bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of the 13-Valent Pneumococcal Conjugate Vaccine on Invasive Pneumococcal Disease After Introduction Into Routine Pediatric Use
Authors: Baxter Roger , Aukes Laurie , Pelton Stephen I , Yee Arnold , Klein Nicola P , Gruber William C , Scott Daniel A , Center Kimberly J 
Published: April 2020

Abstract

Background
In 2010, the 13-valent pneumococcal conjugate vaccine (PCV13) replaced 7-valent PCV (PCV7) for protection against invasive pneumococcal disease (IPD). This study used laboratory surveillance data to examine the effect of PCV13 on IPD before and after PCV13 introduction among children aged 6 weeks to &lt;6 years and those aged ≥6 weeks.

Methods
Observational laboratory-based IPD surveillance data were compared for the periods May 2010–April 2018 and May 2008–April 2010 (the PCV7 period) using a database of Kaiser Permanente Northern California (KPNC) members with laboratory-confirmed IPD.

Results
Among children aged 6 weeks to 6 years, overall IPD incidence decreased from 11.57 per 100 000 during the PCV7 period to 4.09 per 100 000 after PCV13 introduction; PCV13-type IPD incidence decreased from 5.12 to 0.84 per 100 000. Non-PCV13−serotype IPD did not change significantly in this age group (PCV7 period, 1.71 per 100 000 and after PCV13, 2.52 per 100 000). Of cases occurring in this group, bacteremia was the most common clinical diagnosis. Across all ages, IPD decreased from 9.49 to 6.23 per 100 000 and PCV13-type IPD decreased from 4.67 to 1.89 per 100 000, changes being mostly due to decreases in serotypes 19A and 7F. IPD caused by non-PCV13 serotypes did not change (3.34 and 3.35 per 100 000). Overall, pneumococci isolated after PCV13 introduction had increased susceptibility to penicillin, cefotaxime, and ceftriaxone.
This prospective, laboratory-based surveillance study in Kaiser Permanente Northern California members examined annual IPD incidence before and after PCV13 introduction. In children aged 6 weeks to &lt;6 years, IPD caused by PCV13 serotypes decreased significantly (84%) during the surveillance period.

Conclusions
IPD incidence decreased further in every age group after PCV13 introduction, suggesting both direct vaccination effects in the infant population and indirect effects in adults.

Clinical Trials Registration
NCT01128439.
Deep Brain Stimulation in Epilepsy: A Role for Modulation of the Mammillothalamic Tract in Seizure Control?
Authors: Schaper Frédéric L W V J , Plantinga Birgit R , Colon Albert J , Wagner G Louis , Boon Paul , Blom Nadia , Gommer Erik D , Hoogland Govert , Ackermans Linda , Rouhl Rob P W , Temel Yasin 
Published: April 2020

Abstract

BACKGROUND
Deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS) can improve seizure control for patients with drug-resistant epilepsy (DRE). Yet, one cannot overlook the high discrepancy in efficacy among patients, possibly resulting from differences in stimulation site.

OBJECTIVE
To test the hypothesis that stimulation at the junction of the ANT and mammillothalamic tract (ANT-MTT junction) increases seizure control.

METHODS
The relationship between seizure control and the location of the active contacts to the ANT-MTT junction was investigated in 20 patients treated with ANT-DBS for DRE. Coordinates and Euclidean distance of the active contacts relative to the ANT-MTT junction were calculated and related to seizure control. Stimulation sites were mapped by modelling the volume of tissue activation (VTA) and generating stimulation heat maps.

RESULTS
After 1 yr of stimulation, patients had a median 46% reduction in total seizure frequency, 50% were responders, and 20% of patients were seizure-free. The Euclidean distance of the active contacts to the ANT-MTT junction correlates to change in seizure frequency (r2
= 0.24, P = .01) and is ∼30% smaller (P = .015) in responders than in non-responders. VTA models and stimulation heat maps indicate a hot-spot at the ANT-MTT junction for responders, whereas non-responders had no evident hot-spot.

