of several weeks. Comparing the true network to edge-swapped and randomized versions, we find that heterogeneity decreases the severity of COVID-19 in general, and that it drastically improves CT.ConclusionsTo capture heterogeneity, it is necessary to reconsider disease transmission models. Our findings show that heterogeneity is essential for CT, and that CT is effective even if only the most frequent contacts can be tracked down. We find that contact heterogeneity impedes the spread of COVID-19 in comparison with well-mixed networks. In perspective, this means that fitting traditional SEIR models to epidemic data is likely to overestimate the severity.
No impact of smoking status on breast cancer tumor infiltrating lymphocytes, response to neoadjuvant chemotherapy and prognosis
Authors: Simon Vanille , Laot Lucie , Laas Enora , Rozette Sonia , Guerin Julien , Balezeau Thomas , Nicolas Marion , Pierga Jean-Yves , Coussy Florence , Laé Marick , de Croze Diane , Grandal Beatriz , Abecassis Judith , Reyal Fabien , Hamy Anne-Sophie 
Published: June 2020

ABSTRACTINTRODUCTIONTobacco use is associated with an increase in breast cancer (BC) mortality. Pathologic complete response rate to neoadjuvant chemotherapy (NAC) is influenced by tumor-infiltrating lymphocytes (TILs) levels and is associated with a better long-term survival outcome. Whether tobacco modifies either tumoral microenvironment such as TIL levels, either pCR rates remains unclear. The aim of our study is to evaluate the impact of smoking status on TIL levels, response to NAC and prognosis for BC patients.METHODSWe retrospectively evaluated pre and post NAC stromal and intra tumoral TIL levels and pCR rates on a cohort of T1-T3NxM0 BC patients treated with NAC between 2002 and 2012 at Institut Curie. Smoking status (current, ever, never smokers) was collected in clinical records. We analyzed the association between smoking status, TIL levels, pCR rates and survival outcomes among the whole population, and after stratification by BC subtype.RESULTSA total of 956 BC patients with available smoking status information were included in our analysis [current smokers, n=179 (18.7%); ever smokers, n=154 (16.1%) and never smokers, n = 623 (65.2%)]. Median pre-NAC TIL levels, pCR rates, or median post-NAC TIL levels were not significantly different according to smoking status, neither in the whole population, nor after stratification by BC subtype. With a median follow-up of 101.4 months, relapse free survival (RFS) and overall survival (OS) were not significantly different by smoking status.CONCLUSIONIn this study, we did not find any significant effect of tobacco use on pre and post NAC TILs nor response to NAC and. Though our data seem reassuring, BC treatment should still be considered as a window of opportunity to offer BC patients accurate smoking cessation interventions.
An environmental determinant of viral respiratory disease
Authors: Choi Yeon-Woo , Tuel Alexandre , Eltahir Elfatih A. B. 
Published: June 2020

ABSTRACTThe evident seasonality of influenza suggests a significant role for weather and climate as one of several determinants of viral respiratory disease (VRD), including social determinants which play a major role in shaping these phenomena. Based on the current mechanistic understanding of how VRDs are transmitted by small droplets, we identify an environmental variable, Air Drying Capacity (ADC), as an atmospheric state-variable with significant and direct relevance to the transmission of VRD. ADC dictates the evolution and fate of droplets under given temperature and humidity conditions. The definition of this variable is rooted in the Maxwell theory of droplet evolution via coupled heat and mass transfer between droplets and the surrounding environment. We present the climatology of ADC, and compare its observed distribution in space and time to the observed prevalence of influenza and COVID-19 from extensive global data sets. Globally, large ADC values appear to significantly constrain the observed transmission and spread of VRD, consistent with the significant coherency of the observed seasonal cycles of ADC and influenza. Our results introduce a new environmental determinant, rooted in the mechanism of VRD transmission, with potential implications for explaining seasonality of influenza, and for describing how environmental conditions may impact to some degree the evolution of similar VRDs, such as COVID-19.
On the Spread of Coronavirus Infection. A Mechanistic Model to Rate Strategies for Disease Management
Authors: Wang Shiyan , Ramkrishna Doraiswami 
Published: June 2020

AbstractEffective policy making based on ongoing COVID-19 pandemic is an urgent issue. We present a mathematical model describing the viral infection dynamics, which reveals two transmissibility parameters influenced by the management strategies in the area for control of the current pandemic. The parameters readily yield the peak infection rate and means for flattening the curve. Model parameters are shown to be correlated to different management strategies by employing machine learning, enabling comparison of different strategies and suggesting timely alterations. Treatment of population data with the model shows that restricted non-essential business closure, school closing and strictures on mass gathering influence the spread of infection. While a rational strategy for initiation of an economic reboot would call for a wider perspective of the local economics, the model can speculate on its timing based on the status of the infection as reflected by its potential for an unacceptably renewed viral onslaught.