bluuebunny/crossref_metadata_2025_split huggingface dataset:
Is more better? An analysis of toxicity and response outcomes from dose-finding clinical trials in cancer
Authors: Brock Kristian , Homer Victoria , Soul Gurjinder , Potter Claire , Chiuzan Cody , Lee Shing 
Published: August 2020

AbstractThe overwhelming majority of dose-escalation clinical trials use methods that seek a maximum tolerable dose, including rule-based methods like the 3+3, and model-based methods like CRM and EWOC. These methods assume that the incidences of efficacy and toxicity always increase as dose is increased. This assumption is widely accepted with cytotoxic therapies. In recent decades, however, the search for novel cancer treatments has broadened, increasingly focusing on inhibitors and antibodies. The rationale that higher doses are always associated with superior efficacy is less clear for these types of therapies. We extracted dose-level efficacy and toxicity outcomes from 115 manuscripts reporting dose-finding clinical trials in cancer between 2008 and 2014. We analysed the outcomes from each manuscript using flexible non-linear regression models to investigate the evidence supporting the monotonic efficacy and toxicity assumptions. We found that the monotonic toxicity assumption was well-supported across most treatment classes and disease areas. In contrast, we found very little evidence supporting the monotonic efficacy assumption. Our conclusion is that dose-escalation trials routinely use methods whose assumptions are violated by the outcomes observed. As a consequence, dose-finding trials risk recommending unjustifiably high doses that are harmful to patients. We recommend that trialists consider experimental designs that allow toxicity and efficacy outcomes to jointly determine the doses given to patients and recommended for further study.
Comparisons of COVID-19 dynamics in the different countries of the World using Time-Series clustering
Authors: Alvarez Emiliano , Gabriel Brida Juan , Limas Erick 
Published: August 2020

AbstractIn recent months, the world has suffered from the appearance of a new strain of coronavirus, causing the COVID-19 pandemic. There are great scientific efforts to find new treatments and vaccines, at the same time that governments, companies, and individuals have taken a series of actions in response to this pandemic. These efforts seek to decrease the speed of propagation, although with significant social and economic costs. Countries have taken different actions, also with different results. In this article we use non-parametric techniques (HT and MST) with the aim of identifying groups of countries with a similar spread of the coronavirus. The variable of interest is the number of daily infections per country. Results show that there are groups of countries with differentiated contagion dynamics, both in the number of contagions plus at the time of the greatest transmission of the disease. It is concluded that the actions taken by the countries, the speed at which they were taken and the number of tests carried out may explain part of the differences in the dynamics of contagion.
Role of IgM and IgA Antibodies to the Neutralization of SARS-CoV-2
Authors: Klingler Jéromine , Weiss Svenja , Itri Vincenza , Liu Xiaomei , Oguntuyo Kasopefoluwa Y. , Stevens Christian , Ikegame Satoshi , Hung Chuan-Tien , Enyindah-Asonye Gospel , Amanat Fatima , Baine Ian , Arinsburg Suzanne , Bandres Juan C. , Milunka Kojic Erna , Stoever Jonathan , Jurczyszak Denise , Bermudez-Gonzalez Maria , Simon Viviana , Liu Sean , Lee Benhur , Krammer Florian , Zolla-Pazner Susan , Hioe Catarina E. 
Published: August 2020

AbstractSARS-CoV-2 has infected millions of people and is on a trajectory to kill more than one million globally. Virus entry depends on the receptor-binding domain (RBD) of the spike protein. Although previous studies demonstrated anti-spike and –RBD antibodies as essential for protection and convalescent plasma as a promising therapeutic option, little is known about the immunoglobulin (Ig) isotypes capable of blocking virus entry. Here, we studied spike- and RBD-specific Ig isotypes in plasma/sera from two acutely infected and 29 convalescent individuals. Spike- and RBD-specific IgM, IgG1, and IgA1 antibodies were produced by all or nearly all subjects at varying levels and detected at 7–8 days post-disease onset. IgG2, IgG3, IgG4, and IgA2 were also present but at much lower levels. All samples also displayed neutralizing activity. IgM, IgG, and IgA were capable of mediating neutralization, but neutralization titers correlated better with binding levels of IgM and IgA1 than IgG.
A co-infection model for Two-Strain Malaria and Cholera with Optimal Control
Authors: Egeonu K. U. , Inyama S. C. , Omame A. 
Published: August 2020

