bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi-tissue neocortical transcriptome-wide association study implicates 8 genes across 6 genomic loci in Alzheimer’s disease
Authors: Gockley Jake , Montgomery Kelsey S. , Poehlman William L. , Wiley Jesse C. , Liu Yue , Gerasimov Ekaterina , Greenwood Anna K. , Sieberts Solveig K. , Wingo Aliza P. , Wingo Thomas S. , Mangravite Lara M. , Logsdon Benjamin A. 
Published: May 2021

Abstract
Background
Alzheimer’s disease (AD) is an incurable neurodegenerative disease currently affecting 1.75% of the US population, with projected growth to 3.46% by 2050. Identifying common genetic variants driving differences in transcript expression that confer AD risk is necessary to elucidate AD mechanism and develop therapeutic interventions. We modify the FUSION transcriptome-wide association study (TWAS) pipeline to ingest gene expression values from multiple neocortical regions.

Methods
A combined dataset of 2003 genotypes clustered to 1000 Genomes individuals from Utah with Northern and Western European ancestry (CEU) was used to construct a training set of 790 genotypes paired to 888 RNASeq profiles from temporal cortex (TCX = 248), prefrontal cortex (FP = 50), inferior frontal gyrus (IFG = 41), superior temporal gyrus (STG = 34), parahippocampal cortex (PHG = 34), and dorsolateral prefrontal cortex (DLPFC = 461). Following within-tissue normalization and covariate adjustment, predictive weights to impute expression components based on a gene’s surrounding cis-variants were trained. The FUSION pipeline was modified to support input of pre-scaled expression values and support cross validation with a repeated measure design arising from the presence of multiple transcriptome samples from the same individual across different tissues.

Results
Cis-variant architecture alone was informative to train weights and impute expression for 6780 (49.67%) autosomal genes, the majority of which significantly correlated with gene expression; FDR < 5%: N = 6775 (99.92%), Bonferroni: N = 6716 (99.06%). Validation of weights in 515 matched genotype to RNASeq profiles from the CommonMind Consortium (CMC) was (72.14%) in DLPFC profiles. Association of imputed expression components from all 2003 genotype profiles yielded 8 genes significantly associated with AD (FDR < 0.05): APOC1, EED, CD2AP, CEACAM19, CLPTM1, MTCH2, TREM2, and KNOP1.

Conclusions
We provide evidence of cis-genetic variation conferring AD risk through 8 genes across six distinct genomic loci. Moreover, we provide expression weights for 6780 genes as a valuable resource to the community, which can be abstracted across the neocortex and a wide range of neuronal phenotypes.
Characterization of Alzheimer’s tau biomarker discordance using plasma, CSF, and PET
Authors:   the Alzheimer’s Disease Neuroimaging Initiative, Guo Yu , Huang Yu-Yuan , Shen Xue-Ning , Chen Shi-Dong , Hu Hao , Wang Zuo-Teng , Tan Lan , Yu Jin-Tai 
Published: May 2021

Abstract
Background
We aimed to investigate the tau biomarker discrepancies of Alzheimer’s disease (AD) using plasma tau phosphorylated at threonine 181 (p-tau181), cerebrospinal fluid (CSF) p-tau181, and AV1451 positron emission tomography (PET).

Methods
In the Alzheimer’s Disease Neuroimaging Initiative, 724 non-demented participants were categorized into plasma/CSF and plasma/PET groups. Demographic and clinical variables, amyloid-β (Aβ) burden, flortaucipir-PET binding in Braak regions of interest (ROIs), longitudinal changes in clinical outcomes, and conversion risk were compared.

Results
Across different tau biomarker groups, the proportion of participants with a discordant profile varied (plasma+/CSF− 15.6%, plasma−/CSF+ 15.3%, plasma+/PET− 22.4%, and plasma−/PET+ 6.1%). Within the plasma/CSF categories, we found an increase from concordant-negative to discordant to concordant-positive in the frequency of Aβ pathology or cognitive impairment, rates of cognitive decline, and risk of cognitive conversion. However, the two discordant categories (plasma+/CSF− and plasma−/CSF+) showed comparable performances, resulting in similarly reduced cognitive capacities. Regarding plasma/PET categories, as expected, PET-positive individuals had increased Aβ burden, elevated flortaucipir retention in Braak ROIs, and accelerated cognitive deterioration than concordant-negative persons. Noteworthy, discordant participants with normal PET exhibited reduced flortaucipir uptake in Braak stage ROIs and slower rates of cognitive decline, relative to those PET-positive. Therefore, individuals with PET abnormality appeared to have advanced tau pathological changes and poorer cognitive function, regardless of the plasma status. Furthermore, these results were found only in individuals with Aβ pathology.

