bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recent advances in small-molecular therapeutics for COVID-19
Authors: Zhong Lei , Zhao Zhipeng , Peng Xuerun , Zou Jun , Yang Shengyong 
Published: September 2022

Abstract
The COVID-19 pandemic poses a fundamental challenge to global health. Since the outbreak of SARS-CoV-2, great efforts have been made to identify antiviral strategies and develop therapeutic drugs to combat the disease. There are different strategies for developing small molecular anti-SARS-CoV-2 drugs, including targeting coronavirus structural proteins (e.g. spike protein), non-structural proteins (nsp) (e.g. RdRp, Mpro, PLpro, helicase, nsp14, and nsp16), host proteases (e.g. TMPRSS2, cathepsin, and furin) and the pivotal proteins mediating endocytosis (e.g. PIKfyve), as well as developing endosome acidification agents and immune response modulators. Favipiravir and chloroquine are the anti-SARS-CoV-2 agents that were identified earlier in this epidemic and repurposed for COVID-19 clinical therapy based on these strategies. However, their efficacies are controversial. Currently, three small molecular anti-SARS-CoV-2 agents, remdesivir, molnupiravir, and Paxlovid (PF-07321332 plus ritonavir), have been granted emergency use authorization or approved for COVID-19 therapy in many countries due to their significant curative effects in phase III trials. Meanwhile, a large number of promising anti-SARS-CoV-2 drug candidates have entered clinical evaluation. The development of these drugs brings hope for us to finally conquer COVID-19. In this account, we conducted a comprehensive review of the recent advances in small molecule anti-SARS-CoV-2 agents according to the target classification. Here we present all the approved drugs and most of the important drug candidates for each target, and discuss the challenges and perspectives for the future research and development of anti-SARS-CoV-2 drugs.
Symbiotic Nodule Development and Efficiency in the Medicago truncatula Mtefd-1 Mutant Is Highly Dependent on Sinorhizobium Strains
Authors: Jardinaud Marie-Françoise , Carrere Sebastien , Gourion Benjamin , Gamas Pascal 
Published: September 2022

Abstract
Symbiotic nitrogen fixation (SNF) can play a key role in agroecosystems to reduce the negative impact of nitrogen fertilizers. Its efficiency is strongly affected by the combination of bacterial and plant genotypes, but the mechanisms responsible for the differences in the efficiency of rhizobium strains are not well documented. In Medicago truncatula, SNF has been mostly studied using model systems, such as M. truncatula A17 in interaction with Sinorhizobium meliloti Sm2011. Here we analyzed both the wild-type (wt) A17 and the Mtefd-1 mutant in interaction with five S. meliloti and two Sinorhizobium medicae strains. ETHYLENE RESPONSE FACTOR REQUIRED FOR NODULE DIFFERENTIATION (MtEFD) encodes a transcription factor, which contributes to the control of nodule number and differentiation in M. truncatula. We found that, in contrast to Sm2011, four strains induce functional (Fix+) nodules in Mtefd-1, although less efficient for SNF than in wt A17. In contrast, the Mtefd-1 hypernodulation phenotype is not strain-dependent. We compared the plant nodule transcriptomes in response to SmBL225C, a highly efficient strain with A17, versus Sm2011, in wt and Mtefd-1 backgrounds. This revealed faster nodule development with SmBL225C and early nodule senescence with Sm2011. These RNA sequencing analyses allowed us to identify candidate plant factors that could drive the differential nodule phenotype. In conclusion, this work shows the value of having a set of rhizobium strains to fully evaluate the biological importance of a plant symbiotic gene.
Inequality in the availability of residential air conditioning across 115 US metropolitan areas
Authors: Romitti Yasmin , Sue Wing Ian , Spangler Keith R , Wellenius Gregory A 
Published: September 2022

