bluuebunny/crossref_metadata_2025_split huggingface dataset:
AFLAP: assembly-free linkage analysis pipeline using k-mers from genome sequencing data
Authors: Fletcher Kyle , Zhang Lin , Gil Juliana , Han Rongkui , Cavanaugh Keri , Michelmore Richard 
Published: April 2021

AbstractOur assembly-free linkage analysis pipeline (AFLAP) identifies segregating markers as k-mers in the raw reads without using a reference genome assembly for calling variants and provides genotype tables for the construction of unbiased, high-density genetic maps without a genome assembly. AFLAP is validated and contrasted to a conventional workflow using simulated data. AFLAP is applied to whole genome sequencing and genotype-by-sequencing data of F1, F2, and recombinant inbred populations of two different plant species, producing genetic maps that are concordant with genome assemblies. The AFLAP-based genetic map for Bremia lactucae enables the production of a chromosome-scale genome assembly.
The effectiveness of a modified Gui Zhi Fu Ling Wan formulation (Gynoclear™) for the treatment of endometriosis: a study protocol for a placebo-controlled, double-blind, randomised controlled trial
Authors: Armour Mike , Al-Dabbas Mahmoud A. , Ee Carolyn , Smith Caroline A. , Ussher Jane , Arentz Susan , Lawson Kenny , Abbott Jason 
Published: April 2021

Abstract
Background
Endometriosis is the presence of tissue similar to that of the endometrium outside the uterine cavity and is the most common cause of chronic pelvic pain. Current non-surgical treatments such as non-steroidal anti-inflammatories, oral contraceptive pills and hormonal treatments have limited effectiveness, and the side effect profile is bothersome. This study will evaluate the efficacy of Gynoclear™ by change in endometriosis-related pain based on the Endometriosis Pain Daily Diary (EPPD) scores.

Methods
This randomised, double-blind, placebo-controlled trial will recruit a minimum of 90 adult participants across Australia who have a laparoscopic visualisation/confirmation of endometriosis in the last 5 years and have current moderate or greater pelvic pain. Participants will be randomly allocated in a 1:1 ratio to receive either Gynoclear™ (active) or placebo. Gyncolear’s active ingredients are Carthamus tinctorius (Safflower), Cinnamomum cassia (Chinese cinnamon), Poria cocos (Hoelen), Paeonia suffriticosa (Tree peony), Paeonia lactiflora (Peony) and Salvia miltiorrhiza (Red sage). Participants are asked to complete a total of 5 months’ worth of pain diary entries via the EPDD v3, including 1-month screening, 2-month treatment period and 1-month post-treatment follow-up. The primary outcome variable is change in endometriosis-related pain based on the EPDD v3 scores. Secondary outcomes include change in health-related quality of life via the Endometriosis Health Profile (EHP-30), SF-12 and EQ-5D scores as well as changes in rescue analgesic usage, dyspareunia and fatigue via the EPDD.

Discussion
This study will determine the safety and efficacy of Gynoclear™ to reduce the severity and duration of non-cyclical pelvic pain, dysmenorrhoea, dyspareunia and other symptoms of endometriosis. Study outcomes will be of interest to health professionals and members of the public who suffer from endometriosis.

Trial registration
Australia and New Zealand Clinical Trials Registry ACTRN12619000807156. Registered on 3 June 2019.
Regulation of osteoclastogenesis by mast cell in rheumatoid arthritis
Authors: Kim Kyoung-Woon , Kim Bo-Mi , Won Ji-Yeon , Min Hong-Ki , Lee Kyung-Ann , Lee Sang-Heon , Kim Hae-Rim 
Published: April 2021