AbstractA mathematical model for two strains of Malaria and Cholera with optimal control is studied and analyzed to assess the impact of treatment controls in reducing the burden of the diseases in a population, in the presence of malaria drug resistance. The model is shown to exhibit the dynamical property of backward bifurcation when the associated reproduction number is less than unity. The global asymptotic stability of the disease-free equilibrium of the model is proven not to exist. The necessary conditions for the existence of optimal control and the optimality system for the model is established using the Pontryagin’s Maximum Principle. Numerical simulations of the optimal control model reveal that malaria drug resistance can greatly influence the co-infection cases averted, even in the presence of treatment controls for co-infected individuals.
Convalescent plasma for patients with severe COVID-19: a matched cohort study
Authors: Rogers Ralph , Shehadeh Fadi , Mylona Evangelia , Rich Josiah , Neill Marguerite , Touzard-Romo Francine , Geffert Sara , Larkin Jerome , Bailey Jeffrey A. , Lu Shaolei , Sweeney Joseph , Mylonakis Eleftherios 
Published: August 2020

AbstractBackgroundThe efficacy of convalescent plasma (CP) for the treatment of COVID-19 remains unclear.MethodsA matched cohort analysis of hospitalized patients with severe COVID-19. The impact of CP treatment on all cause in-hospital mortality was evaluated using univariate and multivariate Cox proportional-hazards models, and the impact of CP treatment on the time to hospital discharge was assessed using a stratified log-rank analysis.Results64 patients who received CP a median of 7 days after symptom onset were compared to a matched control group of 177 patients. Overall in-hospital mortality was 14.9%. There was no significant difference in the risk of in-hospital mortality between the two groups (adjusted hazard ratio [aHR] 0.93, 95% confidence interval [CI] 0.39 – 2.20). There was also no significant difference in the overall rate of hospital discharge (rate ratio [RR] 1.28, 95% CI 0.91 – 1.81), but a subgroup analysis of patients 65-years-old or greater who received CP demonstrated a significantly increased hospital discharge rate among these patients (RR 1.86, 95% CI 1.03 – 3.36). There was a greater than expected frequency of transfusion reactions in the CP group (2.8% reaction rate observed per unit transfused).ConclusionsThe use of CP in this study was a safe treatment for COVID-19. There was no overall significant reduction of in-hospital mortality or increased rate of hospital discharge associated with the use of CP in this study, although there was a signal for improved outcomes among the elderly. Further adequately powered randomized studies should target this subgroup when assessing the efficacy CP treatment.
Inadequate preparedness for response to COVID-19 is associated with stress and burnout among healthcare workers in Ghana
Authors: Afulani Patience A. , Gyamerah Akua O. , Nutor Jerry John , Laar Amos , Aborigo Raymond , Malechi Hawa , Sterling Mona , Awoonor-Williams John Koku 
Published: August 2020

ABSTRACTIntroductionThe COVID-19 pandemic has compounded the global crisis of stress and burnout among healthcare workers (HCWs). But few studies have empirically examined the factors driving these outcomes. We examined the association between perceived preparedness to respond to the pandemic and HCW stress and burnout and identified potential mediating factors among HCWs in Ghana.MethodsData are from HCWs in Ghana who completed a cross-sectional self-administered online survey; 414 and 409 HCWs completed stress and burnout questions, respectively. Perceived preparedness, stress, and burnout were measured using validated psychosocial measures. We assessed associations using linear regressions with robust standard errors.ResultsThe average score for preparedness was 24 (SD = 8.8), 16.3 (SD = 5.9) for stress, and 37.4 (SD = 15.5) for burnout. In multivariate analysis, HCWs who felt somewhat prepared and prepared had lower stress (β = −1.89, 95%CI:-3.49 to −0.30 and β = –2.66, 95%CI:-4.48 to −0.84) and burnout (β = –7.74, 95%CI:−11.8 to −3.64 and β = –9.25, 95%CI:-14.1 to –4.41) scores than those who did not feel prepared. Appreciation from management and family support were associated with lower stress and burnout, while fear of infection was associated with higher stress burnout. Fear of infection partially mediated the relationship between perceived preparedness and stress/burnout, accounting for about 16 to17% of the effect.ConclusionLow perceived preparedness to respond to COVID-19 increases stress and burnout, and this is partly through fear of infection. Interventions to increase HCWs’ morale and capacity to respond to the pandemic are needed.Strengths and limitations of this studyOur study is among the first to report data on COVID-19 related stress and burnout among HCWs in Africa and to identify contributing factors, including HCWs’ perceived preparedness to respond to the pandemic.We used validated psychosocial measures of stress and burnout, as well as a perceived preparedness for COVID-19 scale developed by our team, which has high validity and reliability; this scale can facilitate similar research in other settings.Our study shows that among healthcare workers in Ghana, low perceived preparedness to respond to the COVID-19 pandemic is associated with higher levels of stress and burnout and this association is partially mediated by fear of infection.Perceived appreciation from management and family support on the other hand are associated with lower stress and burnout.Findings are based on self-reported data from a cross-sectional online survey, thus, there may be social desirability bias; associations described are not causal; and the online survey may limit generalizability.
Environmental risk factors of airborne viral transmission: Humidity, Influenza and SARS-CoV-2 in the Netherlands
Authors: Ravelli Edsard , Martinez Rolando Gonzales 
Published: August 2020