AbstractContinued climate change is increasing the frequency, severity, and duration of populations’ high temperature exposures. Indoor cooling is a key adaptation, especially in urban areas, where heat extremes are intensified—the urban heat island effect (UHI)—making residential air conditioning (AC) availability critical to protecting human health. In the United States, the differences in residential AC prevalence from one metropolitan area to another is well understood, but its intra-urban variation is poorly characterized, obscuring neighborhood-scale variability in populations’ heat vulnerability and adaptive capacity. We address this gap by constructing empirically derived probabilities of residential AC for 45,995 census tracts across 115 metropolitan areas. Within cities, AC is unequally distributed, with census tracts in the urban “core” exhibiting systematically lower prevalence than their suburban counterparts. Moreover, this disparity correlates strongly with multiple indicators of social vulnerability and summer daytime surface UHI intensity, highlighting the challenges that vulnerable urban populations face in adapting to climate-change driven heat stress amplification.
Reading the Ottoman Empire: Intertextuality and Experience in Henry Blount’s Voyage into the Levant (1636)
Authors: Din-Kariuki Natalya 
Published: September 2022

Abstract
The English traveller Henry Blount (1602–1682), author of A Voyage into the Levant (1636), is renowned for attempting to view the Ottoman Empire with an open mind and to understand it on its own terms. Scholars of the Voyage have examined Blount’s attitude to cultural difference, as well as his relationship to emerging discourses of empiricism, especially the works of Francis Bacon. This essay argues that the cultural politics and philosophical outlook of the Voyage are fundamentally connected to, and, in some cases, problematized by, Blount’s intertextual strategies. It shows that Blount’s digestion of his reading shapes his theoretical approach to travel, including his understanding of perception, cognition, and experience, and is central to his description of the Ottoman Empire. As well as identifying Blount’s borrowings from and paraphrases of writings by Bacon, Michel de Montaigne, George Sandys, and, indirectly, Aristotle, my argument demonstrates that early modern travel writing offers an especially striking example of the parallels between observation and reading that characterize the writings of the period more generally.
Trends in prevalence of short sleep duration and trouble sleeping among US adults, 2005–2018
Authors: Wang Shanshan , Rossheim Matthew E , Nandy Rajesh R 
Published: September 2022

Abstract

Study Objectives
To determine trends in prevalence of short sleep duration and trouble sleeping among US adults from 2005 to 2018, and to assess how sleep trends vary by sex and race/ethnicity.

Methods
Seven cycles of the National Health and Nutrition Examination Survey data between 2005–2006 and 2017–2018 were analyzed. Trouble sleeping and sleep duration were self reported. Short sleep duration was defined as sleep duration ≤6 hr. Age-standardized prevalence of reporting trouble sleeping to a health care provider and short sleep duration were estimated among the overall US adult population, and by sex and race/ethnicity.

Results
From 2005 to 2014, the age-adjusted prevalence of short sleep duration remained similar in the overall population (p for trend &gt;0.05). Non-Hispanic Black people had the highest prevalence of short sleep duration among all race/ethnicity groups in all seven cycles. The prevalence of short sleep duration appears lower in 2015–2018 than in 2005–2014 due to different measurement methods applied. However, from 2005 to 2018, there were increasing trends in age-adjusted prevalence of reporting trouble sleeping to a health care provider in the overall population, among both men and women, and all race/ethnicity groups (p for trend &lt;0.05). Among all the race/ethnicity groups, non-Hispanic White people had the highest prevalence of reporting trouble sleeping to a healthcare provider.

Conclusion
Findings depict the persistence of sleep-related issues in the United States and possible risk factors, as well as racial disparities.
Pharmacodynamic Model-Based Safety Management of Eribulin-Induced Myelosuppression in Patients With Breast Cancer
Authors: Kasai Hidefumi , Poppenberg Kim Linda , Fermanelli Valentina , Otani Yuki , Tanigawara Yusuke 
Published: September 2022

Background:
Neutropenia is a major dose-limiting toxicity of cancer chemotherapy. Semimechanistic mathematical models have been applied to describe the time course of neutrophil counts. The objectives of this study were to develop a mathematical model describing changes in neutrophil counts during eribulin treatment, to apply the empirical Bayes method to predict the probability of developing neutropenia ≥ grade 3 during eribulin treatment in each patient, and to propose the implementation of this mathematical tool in clinical practice for individual safety management.