Conclusions
Our results indicate that plasma and CSF p-tau181 abnormalities associated with amyloidosis occur simultaneously in the progression of AD pathogenesis and related cognitive decline, before tau-PET turns positive.
Primary malignant melanoma of the esophagus successfully treated with nivolumab: a case report
Authors: Ito Shingo , Tachimori Yuji , Terado Yuichi , Sakon Ryota , Narita Kazuhiro , Goto Manabu 
Published: May 2021

AbstractIntroductionPrimary malignant melanoma of the esophagus is a rare and aggressive disease that tends to have a poor response to chemotherapies. Previous studies have indicated that currently available treatment for primary malignant melanoma of the esophagus is insufficient. Here, we describe a case of recurrent primary malignant melanoma of the esophagus successfully treated with the immune checkpoint inhibitor nivolumab.Case presentationAn 81-year-old Japanese female presented with a 3-month history of dysphagia. She was medicated for hypertension and sarcoidosis. The patient had no past history of cutaneous, ocular, or other-site melanomas. An esophagoscopy identified a 30-mm giant tumor in the lower esophagus, at a site 30 cm from the incisors. Enhanced computed tomography revealed wall thickening measuring 30 mm in size at the middle-third of the intrathoracic esophagus, with no significant lymph node infiltration or distant metastasis. Esophageal biopsy showed proliferation of large round tumor cells and melanophages. On the basis of these findings, the patient was diagnosed with esophageal malignant melanoma and underwent esophagectomy and lymph node dissection with gastric tube reconstruction. Although the pathological diagnosis was primary malignant melanoma of the esophagus, the patient presented with multiple lymph node and bone metastases 4 months after surgery. Subsequently, treatment with nivolumab 240 mg every 2 weeks was administered as the first-line treatment. Diffusion-weighted imaging with background body signal suppression following eight courses of nivolumab revealed that the multiple lymph node and bone metastases were markedly reduced. The patient received 30 courses of nivolumab and has maintained the partial response. No severe adverse events related to the immunotherapy were recorded.ConclusionThe current study suggests that nivolumab may be a viable option for patients with metastatic primary malignant melanoma of the esophagus. Additional evidence from future clinical trials and research is necessary to fully validate these findings.
Further results on Mittag-Leffler synchronization of fractional-order coupled neural networks
Authors: Wang Fengxian , Wang Fang , Liu Xinge 
Published: May 2021

AbstractIn this paper, we focus on the synchronization of fractional-order coupled neural networks (FCNNs). First, by taking information on activation functions into account, we construct a convex Lur’e–Postnikov Lyapunov function. Based on the convex Lyapunov function and a general convex quadratic function, we derive a novel Mittag-Leffler synchronization criterion for the FCNNs with symmetrical coupled matrix in the form of linear matrix inequalities (LMIs). Then we present a robust Mittag-Leffler synchronization criterion for the FCNNs with uncertain parameters. These two Mittag-Leffler synchronization criteria can be solved easily by LMI tools in Matlab. Moreover, we present a novel Lyapunov synchronization criterion for the FCNNs with unsymmetrical coupled matrix in the form of LMIs, which can be easily solved by YALMIP tools in Matlab. The feasibilities of the criteria obtained in this paper are shown by four numerical examples.
Establishment of a population pharmacokinetics model of vancomycin in 94 infants with septicemia and its application in individualized therapy
Authors: Li Zhiling , Li Hongjing , Wang Chenyu , Jiao Zheng , Xu Feng , Sun Huajun 
Published: May 2021

Abstract
Background
We aim to develop a population pharmacokinetics (PopPK) model of vancomycin for the treatment of septicemia in infants younger than one year. Factors influence of the PK was investigated to optimize vancomycin dosing regimen.

Methods
The nonlinear mixed effects modelling software (NONMEM) was used to develop the PopPK model of vancomycin. The stability and predictive ability of the final model were assessed by using normalized prediction distribution errors (NPDE) and bootstrap methods. The final model was subjected to Monte Carlo simulation in order to determine the optimal dose.