AbstractObjectiveThe relationship between specific humidity and influenza/SARS-CoV-2 in the Netherlands is evaluated over time and at regional level.DesignParametric and non-parametric correlation coefficients are calculated to quantify the relationship between humidity and influenza, using five years of weekly data. Bayesian spatio-temporal models—with a Poisson and a Gaussian likelihood—are estimated to find the relationship between regional humidity and the daily cases of SARS-CoV-2 in the municipalities and provinces of the Netherlands.ResultsAn inverse (negative) relationship is observed between specific humidity and the incidence of influenza between 2015 and 2019. The space-time analysis indicates that an increase of specific humidity of one gram of water vapor per kilogram of air (1 g/kg) is related to a reduction of approximately 5% in the risk of COVID-19 infections.ConclusionsThe increase in humidity during the outbreak of the SARS-CoV-2 in the Netherlands helped to reduce the risk of regional COVID-19 infections. Public policies that promote higher levels of specific humidification—above 6 g/Kg—can lead to significant reductions in the spread of respiratory viruses, such as influenza and SARS-CoV-2.
Life course longitudinal growth and risk of knee osteoarthritis at age 53 years: evidence from the 1946 British birth cohort study
Authors: Staines Katherine A. , Hardy Rebecca , Samvelyan Hasmik J. , Ward Kate A. , Cooper Rachel 
Published: August 2020

AbstractObjectivesTo examine the relationship between height gain across childhood and adolescence with knee osteoarthritis in the MRC National Survey of Health and Development (NSHD).MethodsData are from 3035 male and female participants of the NSHD. Height was measured at ages 2, 4, 6, 7, 11 and 15 years, and self-reported at ages 20 and 26 years. Associations between (i) height at each age (ii) height gain during specific life periods (iii) Super-Imposition by Translation And Rotation (SITAR) growth curve variables of height size, tempo and velocity, and knee osteoarthritis at 53 years were tested.ResultsIn sex-adjusted models, taller height at 4 and 6 years were modestly associated with decreased odds of knee osteoarthritis at age 53 (ORs per 1cm increase in height at age 6: 0.97 and age 4: 0.98 (95% CI: 0.95-1.00)). These associations were attenuated after adjustment for potential confounders. Similarly, taller adult achieved height measured at 26 and 53 years of age were associated with decreased odds of knee osteoarthritis (OR per 1cm increase in height: 0.98 (95% CI 0.96 to 1.00)). No associations were found between height gain during specific life periods or the SITAR growth curve variables and odds of knee osteoarthritis.ConclusionsThere was some limited evidence to suggest that taller height in childhood is associated with decreased odds of knee osteoarthritis at age 53 years in this cohort. This work enhances our understanding of osteoarthritis predisposition and the contribution of life course height to this.
Potentially zoonotic gastrointestinal nematodes co-infecting free ranging non-human primates in Kenyan urban centres
Authors: Mbuthia Peris , Murungi Edwin , Owino Vincent , Akinyi Mercy , Eastwood Gillian , Nyamota Richard , Lekolool Isaac , Jeneby Maamun 
Published: August 2020