Methods:
The present model analysis and subsequent external evaluation were performed using the data of 481 patients with breast cancer, previously obtained from a postmarketing surveillance (training set) and a phase 2 clinical study (validation set). The model we previously reported (Kawamura et al 2018) was modified to improve its predictive capability. The individual time course of neutrophil changes during the treatment period was predicted by the empirical Bayes method using the observed neutrophil counts at baseline and the first measurement after the first eribulin dose. To evaluate the predictability of this method, the predicted neutrophil counts were compared with those of the observed values.

Results:
The developed model provided good individual predictions, as indicated by the goodness-of-fit plots between the predicted and observed neutrophil counts, especially for a lower neutrophil count range. Days required to reach the nadir after the dose were also well-predicted. The sensitivity, specificity, and accuracy of the prediction of neutropenia grade ≥3 were 76%, 53%, and 71%, respectively.

Conclusions:
We developed a mathematical method for predicting and managing the risk of neutropenia during eribulin treatment. This method is generally applicable to other cases of chemotherapy-induced neutropenia and can be a new practical tool for individual safety management.
Whole-Genome Promoter Profiling of Plasma Cell-Free DNA Exhibits Predictive Value for Preterm Birth
Authors: Guo Zhiwei , Wang Ke , Huang Xiang , Li Kun , Ouyang Guojun , Yang Xu , Tan Jiayu , Shi Haihong , Luo Liangping , Zhang Xincai , Zhang Min , Han Bowei , Zhai Xiangming , Wu Yingsong , Yang Fang , Yang Xuexi , Tang Jia 
Published: September 2022

AbstractPreterm birth (PTB) occurs in around 11% of all births worldwide, resulting in significant morbidity and mortality for both mothers and offspring. Identification of pregnancies at risk of preterm birth in early pregnancy may help improve intervention and reduce its incidence. However, there exist few methods for PTB prediction developed with large sample size, high throughput screening and validation in independent cohorts. Here, we established a large-scale, multi-center, and case-control study that included 2,590 pregnancies (2,072 full-term and 518 preterm pregnancies) from three independent hospitals to develop a preterm birth classifier. We implemented whole-genome sequencing on their plasma cfDNA and then their promoter profiling (read depth spanning from −1 KB to +1 KB around the transcriptional start site) was analyzed. Using three machine learning models and two feature selection algorithms, classifiers for predicting preterm delivery were developed. Among them, a classifier based on the support vector machine model and backward algorithm, named PTerm (Promoter profiling classifier for pretermprediction), exhibited the largest AUC value of 0.878 (0.852–0.904) following LOOCV cross-validation. More importantly, PTerm exhibited good performance in three independent validation cohorts and achieved an overall AUC of 0.849 (0.831–0.866). Taken together, PTerm could be based on current noninvasive prenatal test (NIPT) data without changing its procedure or adding detection cost, which can be easily adapted for preclinical tests.
Low-coverage genome sequencing for the detection of clinically relevant copy-number and mtDNA variants
Authors: Pajusalu Sander , Tooming Mikk , Oja Kaisa Teele , Šamarina Ustina , Kahre Tiina , Õunap Katrin 
Published: September 2022

AbstractBackgroundCompared to exome sequencing, genome sequencing is widely appreciated for its superior ability to detect a wide range of genetic variations including copy-number variants (CNVs) and mitochondrial (mtDNA) variants. We assessed whether low-coverage genome sequencing, a considerably cheaper approach, would detect clinically relevant CNVs and mtDNA variants and would thus be a cost-efficient supplement to exome sequencing in rare disease diagnostics.MethodsTo assess the level of sequencing depth needed for variant detection, first, 30x mean coverage genome sequencing data were subsampled to 0.5x, 1x, 2x, and 4x coverage files in silico followed by CNV and mtDNA detection. Based on the analysis, 2x short-read sequencing was selected to be performed in 16 patients with putatively pathogenic CNVs or mtDNA variants to assess the empirical sensitivity.ResultsFor CNV calling, 2x coverage was sufficient to detect all heterozygous CNVs greater than 10kb in size from in silico subsampled data. In experimental data, the results were similar, although a 16kb heterozygous deletion was once not detected. Regarding mtDNA variants, 2x coverage sufficed for variant confident variant calling and heteroplasmy assessment for all samples.ConclusionsLow-coverage genome sequencing may be used to complement exome sequencing for simultaneous mtDNA variant and CNV detection.
Spliceosome Inhibition in SF3B1-Mutated Uveal Melanoma
Authors: Nguyen Josephine Q.N. , Drabarek Wojtek , Leeflang Aïsha M.C.H.J. , Brands Tom , van den Bosch Thierry P.P. , Verdijk Robert M. , van de Werken Harmen J.G. , van Riet Job , Paridaens Dion , de Klein Annelies , Brosens Erwin , Kiliç Emine 
Published: September 2022