CONCLUSION
Stimulation at the ANT-MTT junction correlates to increased seizure control. Our findings suggest a relationship between the stimulation site and therapy response in ANT-DBS for epilepsy with a potential role for the MTT. DBS directed at white matter merits further exploration for the treatment of epilepsy.
Development of mouse preimplantation embryos in space
Authors: Lei Xiaohua , Cao Yujing , Ma Baohua , Zhang Yunfang , Ning Lina , Qian Jingjing , Zhang Liwen , Qu Yongcun , Zhang Tao , Li Dehong , Chen Qi , Shi Junchao , Zhang Xudong , Ma Chiyuan , Zhang Ying , Duan Enkui 
Published: April 2020

AbstractThe development of life beyond planet Earth is a long-standing quest of the human race, but whether normal mammalian embryonic development can occur in space is still unclear. Here, we show unequivocally that preimplantation mouse embryos can develop in space, but the rate of blastocyst formation and blastocyst quality are compromised. Additionally, the cells in the embryo contain severe DNA damage, while the genome of the blastocysts developed in space is globally hypomethylated with a unique set of differentially methylated regions. The developmental defects, DNA damage and epigenetic abnormalities can be largely mimicked by the treatment with ground-based low-dose radiation. However, the exposure to simulated microgravity alone does not cause major disruptions of embryonic development, indicating that radiation is the main cause for the developmental defects. This work advances the understanding of embryonic development in space and reveals long-term extreme low-dose radiation as a hazardous factor for mammalian reproduction.
The Weaknesses of Weak Preemptionism
Authors: Hauswald Rico 
Published: April 2020

Abstract
According to preemptionism, a layperson should treat the fact that an epistemic authority believes p as a reason to believe p that replaces her other reasons relevant to believing p and is not simply added to them. Many authors have found the unqualified version of preemptionism, as defended by Linda Zagzebski, too strong. At the same time, a number of them have recently advocated weakened or qualified preemptionist accounts. In this paper, I criticise these accounts. I argue that some of them cannot explain the possibility of rational persistent disagreements between laypeople and epistemic authorities, while those that can explain it fail to account either for the extent to which justification is a holistic phenomenon or for the role of what I call ‘control reasons’ in the laypeople's epistemic conduct.
What Do Fund Flows Reveal about Asset Pricing Models and Investor Sophistication?
Authors: Jegadeesh Narasimhan , Mangipudi Chandra Sekhar 
Published: April 2020

Abstract
Recent evidence indicates that market model alphas are stronger predictors of mutual fund flows than alphas with other models. Some recent papers have interpreted this evidence to mean that CAPM is the best asset pricing model, but some others have interpreted it as evidence against investor sophistication. We evaluate the merits of these mutually exclusive interpretations. We show that no tenable inference about the validity of any asset pricing model can be drawn from this evidence. Rejecting the investor sophistication hypothesis is tenable, but the appropriate benchmark to judge sophistication is different from that used in this literature.
New Gambling Task Reveals an Atypical Relation Between Social Anxiety and Social Avoidance in Schizophrenia
Authors: Muthesius Ana , Hölzer Susanne , Grothey Anna Farina , Rubruck Jirko , Vogeley Kai , Schultz Johannes 
Published: April 2020

Abstract
A core symptom of schizophrenia is a deficit in social cognition. Furthermore, many patients suffer from relevant social anxiety. How social anxiety relates to social avoidance in schizophrenia is, however, still unclear. To address this question empirically, 30 participants with schizophrenia were compared to individually matched controls in a recently developed experimental task. In each trial, participants chose between a monetary gamble with a human partner providing social feedback and a defined monetary amount that varied across trials. The tendency to avoid the interaction under acceptance of monetary loss served as a measure of social avoidance. Patients showed higher levels of social anxiety assessed using the Liebowitz Social Anxiety Scale (LSAS) than controls, took longer to decide whether to engage in the social interaction and rated social feedback as less intense. Despite making rational decisions, patients surprisingly showed no social avoidance. We assume that the lack of experimentally induced social avoidance in contrast to the well-known social avoidance behavior in everyday life, also reflected by elevated self-rated LSAS scores, was due to a partial compensation of delayed social information processing in the absence of the time constraints in our task. This additional time may have allowed rational decisions and masked potential social avoidance behavior. We conclude that social anxiety in schizophrenia may have different characteristics than in individuals without schizophrenia, namely avoidance of negative feedback caused by prolonged social processing instead of fear of supposed negative feedback. Treatment strategies for social anxiety in schizophrenia may benefit from considering these differences.
Targeting the catecholamine-cytokine axis to prevent SARS-CoV-2 cytokine storm syndrome
Authors: Konig Maximilian F. , Powell Mike , Staedtke Verena , Bai Ren-Yuan , Thomas David L. , Fischer Nicole , Huq Sakibul , Khalafallah Adham M. , Koenecke Allison , Xiong Ruoxuan , Mensh Brett , Papadopoulos Nickolas , Kinzler Kenneth W. , Vogelstein Bert , Vogelstein Joshua T. , Athey Susan , Zhou Shibin , Bettegowda Chetan 
Published: April 2020