AbstractBackgroundIn the pathogenesis of rheumatoid arthritis (RA), the role of mast cells has not been revealed clearly. We aimed to define the inflammatory and tissue-destructive roles of mast cells in rheumatoid arthritis (RA).MethodsSerum and synovial fluid (SF) concentration levels of tryptase, chymase, and histamine were quantified using ELISA. After activating mast cells using IL-33, the production of TNF-α, IL-1β, IL-6, IL-17, RANKL, and MMPs was determined using real-time PCR and ELISA. Osteoclastogenesis was assessed in CD14+ monocytes from peripheral blood and SF, which were cultured with IL-33-activated mast cells, by counting TRAP-positive multinucleated cells.ResultsThe concentration levels of serum tryptase, chymase, and histamine and SF histamine were higher in patients with RA than in controls. FcεR1 and c-kit-positive mast cells were higher in RA synovium than in osteoarthritic (OA) synovium. Stimulation of mast cells by IL-33 increased the number of trypatse+chymase− and tryptase+chymase+ mast cells. IL-33 stimulation also increased the gene expression levels of TNF-α, IL-1β, IL-6, IL-17, RANKL, and MMP-9 in mast cells. Furthermore, IL-33 stimulated human CD14+ monocytes to differentiate into TRAP+ multinucleated osteoclasts. When CD14+ monocytes were co-cultured with mast cells, osteoclast differentiation was increased. Additionally, IL-33-activated mast cells stimulated osteoclast differentiation. The inhibition of intercellular contact between mast cells and monocytes using inserts reduced osteoclast differentiation.ConclusionsIL-33 increased inflammatory and tissue-destructive cytokines by activation of mast cells. Mast cells stimulated osteoclast differentiation in monocytes. Mast cells could stimulate osteoclastogenesis indirectly through production of tissue-destructive cytokines and directly through stimulation of osteoclast precursors.
Survival time among patients who were diagnosed with tuberculosis, the precocious deaths and associated factors in southern Brazil
Authors: dos Santos Danielle Talita , Arroyo Luiz Henrique , Alves Yan Mathias , Alves Luana Seles , Berra Thais Zamboni , Crispim Juliane de Almeida , Alves Josilene Dália , Ramos Denisse Andrea Cartagena , Alonso Jonas Bodini , de Assis Ivaneliza Simionato , Ramos Antônio Vieira , Dessunti Elma Mathias , Carvalho Pinto Ione , Palha Pedro Fredemir , Arcêncio Ricardo Alexandre , Nunes Carla 
Published: April 2021

Abstract
Background
A diagnosis of tuberculosis (TB) does not mean that the disease will be treated successfully, since death may occur even among those who are known to the health services. Here, we aimed to analyze patient survival time from the diagnosis of TB to death, precocious deaths, and associated factors in southern Brazil.

Methods
We conducted a longitudinal study with patients who were diagnosed with TB and who died due to the disease between 2008 and 2015 in southern Brazil. The starting point for measuring survival time was the patient’s diagnosis date. Techniques for survival analysis were employed, including the Kaplan-Meier test and Cox’s regression. A mixed-effect model was applied for identifying the associated factors to precocious deaths. Hazard ratio (HR) and odds ratio (OR) with 95% confidence intervals (95% CI) were estimated. We defined p value <0.05 as statistically significant for all statistics applied.

Results
One hundred forty-six patients were included in the survival analysis, observing a median survival time of 23.5 days. We observed that alcoholism (HR=1.55, 95% CI=1.04-2.30) and being male (HR=6.49, 95% CI=1.03-2.68) were associated with death. The chance of precocious death within 60 days was 10.48 times greater than the chance of early death within 30 days.

Conclusion
Most of the deaths occurred within 2 months after the diagnosis, during the intensive phase of the treatment. The use of alcohol and gender were associated with death, revealing inequality between men and women. This study advanced knowledge regarding the vulnerability associated with mortality. These findings must be addressed to fill a gap in the care cascades for active TB and ensure equity in health.
LncRNA LPAL2/miR-1287-5p/EGFR Axis Modulates TED-Derived Orbital Fibroblast Activation Through Cell Adhesion Factors
Authors: Wang Nuo , Hou Shi-ying , Qi Xin , Deng Mi , Cao Jia-min , Tong Bo-Ding , Xiong Wei 
Published: April 2021

Abstract

Context
The activation of orbital fibroblasts, the prime targets in thyroid eye disease (TED), is central to its underlying pathogenesis.

Objective
We aimed to investigate the mechanism of TED orbital fibroblast activation from the perspective of noncoding RNA regulation.

Methods
Immunofluorescence (IF) staining was applied to evaluate the fibrotic changes in target cells. Cell proliferation was evaluated by 5-ethoxy 2-deoxyuridine and colony-formation assays. Collagen I concentration was determined by enzyme-linked immunosorbent assay. Human microarray analysis was performed on 3 TED and 3 healthy control orbital tissue samples.