AbstractBackgroundNatural infections with soil transmitted nematodes occur in non-human primates (NHPs) and have the potential to cross primate-species boundaries and cause diseases of significant public health concern. Despite their presence in most urban centres in Kenya, comprehensive studies on their gastrointestinal parasites are scant.ObjectiveConduct a cross-sectional survey to identify zoonotic nematodes in free-ranging NHPs found within four selected urban and peri-urban centres in Kenya.MethodsA total of 86 NHPs: 41 African green monkeys [AGM] (Chlorocebus aethiops), 30 olive baboons (Papio anubis), 5 blue monkeys (Cercopithecus mitis stuhlmanni) and 10 red tailed monkeys (Cercopithecus ascanius) were sampled once in situ and released back to their habitat. Microscopy was used to identify nematodes egg and larvae stages in the samples. Subsequently, PCR coupled with high-resolution melting (PCR-HRM) analysis and sequencing were used to identify nodule worms.ResultsNHPs inhabiting densely populated urban environs in Kenya were found infected with a rich diversity of nematodes including three potentially zoonotic nematodes including Oesophagostomum stephanostomum, Oesophagostomum bifurcum and Trichostrongylus colubriformis and co-infections were common.ConclusionPhylogenetic analysis showed that O. stephanostomum from red tailed and blue monkeys have a close evolutionary relatedness to human isolates suggesting the zoonotic potential of this parasite. Moreover, we also report the first natural co-infection of O. bifurcum and O. stephanostomum in free-ranging AGMs.
Targeting pentose phosphate pathway for SARS-CoV-2 therapy
Authors: Bojkova Denisa , Costa Rui , Bechtel Marco , Ciesek Sandra , Michaelis Martin , Cinatl Jindrich 
Published: August 2020

AbstractIt becomes more and more obvious that deregulation of host metabolism play an important role in SARS-CoV-2 pathogenesis with implication for increased risk of severe course of COVID-19. Furthermore, it is expected that COVID-19 patients recovered from severe disease may experience long-term metabolic disorders. Thereby understanding the consequences of SARS-CoV-2 infection on host metabolism can facilitate efforts for effective treatment option. We have previously shown that SARS-CoV-2-infected cells undergo a shift towards glycolysis and that 2-deoxy-D-glucose (2DG) inhibits SARS-CoV-2 replication. Here, we show that also pentose phosphate pathway (PPP) is remarkably deregulated. Since PPP supplies ribonucleotides for SARS-CoV-2 replication, this could represent an attractive target for an intervention. On that account, we employed the transketolase inhibitor benfooxythiamine and showed dose-dependent inhibition of SARS-CoV-2 in non-toxic concentrations. Importantly, the antiviral efficacy of benfooxythiamine was further increased in combination with 2DG.
Efficient 5-OP-RU-induced enrichment of Mucosal-associated invariant T cells in the murine lung does not enhance control of aerosolMycobacterium tuberculosisinfection
Authors: Vorkas Charles Kyriakos , Levy Olivier , Skular Miroslav , Li Kelin , Aubé Jeffrey , Glickman Michael S. 
Published: August 2020

AbstractMucosal-associated invariant T (MAIT) cells are an innate-like T cell subset in mammals that recognize microbial vitamin B metabolites presented by the evolutionarily conserved MHC I-related molecule MR1. Emerging data suggest that MAIT cells may be an attractive target for vaccine-induced protection against bacterial infections because of their rapid cytotoxic responses at mucosal services to a widely conserved bacterial ligand. In this study, we tested whether a MAIT cell priming strategy could protect against aerosolMycobacterium tuberculosis(Mtb) infection in mice. Intranasal co-stimulation with the lipopeptide TLR 2/6 agonist, Pam2Cys (P2C), and the synthetic MR1 ligand, 5-OP-RU, resulted in robust expansion of MAIT cells in lung. Although MAIT cell priming significantly enhanced MAIT cell activation and expansion early afterMtbchallenge, these MAIT cells did not restrictMtbbacterial load. MAIT cells were depleted later in infection, with decreased detection of granzyme B+and IFNγ+MAIT cells relative to uninfected P2C/5-OP-RU-treated mice. Decreasing the infectious inoculum, varying the time between priming and aerosol infection, and testing MAIT cell priming in NOS2 deficient mice all failed to reveal an effect of P2C/5-OP-RU induced MAIT cells onMtbcontrol. We conclude that intranasal MAIT cell priming in mice induces early MAIT cell activation and expansion afterMtbexposure, without attenuatingM. tuberculosisgrowth, suggesting thatMtbevades MAIT cell-dependent immunity.
Genome-scale mapping reveals complex regulatory activities of RpoN inYersinia pseudotuberculosis
Authors: Mahmud F.A.K.M. , Nilsson K. , Fahlgren A. , Navais R. , Choudhry R. , Avican K. , Fallman M. 
Published: August 2020