Results
A total of 205 trough and peak concentrations in 94 infants (0–1 year of age) with septicemia were analyzed. The interindividual variability of the PK parameter was described by the exponential model. Residual error was better described by the proportional model than the mixed proportional and addition models. Serum creatinine concentration and body weight are the major factors that affect the PK parameters of vancomycin. The clearance was shown to be higher when ceftriaxone was co-treated. More than two model evaluation methods showed better stability than the base model, with superior predictive performance, which can develop individualized dosing regimens for clinical reference. Through prediction of final model, the trough concentration was more likely < 5 mg/L when a routine dose of 10 mg/kg is administered every 6 h to 3–9-month-old infants. Therefore, the dose should be increased in the treatment of infant septicemia.

Conclusions
The stable and effective PopPK model of vancomycin in Chinese infants with septicemia was established. This model has satisfactory predictive ability for clinically individualized dosing regimens in this vulnerable population.
Predictors of Cognitive Performance Among Infants Treated for Brain Tumors: Findings From a Multisite, Prospective, Longitudinal Trial
Authors: Ali Jeanelle S. , Ashford Jason M. , Swain Michelle A. , Harder Lana L. , Carlson-Green Bonnie L. , Miller Jonathan M. , Wallace Joanna , Kaner Ryan J. , Billups Catherine A. , Onar-Thomas Arzu , Merchant Thomas E. , Gajjar Amar , Conklin Heather M. 
Published: May 2021

PURPOSE Infants treated for CNS malignancies experience a significantly poorer response to treatment and are particularly at risk for neuropsychological deficits. The literature is limited and inconsistent regarding cognitive outcomes among this group. We investigated predictors of cognitive outcomes in children treated for brain tumors during infancy as part of a large, prospective, multisite, longitudinal trial. PATIENTS AND METHODS One hundred thirty-nine infants with a newly diagnosed CNS tumor were treated with chemotherapy, with or without focal proton or photon radiation therapy (RT). Cognitive assessments were conducted at baseline, 6 months, 1 year, and then annually for 5 years. The median length of follow-up was 816 days (26.8 months). Neurocognitive testing included assessment of intellectual functioning (intellectual quotient [IQ]), parent ratings of executive functioning and emotional and behavioral functioning, and socioeconomic status. RESULTS At baseline, IQ, parent-reported working memory, and parent-reported adaptive functioning were worse than normative expectations. Baseline cognitive difficulties were associated with younger age at diagnosis and lower socioeconomic status. Linear mixed models did not demonstrate a decline in IQ over time. There were increased parent-reported attention and executive problems over time. Increased concerns were related to supratentorial tumor location and CSF diversion. There were no differences in cognitive outcomes based on treatment exposure (chemotherapy-only v chemotherapy with RT and proton v photon focal RT). CONCLUSION Even before adjuvant therapy, young children with brain tumors experience cognitive difficulties that can affect quality of life. Changes in cognitive functioning over time were dependent on tumor location and surgical factors rather than adjuvant therapy. These findings may serve to guide treatment planning and indicate targets for cognitive monitoring and intervention.
Mineralocorticoid Receptor Antagonist Effect on Aldosterone to Renin Ratio in Patients With Primary Aldosteronism
Authors: Pecori Alessio , Buffolo Fabrizio , Burrello Jacopo , Mengozzi Giulio , Rumbolo Francesca , Avataneo Valeria , D’Avolio Antonio , Rabbia Franco , Bertello Chiara , Veglio Franco , Mulatero Paolo , Monticone Silvia 
Published: May 2021

Abstract

Context
Although current international guidelines recommend to avoid mineralocortcoid receptor antagonists in patients undergoing screening test for primary aldosteronism, a recent report suggested that mineralocorticoid receptor antagonist treatment can be continued without significant influence on screening results.

Objective
We aimed to evaluate the effect of mineralocorticoid receptor antagonists on the aldosterone to renin ratio in patients with primary aldosteronism.

Methods
We prospectively enrolled 121 patients with confirmed primary aldosteronism who started mineralocorticoid receptor antagonist (canrenone) treatment. Eighteen patients (11 with unilateral and 7 with bilateral primary aldosteronism) constituted the short-term study cohort and underwent aldosterone, renin, and potassium measurement after 2 and 8 weeks of canrenone therapy. The long-term cohort comprised 102 patients (16 with unilateral and 67 with bilateral primary aldosteronism, and 19 with undetermined subtype) who underwent hormonal and biochemical re-assessment after 2 to 12 months of canrenone therapy.