Results
Bioinformatics analysis showed that cell adhesion signaling factors were differentially expressed in TED tissues, including intercellular adhesion molecule (ICAM)-1, ICAM-4, vascular cell adhesion molecule, and CD44, which were all upregulated in diseased orbital tissues. Long noncoding RNA LPAL2 level was also upregulated in orbital tissues and positively correlated with ICAM-1 and ICAM-4 expression. Stimulation of the TED orbital fibroblasts by transforming growth factor-β1 (TGF-β1) significantly increased the expression of ICAM-1, ICAM-4, and LPAL2. Knockdown of LPAL2 in orbital fibroblasts inhibited TGF-β1–induced increases in cell adhesion factor levels and orbital fibroblast activation. Microarray profiling was performed on TED and normal orbital tissues to identify differentially expressed microRNAs, and miR-1287-5p was remarkably reduced within diseased orbital samples. miR-1287-5p was directly bound to the epidermal growth factor receptor (EGFR) 3′ untranslated region and LPAL2, and LPAL2 modulated EGFR/protein kinase B (AKT) signaling through targeting miR-1287-5p.

Conclusion
The LPAL2/miR-1287-5p axis modulated TGF-β1–induced increases in cell adhesion factor levels and TED orbital fibroblast activation through EGFR/AKT signaling.
Thyroid Immune-related Adverse Events Following Immune Checkpoint Inhibitor Treatment
Authors: Muir Christopher A , Clifton-Bligh Roderick J , Long Georgina V , Scolyer Richard A , Lo Serigne N , Carlino Matteo S , Tsang Venessa H M , Menzies Alexander M 
Published: April 2021

Abstract

Context
Thyroid dysfunction occurs commonly following immune checkpoint inhibition. The etiology of thyroid immune-related adverse events (irAEs) remains unclear and clinical presentation can be variable.

Objective
This study sought to define thyroid irAEs following immune checkpoint inhibitor (ICI) treatment and describe their clinical and biochemical associations.

Methods
We performed a retrospective cohort study of thyroid dysfunction in patients with melanoma undergoing cytotoxic T-lymphocyte antigen-4 (CTLA-4) and/or programmed cell death protein-1 (PD-1) based ICI treatment from November 1, 2009, to December 31, 2019. Thyroid function was measured at baseline and at regular intervals following the start of ICI treatment. Clinical and biochemical features were evaluated for associations with ICI-associated thyroid irAEs. The prevalence of thyroid autoantibodies and the effect of thyroid irAEs on survival were analyzed.

Results
A total of 1246 patients were included with a median follow-up of 11.3 months. Five hundred and eighteen (42%) patients developed an ICI-associated thyroid irAE. Subclinical thyrotoxicosis (n = 234) was the most common thyroid irAE, followed by overt thyrotoxicosis (n = 154), subclinical hypothyroidism (n = 61), and overt hypothyroidism (n = 39). Onset of overt thyrotoxicosis occurred a median of 5 weeks (interquartile range [IQR] 2-8) after receipt of a first dose of ICI. Combination immunotherapy was strongly associated with development of overt thyrotoxicosis (odds ratio [OR] 10.8, 95% CI 4.51-25.6 vs CTLA-4 monotherapy; P &lt; .001), as was female sex (OR 2.02, 95% CI 1.37-2.95; P &lt; .001) and younger age (OR 0.83 per 10 years, 95% CI 0.72-0.95; P = .007). By comparison, median onset of overt hypothyroidism was 14 weeks (IQR 8-25). The frequency of overt hypothyroidism did not differ between different ICI types. The strongest associations for hypothyroidism were higher baseline thyroid-stimulating hormone (OR 2.33 per mIU/L, 95% CI 1.61-3.33; P &lt; .001) and female sex (OR 3.31, 95% CI 1.67-6.56; P = .01). Overt thyrotoxicosis was associated with longer progression free survival (hazard ratio [HR] 0.68, 95% CI 0.49-0.94; P = .02) and overall survival (HR 0.57, 95% CI 0.39-0.84; P = .005). There was no association between hypothyroidism and cancer outcomes.