SummaryIn Coronavirus disease 2019 (COVID-19), the initial viral-replication phase is often followed by a hyperinflammatory reaction in the lungs and other organ systems that leads to acute respiratory distress syndrome (ARDS), the need for mechanical ventilation, and death despite maximal supportive care. As no antiviral treatments have yet proven effective, efforts to prevent progression to the severe stages of COVID-19 without inhibiting antiviral immune responses are desperately needed. We have previously demonstrated that a common, inexpensive, and well-tolerated class of drugs called alpha-1 adrenergic receptor (α1-AR) antagonists can prevent hyperinflammation (“cytokine storm”) and death in mice. We here present clinical data that supports the use of α1-AR antagonists in the prevention of severe complications of pneumonia, ARDS, and COVID-19.
Interaction between malarial transmission and BCG vaccination with COVID-19 incidence in the world map: A cross-sectional study
Authors: Goswami Rudra Prosad , Mittal Dheeraj , Goswami Rama Prosad 
Published: April 2020

AbstractBackgroundCOVID-19 (Corona virus Disease-2019) is a new public health emergency and is a pandemic currently. Incidence and mortality of COVID-19 vary in different geographical areas. In this study we aimed to analyse the relationship between malaria transmission and BCG vaccination with COVID-19 incidence in the world map.Materials and methodsWe collected malaria cases data (World Health Organisation (WHO), 2018), worldwide COVID-19 cases and mortality data (European Centre for Disease Prevention and Control) and data on BCG vaccination. COVID-19 incidence and mortality was compared.FindingsData on 5316978938 persons from 166 countries were analysed. Malaria incidence rate was negatively correlated with COVID-19 incidence rate (correlation coefficient = -0.513, p<0.001). Malaria free countries had significantly higher number of COVID-19 cases compared to malaria endemic countries. In Europe and Americas, countries, which have higher BCG vaccination coverage, had significantly less mortality per thousand population compared to those with low BCG coverage (median 0.0002 (0-0.0005) vs 0.0029 (0.0002-0.0177), p=0.017). The case fatality ratio of COVID-19 was related nonlinearly to the malaria incidence.ConclusionsThe results suggest the changing human immune system as we progress to eliminate parasitic diseases with time. Chloroquine exposure in malaria endemic zones might have a protective effect.Summary box“What is already known on this subject?”To the best of the authors no similar evidence, of the effect of malarial transmission on the COVID-19 global distribution is known. The effect of the Bacille Calmette Guérin (BCG) vaccine on modifying the human immune system has been reported before and is postulated to protective against certain viral infections like Influenza A (H1N1) and herpes virus.“What this study adds?”This study finds that COVID-19 incidence, worldwide is less in countries, which are malaria-endemic. In the European and American countries, increased BCG coverage may have some mortality advantage against COVID-19. The case fatality rate was related to malaria incidence, however, in a complex way. This could be a window into the changing landscape of human immune system as we progress to eliminate parasitic disease with time or this could be due to long-term protective body level of anti-malarials like chloroquine or hydroxychloroquine in countries with higher malaria incidence rate.
Anti-apoptotic clone 11 derived peptides induce in vitro death of CD4+ T cells susceptible to HIV-1 infection
Authors: Mikhailova Anastassia , Valle-Casuso José Carlos , David Annie , Monceaux Valérie , Volant Stevenn , Passaes Caroline , Elfidha Amal , Müller-Trutwin Michaela , Poyet Jean-Luc , Sáez-Cirión Asier 
Published: April 2020