Results
Renin and potassium levels showed a significant increase, and the aldosterone to renin ratio displayed a significant reduction compared with baseline after both a short- and long-term treatment. These effects were progressively more evident with higher doses of canrenone and after longer periods of treatment. We demonstrated that canrenone exerted a deep impact on the diagnostic accuracy of the screening test for primary aldosteronism: the rate of false negative tests was raised to 16.7%, 38.9%, 54.5%, and 72.5% after 2 weeks, 8 weeks, 2 to 6 months, and 7 to 12 months of mineralocorticoid receptor antagonist treatment, respectively.

Conclusion
Mineralocorticoid receptor antagonists should be avoided in patients with hypertension before measurement of renin and aldosterone for screening of primary aldosteronism.
Rethinking the Boundaries of Class: Labor History and Theories of Class and Capitalism
Authors: Greene Julie 
Published: May 2021

AbstractThis article examines how the field of labor and working-class history has conceptualized class and assesses theories of class that can help us develop maximally illuminating concepts. Labor historians, particularly those whose work employs a transnational, gender, or racial lens of analysis, have advanced our understanding of how working people's lives are shaped by class. By connecting that scholarship to class theory, the article argues for reconceptualizing class to focus on the complex ways capitalism generates class relationships, embedding race, gender, and other historical dynamics within its formative parameters. It relies on work by Tithi Bhattacharya and Stuart Hall to articulate a specific vision of class relations under capitalism. Finally, the article concludes with praxis by applying Hall's and Bhattacharya's insights to the challenges academic knowledge workers face today amid the crisis of higher education, which is growing more pressing as a result of the economic disaster related to the COVID-19 pandemic. It concludes by addressing how our conceptualizations of class could shape efforts to build broad solidarities among knowledge workers in higher education.
(Dis)Solving the problem of aberrant protein states
Authors: Fare Charlotte M. , Shorter James 
Published: May 2021

ABSTRACT
Neurodegenerative diseases and other protein-misfolding disorders represent a longstanding biomedical challenge, and effective therapies remain largely elusive. This failure is due, in part, to the recalcitrant and diverse nature of misfolded protein conformers. Recent work has uncovered that many aggregation-prone proteins can also undergo liquid–liquid phase separation, a process by which macromolecules self-associate to form dense condensates with liquid properties that are compositionally distinct from the bulk cellular milieu. Efforts to combat diseases caused by toxic protein states focus on exploiting or enhancing the proteostasis machinery to prevent and reverse pathological protein conformations. Here, we discuss recent advances in elucidating and engineering therapeutic agents to combat the diverse aberrant protein states that underlie protein-misfolding disorders.
Moral Standards in the Organization: the Regulatory Nature and Management of Ethical Behavior of Employees
Authors: Romanova I. , Laas N. , Gurova E. 
Published: May 2021

The article presents the results of a study (questionnaire survey) of managers and ordinary employees of public and private Russian organizations on the problem of the regulatory role of ethical rules for labor / organizational behavior and the management of ethical actions of personnel. The answers of respondents to the questionnaire about the mission of moral standards in the organization and the importance of their observance are analyzed in detail and presented; on the state of compliance with ethical canons in the organization, detailed reasons and forms of their violation; on the preferred sanctions for violation / observance of moral standards; o the presence of Ethical Codes in companies and their purpose.
The results of the survey showed that ethical norms are the most important regulator of labor / organizational behavior, and their most important purpose is "the development of good relations between employees." Most of the respondents are satisfied with the state of observance of moral standards in their organizations, and also believe that the management pays sufficient attention to their observance. The study revealed that the main cause of violation of moral standards in companies is the personal characteristics of employees, then the management style, and then organizational factors. The most “popular” form of deviation from moral rules in the eyes of respondents is shirking orders. At the same time, the leading role of management is indicated as a role model, which is followed by ordinary employees when choosing ethical or unethical actions. For the most part, the organizations have not developed and do not have Codes of Ethics, the mission of which, according to the participants of the survey, is to orient staff towards ethical behavior and resolve the moral problems of the organization. At the same time, the respondents indicated that it is necessary to apply sanctions both for deviating from moral rules and for observing them.
The research results are practice-oriented. At the same time, they cannot reflect the entire variety of aspects of the influence of the regulatory essence of moral canons on labor / organizational behavior and its management system.
Better choice of the type of specimen used for untargeted metagenomic sequencing in the diagnosis of periprosthetic joint infections
Authors: He Renke , Wang Qiaojie , Wang Jin , Tang Jin , Shen Hao , Zhang Xianlong 
Published: May 2021