Conclusion
Thyroid irAEs are common and there are multiple distinct phenotypes. Different thyroid irAE subtypes have unique clinical and biochemical associations, suggesting potentially distinct etiologies for thyrotoxicosis and hypothyroidism arising in this context.
Endocrine Influence on Cardiac Metabolism in Development and Regeneration
Authors: Graham Niall , Huang Guo N 
Published: April 2021

Abstract
Mammalian cardiomyocytes mostly utilize oxidation of fatty acids to generate ATP. The fetal heart, in stark contrast, mostly uses anaerobic glycolysis. During perinatal development, thyroid hormone drives extensive metabolic remodeling in the heart for adaptation to extrauterine life. These changes coincide with critical functional maturation and exit of the cell cycle, making the heart a post-mitotic organ. Here, we review the current understanding on the perinatal shift in metabolism, hormonal status, and proliferative potential in cardiomyocytes. Thyroid hormone and glucocorticoids have roles in adult cardiac metabolism, and both pathways have been implicated as regulators of myocardial regeneration. We discuss the evidence that suggests these processes could be interrelated and how this can help explain variation in cardiac regeneration across ontogeny and phylogeny, and we note what breakthroughs are still to be made.
Advances in Type 1 Diabetes Prediction Using Islet Autoantibodies: Beyond a Simple Count
Authors: So Michelle , Speake Cate , Steck Andrea K , Lundgren Markus , Colman Peter G , Palmer Jerry P , Herold Kevan C , Greenbaum Carla J 
Published: April 2021

AbstractIslet autoantibodies are key markers for the diagnosis of type 1 diabetes. Since their discovery, they have also been recognized for their potential to identify at-risk individuals prior to symptoms. To date, risk prediction using autoantibodies has been based on autoantibody number; it has been robustly shown that nearly all multiple-autoantibody-positive individuals will progress to clinical disease. However, longitudinal studies have demonstrated that the rate of progression among multiple-autoantibody-positive individuals is highly heterogenous. Accurate prediction of the most rapidly progressing individuals is crucial for efficient and informative clinical trials and for identification of candidates most likely to benefit from disease modification. This is increasingly relevant with the recent success in delaying clinical disease in presymptomatic subjects using immunotherapy, and as the field moves toward population-based screening. There have been many studies investigating islet autoantibody characteristics for their predictive potential, beyond a simple categorical count. Predictive features that have emerged include molecular specifics, such as epitope targets and affinity; longitudinal patterns, such as changes in titer and autoantibody reversion; and sequence-dependent risk profiles specific to the autoantibody and the subject’s age. These insights are the outworking of decades of prospective cohort studies and international assay standardization efforts and will contribute to the granularity needed for more sensitive and specific preclinical staging. The aim of this review is to identify the dynamic and nuanced manifestations of autoantibodies in type 1 diabetes, and to highlight how these autoantibody features have the potential to improve study design of trials aiming to predict and prevent disease.
Trends in Mothers' Parenting Time by Education and Work From 2003 to 2017
Authors: Prickett Kate C. , Augustine Jennifer March 
Published: April 2021

AbstractScholars have been increasingly concerned about the rise in “intensive mothering” and its implications for the well-being of children and women and for inequality more broadly. These concerns, however, reflect a key assumption: that socioeconomic disparities in mothers' parenting time observed in earlier eras have continued to grow. Using the American Time Use Survey (ATUS) from 2003–2005 and 2015–2017 (n = 13,755), we test this assumption by examining whether maternal education gaps in active time spent with children have persisted across the 2000s. We pay particular attention to the continued socioeconomic bifurcation in women's access to full-time stable work, assessing whether changes in the education-related time gap are due to changes in who works and how much. We find that the gap in active childcare time between mothers with a college degree and those without has closed dramatically. Although some of this narrowing was driven by declines in time among college-educated mothers, most was driven by increases among mothers with less education. These trends, however, are observed only among mothers who were not employed full-time. Blinder-Oaxaca decomposition analyses further reveal that although most of the increase in active care time among nonworking mothers with less education was attributable to behavioral change, 58% of the decline among nonworking, college-educated mothers was a result of sociodemographic compositional changes. These findings illuminate population-level trends in mothers' active parenting time, provide insights into the driving factors, and help update theories, qualitative findings, and policy considerations related to mothers' and children's well-being.
Socioeconomic Segregation, Campus Social Context, and Disparities in Bachelor's Degree Attainment
Authors: Gelbgiser Dafna 
Published: April 2021