AbstractTreatment of uveal melanoma (UM) patients with metastatic disease is unfortunately limited. Twenty percent of UM harbor a mutation in splicing factor gene SF3B1, suggesting that aberrant spliceosome functioning plays a vital role in tumorigenesis. Splicing inhibitors exploit the preferential sensitivity of spliceosome compromised leukemic cells to these compounds. We have studied the effect of splicing inhibitor E7107 using two UM cell lines and ex vivo cultured SF3B1 and BAP1 mutated primary UM tumor slices. These UM cell lines and ex vivo tumor slices were exposed for 24h to different concentrations of E7107. Tumor slices were stained with H&E and incubated with BAP1, MelanA, MIB-1 and caspase-3 antisera. E7107 exposed UM cell lines showed decreased cell viability and increased apoptosis with the largest effect sizes in SF3B1-mutated UM. A similar effect was observed upon exposure of E7107 on UM tumor slices. Additionally, RNA was isolated for transcriptome analysis and the type and number of alternative and aberrant transcripts was evaluated. Ninety-seven transcripts had a decrease in aberrant transcripts in all samples after E7107 exposure, and this effect was mostly in intron retention. This study indicates / suggests that mutated SF3B1 UM cells are more sensitive to splicing inhibitor E7107 compared to wild-type SF3B1 UM cells.Simple SummaryUveal melanoma (UM) is an aggressive malignancy of the eye. UM prognosis varies and depends on mutational status. Mutations in spliceosome gene Splicing Factor 3b subunit 1 (SF3B1) are in UM associated with late onset metastasis. Also in other malignancies, such as breast cancer or leukemia, SF3B1 mutations have been implied as drivers for tumor formation. Targeting the spliceosome with inhibitors is possible and would make SF3B1-mutated UM amenable for treatment. We investigated and demonstrated using two cell lines and ex-vivo culturing of 3 SF3B1-mutated tumors and 17 SF3B1-wildtype tumors that spliceosome inhibitor E7107 decreased the cell viability of both SF3B1-mutated and SF3B1-wildtype UM cell line, but significantly more in SF3B1-mutated UM cell line. Therefore, inhibiting the spliceosome has the highest therapeutic potential in SF3B1-mutated UM, but further research is recommended to determine the best suited strategy to minimize risk and maximize efficacy in a therapeutic setting.
A Process-Mining Model to Detect Adverse Postoperative Blood Transfusions
Authors: Sumer Ahmet Murat , Ceylan Cemil 
Published: September 2022