Aims As a proven and comprehensive molecular technique, metagenomic next-generation sequencing (mNGS) has shown its potential in the diagnosis of pathogens in patients with periprosthetic joint infection (PJI), using a single type of specimen. However, the optimal use of mNGS in the management of PJI has not been explored. In this study, we evaluated the diagnostic value of mNGS using three types of specimen with the aim of achieving a better choice of specimen for mNGS in these patients. Methods In this prospective study, 177 specimens were collected from 59 revision arthroplasties, including periprosthetic tissues, synovial fluid, and prosthetic sonicate fluid. Each specimen was divided into two, one for mNGS and one for culture. The criteria of the Musculoskeletal Infection Society were used to define PJI (40 cases) and aseptic failure (19 cases). Results The sensitivity and specificity of mNGS in the diagnosis of PJI were 95% and 94.7%, respectively, for all types of specimen. The sensitivity and specificity were 65% and 100%, respectively, for periprosthetic tissues, 87.5% and 94.7%, respectively, for synovial fluid, and 92.5% and 94.7%, respectively, for prosthetic sonicate fluid. The mNGS of prosthetic sonicate fluid outperformed that for other types of specimen in the rates of detection of pathogens (84.6%), sequencing reads (> ten-fold) and the rate of genome coverage (> five-fold). Conclusion mNGS could serve as an accurate diagnostic tool in the detection of pathogens in patients with a PJI using three types of specimen. Due to its superior perfomance in identifying a pathogen, mNGS of prosthetic sonicate fluid provides the most value and may partly replace traditional tests such as bacteriological culture in these patients. Cite this article: Bone Joint J 2021;103-B(5):923–930.
Particulate Matter Concentrations and Emission Rates at Two Retrofitted Manure-Belt Layer Houses
Authors: Knight Reyna M. , Tong Xinjie , Zhao Lingying , Manuzon Roderick B. , Darr Matthew J. , Heber Albert J. , Ni Ji-Qin 
Published: May 2021

HighlightsAnnual average PM10 (daily) and PM2.5 (hourly) concentrations of 509 ±203 and 43.3 ±36.1 µg m-3, respectively.Significant seasonal and diurnal variations in PM concentrations; higher in colder seasons and during daytime.Annual average PM10 (daily) and PM2.5 (hourly) emission rates of 17.9 ±9.6 and 1.41 ±1.53 mg d-1 hen-1, respectively.Significant diurnal variations in PM emission rates but inconsistent seasonal variations; higher during daytime.Abstract. Particulate matter (PM) concentration and emission rate information is needed to assess air quality concerns and environmental impacts related to egg production. Many egg layer buildings were retrofitted from high-rise to manure-belt houses over the past few decades. However, no studies have reported these PM data for the retrofitted layer houses. In this study, concentrations and emission rates of PM10 and PM2.5 were continuously monitored for 12 months at two commercial retrofitted manure-belt layer houses in the Midwestern U.S. The average daily mean PM10 and average hourly mean PM2.5 concentrations in the houses were 509 ±203 µg m-3 and 43.3 ±36.1 µg m-3, respectively. Significant seasonal and diurnal variations in PM concentrations were observed, with higher concentrations in colder seasons and during daytime. The average daily mean PM10 and average hourly mean PM2.5 emission rates from the two houses were 17.9 ±9.6 mg d-1 hen-1 and 1.41 ±1.53 mg d-1 hen-1, respectively. There were no consistent patterns in seasonal variations. Significant diurnal variations were also observed for PM emission rates, with higher PM emission rates observed during daytime. The PM concentrations were significantly correlated with ambient temperature, ventilation rate, bird age, egg production, daily mortality, and feed conversion ratio, while PM emission rates were significantly correlated with ambient temperature, bird age, bird mass, egg mass, and ventilation rate. Keywords: Diurnal variation, Dust, Egg production, PM, Poultry, Seasonal variation.