AbstractIt is well established that students from different socioeconomic backgrounds attend different colleges, net of their academic preparation. An unintended consequence of these disparities is that in the aggregate, they enhance socioeconomic segregation across institutions of higher education, cultivating separate and distinct social environments that can influence students' outcomes. Using information on the academic careers of a nationally representative sample of U.S. high school students who entered college in the mid-2000s, matched with external information on the social context of each college, this study evaluates the extent of socioeconomic segregation by social context in higher education and its implications for socioeconomic inequality in bachelor's degree attainment. Results confirm that social context is highly consequential for inequality in student outcomes. First, disparities in social context are extensive, even after differences in demographics, skills, attitudes, and college characteristics are accounted for. Second, the social context of campus, as shaped by segregation, is a robust predictor of students' likelihood of obtaining a bachelor's degree. Finally, the degree attainment rates of all students are positively associated with higher concentrations of economic advantages on campus. Combined, these results imply that socioeconomic segregation across colleges exacerbates disparities in degree attainment by placing disadvantaged students in social environments that are least conducive to their academic success.
Inorganic Carbon Acquisition by The Hydrothermal Vent Tubeworm Riftia Pachyptila Depends Upon High External And Upon Proton-Equivalent Ion Transport by The Worm
Authors: Goffredi Shana K. , Childress James J. , Desaulniers Nicole T. , Lee Raymond W. , Lallier Francois H. , Hammond Doug 
Published: April 2021

ABSTRACT
Riftia pachyptila is the most conspicuous organism living at deep sea hydrothermal vents along the East Pacific Rise. To support its large size and high growth rates, this invertebrate relies exclusively upon internal chemosynthetic bacterial symbionts. The animal must supply inorganic carbon at high rates to the bacteria, which are far removed from the external medium. We found substantial differences in body fluid total inorganic carbon (ΣCO2) both within and between vent sites when comparing freshly captured worms from a variety of places. However, the primary influence on body fluid ΣCO2 was the chemical characteristics of the site from which the worms were collected. Studies on tubeworms, both freshly captured and maintained in captivity, demonstrate that the acquisition of inorganic carbon is apparently limited by the availability of CO2, as opposed to bicarbonate, and thus appears to be accomplished via diffusion of CO2 into the plume, rather than by mediated transport of bicarbonate. The greatly elevated measured at the vent sites (up to 12.6 kPa around the tubeworms), which is a result of low environmental pH (as low as 5.6 around the tubeworms), and elevated ΣCO2 (as high as 7.1 mmol l−1 around the tubes) speeds this diffusion. Moreover, despite large and variable amounts of internal ΣCO2, these worms maintain their extracellular fluid pH stable, and alkaline, in comparison with the environment. The maintenance of this alkaline pH acts to concentrate inorganic carbon into extracellular fluids. Exposure to N-ethylmaleimide, a non-specific H+-ATPase inhibitor, appeared to stop this process, resulting in a decline in extracellular pH and ΣCO2. We hypothesize that the worms maintain their extracellular pH by active proton-equivalent ion transport via high concentrations of H+-ATPases. Thus, Riftia pachyptila is able to support its symbionts’ large demand for inorganic carbon owing to the elevated in the vent environment and because of its ability to control its extracellular pH in the presence of large inward CO2 fluxes.
Informed consent in interventional radiology – are we doing enough?
Authors: Prashar Akash , Butt Saqib , Castiglione Davide Giuseppe , Shaida Nadeem 
Published: April 2021

Objectives:
Obtaining informed consent is a mandatory part of modern clinical practice. The aim of this study was to identify how often complications relating to Interventional Radiology (IR) procedures were discussed with the patient prior to the procedure.

Methods:
A retrospective analysis of 100 patients who experienced a complication related to an IR procedure was performed. The patient’s procedure consent form was examined to identify whether the complication they experienced had been discussed as a possible risk. Other parts of the consent form relating to need for blood transfusion and the need for further procedures were also examined.

Results:
39% of patients who experienced a complication did not have the complication documented as a potential risk on the consent form. 14% of patients required a blood transfusion but were not consented for this. 42% of patients required a further procedure or operation but were not warned of this.

Conclusion:
The model of gaining informed consent on the day of procedure is no longer valid. Better education and the use of clinics, patient information sheets and other resources is essential.

Advances in knowledge:
The paper highlights the inadequacies of the current model in gaining consent for IR procedures. A more comprehensive consent process making use of all available resources is essential.