ABSTRACTRpoN, an alternative sigma factor commonly known as sigma 54, is implicated in persistent stages ofYersinia pseudotuberculosisinfections in which genes associated with this regulator are upregulated. We here combined phenotypic and genomic assays to provide insight into its role and function in this pathogen. RpoN was found essential forY. pseudotuberculosisvirulence in mice, andin vitrofunctional assays showed that it controls biofilm formation and motility. Mapping genome-wide associations ofY. pseudotuberculosisRpoN using chromatin immunoprecipitation coupled with next-generation sequencing identified an RpoN-binding motif located at 103 inter- and intragenic sites on both sense and anti-sense strands. Deletion ofrpoNhad a large impact on gene expression, including down-regulation of genes encoding proteins involved in flagellar assembly, chemotaxis, and quorum sensing. There were also clear indications of cross talk with other sigma factors, together with indirect effects due to altered expression of other regulators. Matching differential gene expression with locations of the binding sites implicated around 130 genes or operons potentially activated or repressed by RpoN. Mutagenesis of selected intergenic binding sites confirmed both positive and negative regulatory effects of RpoN binding. Corresponding mutations of intragenic sense sites had less impact on associated gene expression. Surprisingly, mutating intragenic sites on the anti-sense strand commonly reduced expression of genes encoded by the corresponding sense strand.IMPORTANCEThe alternative sigma factor, RpoN (σ 54), which is widely distributed in eubacteria have been implicated to control gene expression of importance for numerous functions including virulence. Proper responses to host environments are crucial for bacteria to establish infection and regulatory mechanisms involved are therefore of high interest for development of future therapeutics. Little is known about the function of RpoN in the intestinal pathogenY. pseudotuberculosisand we therefore investigated its regulatory role in this pathogen. This regulator was indeed found to be critical for establishment of infection in mice, likely involving its requirement for motility and biofilm formation. The RpoN regulon involved both activating and suppressive effects on gene expression which could be confirmed with mutagenesis of identified binding sites. This is the first of its kind study of RpoN inY. pseudotuberculosisrevealing complex regulation of gene expression involving both productive and silent effects of its binding to DNA providing important information about RpoN regulation in enterobacteria.
Methanotrophic Community Detected by DNA-SIP at Bertioga’s Mangrove Area, Southeast Brazil
Authors: Carmo Linhares Débora do , Saia Flávia Talarico , Delgado Duarte Rubens Tadeu , Nakayama Cristina Rossi , de Melo Itamar Soares , Pellizari Vivian Helena 
Published: August 2020

AbstractMethanotrophic bacteria can use methane as sole carbon and energy source. Its importance in the environment is related to the mitigation of methane emissions from soil and water to the atmosphere. Brazilian mangroves are highly productive, have potential to methane production, and it is inferred that methanotrophic community is of great importance for this ecosystem. The scope of this study was to investigate the functional and taxonomic diversity of methanotrophic bacteria present in the anthropogenic impacted sediments from Bertioga’s mangrove (SP, Brazil). Sediment sample was cultivated with methane and the microbiota actively involved in methane oxidation was identified by DNA-based stable isotope probing (DNA-SIP) using methane as a labeled substrate. After 4 days of incubation and consumption of 0.7 mmol of methane, the most active microorganisms were related to methanotrophs Methylomonas and Methylobacter as well as to methylotrophic Methylotenera, indicating a possible association of these bacterial groups within a methane derived food chain in the Bertioga mangrove. The abundance of genera Methylomonas, able to couple methane oxidation to nitrate reduction, may indicate that under low dissolved oxygen tensions some aerobic methanotrophs could shift to intraerobic methane oxidation to avoid oxygen starvation.