ABSTRACTHIV-1 successfully establishes long-term infection in its target cells despite viral cytotoxic effects. We have recently shown that cell metabolism is an important factor driving CD4+ T-cell susceptibility to HIV-1 and the survival of infected cells. We show here that expression of anti-apoptotic clone 11 (AAC-11), an anti-apoptotic factor upregulated in many cancers, increased with progressive CD4+ T cell memory differentiation in association with the expression of cell cycle, activation and metabolism genes and correlated with susceptibility to HIV-1 infection. Synthetic peptides based on the LZ domain sequence of AAC-11, responsible for its interaction with molecular partners, were previously shown to be cytotoxic to cancer cells. Here we observed that these peptides also blocked HIV-1 infection by inducing cell death of HIV-1 susceptible primary CD4+ T-cells across all T-cell subsets. The peptides targeted metabolically active cells and had the greatest effect on effector and transitional CD4+ T cell memory subsets. Our results suggest that AAC-11 survival pathway is potentially involved in the survival of HIV-1 infectable cells and provide a proof of principle that some cellular characteristics can be targeted to eliminate the cells offering the best conditions to sustain HIV-1 replication.IMPORTANCEAlthough antiretroviral treatment efficiently blocks HIV multiplication, it cannot eliminate the cells already carrying integrated proviruses. In the search for a HIV cure the identification of new potential targets to selectively eliminate infected cells is of the outmost importance. We show here that peptides derived from the anti-apoptotic clone 11 (AAC-11), which expression levels correlated with susceptibility to HIV-1 infection of CD4+ T-cells, induced cytotoxicity in CD4+ T-cells showing the highest levels of activation and metabolic activity, conditions known to favor HIV-1 infection. Accordingly, CD4+ T-cells that survived the cytotoxic action of the AAC-11 peptides were resistant to HIV-1 replication. Our results identify a new potential molecular pathway to target HIV-1 infection.
Understanding the CoVID-19 pandemic Curve through statistical approach
Authors: Akhtar Ibrar ul Hassan 
Published: April 2020

AbstractCurrent research is an attempt to understand the CoVID-19 pandemic curve through statistical approach of probability density function with associated skewness and kurtosis measures, change point detection and polynomial fitting to estimate infected population along with 30 days projection. The pandemic curve has been explored for above average affected countries, six regions and global scale during 64 days of 22nd January to 24th March, 2020. The global cases infection as well as recovery rate curves remained in the ranged of 0 – 9.89 and 0 – 8.89%, respectively. The confirmed cases probability density curve is high positive skewed and leptokurtic with mean global infected daily population of 6620. The recovered cases showed bimodal positive skewed curve of leptokurtic type with daily recovery of 1708. The change point detection helped to understand the CoVID-19 curve in term of sudden change in term of mean or mean with variance. This pointed out disease curve is consist of three phases and last segment that varies in term of day lengths. The mean with variance based change detection is better in differentiating phases and associated segment length as compared to mean. Global infected population might rise in the range of 0.750 to 4.680 million by 24thApril 2020, depending upon the pandemic curve progress beyond 24th March, 2020. Expected most affected countries will be USA, Italy, China, Spain, Germany, France, Switzerland, Iran and UK with at least infected population of over 0.100 million. Infected population polynomial projection errors remained in the range of −78.8 to 49.0%.
A systematic framework for assessing the clinical impact of polygenic risk scores
Authors: Kulm Scott , Marderstein Andrew , Mezey Jason , Elemento Olivier 
Published: April 2020