ABSTRACTImportanceErrors that threaten patient safety can cause patient harm, death, and rising health care costs. Manual process to expose adverse events (AE) increase time spend to detect them and increase costs of detection.ObjectiveThis study aims to make it easier and faster to expose AEs related with postoperative blood usages by process mining.DesignThese errors can be reported voluntarily by healthcare givers or exposed by Global Trigger Tool (GTT) determined by the Institute for Healthcare Improvement (IHI). With process mining ‘Transfusion of Blood or Use of Blood Products’ (C1) cases were exposed in a data set. Actual life process was discovered and GTT C1 was searched as a process pattern in the discovered process. Instead of reviewing all cases manually, only detected cases were reviewed by patient safety subject matter experts.Setting and ParticipantsAnadolu Medical Center, Turkey was selected as the reference site for this quality improvement study. The data set includes 42,086 records, 2,870 cases and 20 activities for the period between October and December 2018.Main Outcomes and MeasuresWith the new process mining model, data was reduced to 2,704 records, 57 cases and 16 activities. 57 cases detected by the model were analyzed by the expert group and 10 of them are defined as AEs. Rate of C1 AEs per medical record is 1.0%. The rate of C1 AEs per medical record was between 1.3% and 8.3% in other research papers.Conclusions and RelevanceInstead of running the classic GTT model manually, only detected 57 patient files were analyzed. The new model 95% decreases time of experts who will review medical records to expose AEs.
Higher risk of SARS-CoV-2 Omicron BA.4/5 infection than of BA.2 infection after previous BA.1 infection, the Netherlands, 2 May to 24 July 2022
Authors: Andeweg Stijn P. , de Gier Brechje , Vennema Harry , van Walle Ivo , van Maarseveen Noortje , Kusters Nina E. , de Melker Hester E. , Hahné Susan J.M. , van den Hof Susan , Eggink Dirk , Knol Mirjam J. 
Published: September 2022

AbstractWe investigate differences in protection from previous infection and/or vaccination against infection with Omicron BA.4/5 or BA.2. We observed a higher percentage of registered previous SARS-CoV-2 infections among 19836 persons infected with Omicron BA.4/5 compared to 7052 persons infected with BA.2 (31.3% vs. 20.0%) between 2 May and 24 July 2022 (adjusted odds ratio (aOR) for testing week, age group and sex: 1.4 (95%CI: 1.3-1.5)). No difference was observed in the distribution of vaccination status between BA.2 and BA.4/5 cases (aOR: 1.1 for primary and booster vaccination). Among reinfections, those newly infected with BA4/5 had a shorter interval between infections and the previous infection was more often caused by BA.1, compared to those newly infected with BA.2 (aOR: 1.9 (1.5-2.6). This suggests immunity induced by BA.1 is less effective against a BA.4/5 infection than against a BA.2 infection.
Brain and systemic inflammation in de novo Parkinson’s disease
Authors: Yacoubian Talene A. , Fang Yu-Hua Dean , Gerstenecker Adam , Amara Amy , Stover Natividad , Ruffrage Lauren , Collette Christopher , Kennedy Richard , Zhang Yue , Hong Huixian , Qin Hongwei , McConathy Jonathan , Benveniste Etty N. , Standaert David G. 
Published: September 2022

ABSTRACTObjectiveTo assess the presence of brain and systemic inflammation in subjects newly diagnosed with Parkinson’s disease (PD).BackgroundEvidence for a pathophysiologic role of inflammation in PD is growing. However, several key gaps remain as to the role of inflammation in PD, including the extent of immune activation at early stages, potential effects of PD treatments on inflammation, and whether pro-inflammatory signals are associated with clinical features and/or predict more rapid progression.MethodsWe enrolled subjects with de novo PD (n=58) and age-matched controls (n=62). Subjects underwent clinical assessments, including the Movement Disorder Society-United Parkinson’s Disease rating scale (MDS-UPDRS). Comprehensive cognitive assessment meeting MDS Level II criteria for mild cognitive impairment (MCI) testing was performed. Blood was obtained for flow cytometry and cytokine/chemokine analyses. Subjects underwent imaging with 18F-DPA-714, a translocator protein 18kd (TSPO) ligand, and lumbar puncture if eligible and consented.ResultsBaseline demographics and medical history were comparable between groups. PD subjects showed significant differences in University of Pennsylvania Smell Identification Test, Schwab and England Activities of Daily Living, Scales for Outcomes in PD autonomic dysfunction, and MDS-UPDRS scores. Cognitive testing demonstrated significant differences in cognitive composite, executive function, and visuospatial domain scores at baseline. PET imaging showed increased 18F-DPA-714 signal in PD subjects. 18F-DPA-714 signal correlated with several cognitive measures and some chemokines.Conclusions18F-DPA-714 imaging demonstrated increased central inflammation in de novo PD subjects compared to controls. Longitudinal follow-up will be important to determine whether the presence of inflammation predicts cognitive decline.