ABSTRACTRisk prediction models provide empirical recommendations that ultimately aim to deliver optimal patient outcomes. Genetic information, in the form of a polygenic risk score (PRS), may be included in these models to significantly increase their accuracy. Several analyses of PRS accuracy have been completed, nearly all focus on only a few diseases and report limited statistics. This narrow approach has limited our ability to assess as a whole whether PRSs can provide actionable disease predictions. This investigation aims to address this uncertainty by comprehensively analyzing 23 diseases within the UK Biobank. Our results show that including the PRS to a base model containing age, sex and the top ten genetic principal components significantly improves prediction accuracy, as measured by ROC curves, in a majority 21 of 23 diseases and reclassifies on average 68% of the individuals in the top 5% risk group. For heart failure, breast cancer, prostate cancer and gout, decision curve analyses using the 5% risk threshold determined that including the PRS in the base model would correctly identity at least 60 more individuals who develop the disease for every 1000 individuals screened, without making any incorrect predictions. Analyses that included disease-specific risk factors, such as Body-Mass Index, and consider time of disease onset found similar PRS benefits. The improved prediction accuracy was translated to 10 instances in which medications/supplements and 94 instances in which lifestyle modifications lead to significantly greater reduction in disease risk for individuals in the top PRS quintile compared to the bottom PRS quintile. Finally we provide guidance for tailored, future PRS generation by comprehensively ranking methods that generate PRS weights and identifying genome wide association study characteristics that influence PRS predictions. The unification of significantly enhanced disease predictions, novel risk mitigation opportunities and improved methodological clarity indicate that PRSs carry far greater clinical impact than previously known.
Metagenomic evidence for a polymicrobial signature of sepsis
Authors: Tan Cedric Chih Shen , Acman Mislav , van Dorp Lucy , Balloux Francois 
Published: April 2020

AbstractOur understanding of the host component of sepsis has made significant progress. However, detailed study of the microorganisms causing sepsis, either as single pathogens or microbial assemblages, has received far less attention. Metagenomic data offer opportunities to characterise the microbial communities found in septic and healthy individuals. In this study we apply gradient-boosted tree classifiers and a novel computational decontamination technique built upon SHapley Additive exPlanations (SHAP) to identify microbial hallmarks which discriminate blood metagenomic samples of septic patients from that of healthy individuals. Classifiers had high performance when using the read assignments to microbial genera (AUROC = 0.995), including after removal of species ‘confirmed’ as the cause of sepsis through clinical testing (AUROC = 0.915). Models trained on single genera were inferior to those employing a polymicrobial model and we identified multiple co-occurring bacterial genera absent from healthy controls.ImportanceWhile prevailing diagnostic paradigms seek to identify single pathogens, our results point to the involvement of a polymicrobial community in sepsis. We demonstrate the importance of the microbial component in characterising sepsis, which may offer new biological insights into the aetiology of sepsis and allow the development of clinical diagnostic or even prognostic tools.
Crystal structure of full-length cytotoxic necrotizing factor CNFYreveals molecular building blocks for intoxication
Authors: Chaoprasid Paweena , Lukat Peer , Mühlen Sabrina , Heidler Thomas , Gazdag Emerich-Mihai , Dong Shuangshuang , Bi Wenjie , Rüter Christian , Kirchenwitz Marco , Steffen Anika , Jänsch Lothar , Stradal Theresia E. B. , Dersch Petra , Blankenfeldt Wulf 
Published: April 2020

AbstractCytotoxic necrotizing factors (CNFs) are bacterial single-chain exotoxins that modulate cytokinetic/oncogenic and inflammatory processes through activation of host cell Rho GTPases. To achieve this, they are secreted, bind surface receptors to induce endocytosis and translocate a catalytic unit into the cytosol to intoxicate host cells. A three-dimensional structure that provides insight into the underlying mechanisms is still lacking. Here, we determined the crystal structure of full-lengthYersinia pseudotuberculosisCNFY. CNFYconsists of five domains (D1-D5), and by integrating structural and functional data we demonstrate that D1-3 act as export and translocation module for the catalytic unit (D4-5) or fused β-lactamase reporter proteins. We further found that domain D4, which possesses structural similarity to ADP-ribosyl transferases, but had no equivalent catalytic activity, changed its position to interact extensively with D5 in the crystal structure of the free D4-5 fragment. This liberates D5 from a semi-blocked conformation in full-length CNFY, leading to higher deamidation activity. Finally, sequence comparisons identified the CNF translocation module in many uncharacterized bacterial proteins, suggesting its usability as a universal drug delivery tool.